By Gopi Nayak, MD

Faculty Peer Reviewed

This week as Labor Day weekend marks the end of summer, President Obama calls for major spending on public works to jump-start the economy, while tennis stars continue to battle it out at Arthur Ashe stadium.

 In medical news, this week’s JAMA featured a prospective multicenter cohort study of women with BRCA1 and BRCA2 mutations to estimate the risk and mortality reduction following prophylactic mastectomy [1] and salpingo-oophorectomy, specifically stratifying risk reduction based on mutation status and prior history of breast cancer.

 The study confirmed the benefit of risk-reducing mastectomy (RRM) to prevent the occurrence of breast cancer with a difference of 0 new breast cancer diagnoses over a 3 year follow-up period among women who underwent RRM vs 7% in women undergoing aggressive screening alone.  In women who underwent risk-reducing salpingo-oopherectomy (RRSO), the risk of ovarian cancer decreased by 85% and 70% in BRCA1 mutation carriers with and without a history of prior breast cancer, respectively.  No primary peritoneal cancers were observed in BRCA2-positive women who underwent RRSO vs 3% observed in women who did not have RRSO.  Next the authors looked at the effect of RRSO on breast cancer risk.  RRSO was associated with a significant reduction in breast cancer risk in women without a previous diagnosis of breast cancer, more prominent in BRCA2 carriers (64% reduction) vs BRCA1 carriers (37% reduction) perhaps owing to the higher percent of ER-positive breast tumors in BRCA2 vs BRCA1. The study showed no decrease in risk of a second primary breast cancer in women who had a prior breast cancer diagnosis at the time of RRSO.  The study also showed a significant reduction in all-cause mortality, breast cancer-specific mortality and ovarian cancer mortality after risk-reducing salpingo-oopherectomy; there was also a suggestion that earlier intervention (prior to age 50) may be more beneficial than later ones.   

 Overall the risk reduction estimates afforded by RRM and RRSO are striking, however further refining the estimates based on mutation status and prior cancer history may change how physicians counsel their patients and will allow women with known BRCA mutations to make better informed decisions regarding their treatment.  Though it may make the decision to delay or not undergo RRM or RRSO even more difficult, especially for younger women who want to preserve their ovarian and breast function.   

 In other cancer-related news, The Lancet reports Trastuzumab may increase overall survival in HER2-positive advanced gastric or gastro-esophageal junction cancer [2] when used in combination with chemotherapy.  This randomized, multicenter international phase 3 trial of chemotherapy with trastuzumab vs standard chemotherapy demonstrated a median overall survival increase from 11.1 to 13.8 months and a median progression-free survival increase from 5.5 to 6.7 months, with a stronger effect seen in patients with tumors expressing high levels of HER2 protein.  Longer term survival rates in both groups were similar. There was no difference in overall rates of adverse events, however patients in the trastuzumab plus chemotherapy group had higher rates of certain side effects such as diarrhea, stomatitis and thrombocytopenia, and treatment related mortality was slightly higher (3% vs 1%).  Based on the results of this study the authors concluded that trastuzumab can be considered “a new standard option for patients with HER2-positve gastric or G-E junction cancer when combined with current chemotherapy regimens.”  However, as pointed out in a commentary by Munro and Niblick, the cost of treatment for one patient is approximately ~$21 000, equivalent to the totally yearly health spending for 3 US citizens or 500 citizens in India.  The authors question whether 2 ½ months is a large enough increase in survival time to warrant an expenditure of that size.  The authors of this study, funded by F Hoffman-La Roche, the makers of Trastuzumab, certainly suggest yes, but in the face of a potential worldwide market worth more than ₤265 ($408) million per year, it may have been hard to say no.

 The Archives of Internal Medicine addressed the question of biochemical recurrence (increasing PSA after radical prostatectomy or radiation therapy) [3] and its association with prostate cancer specific mortality.  This observational VA study demonstrated a biochemical recurrence (BCR) rate of 34%, 37%, and 37% at 5, 10, and 15 years after prostatectomy and a prostate cancer mortality of 3%, 11%, and 21% at 5, 10, and 15 years.  Following radiation therapy, BCR rates were 35%, 46%, and 48%, with prostate cancer mortality rates of 11%, 20%, and 42% at 5, 10, and 15 years.  As expected, biochemical recurrence is associated with an increased rate of prostate specific mortality, yet the relative risk even after BCR, remains low, with death caused by prostate cancer seen in less than half of men with BCR.  For patients this information may provide some relief or perhaps just increased uncertainty. 

 In cardiovascular news, given the discrepancy between dosing strategies among physicians, the CURRENT-OASIS 7 trial sought to identify optimal dosing regimens of clopidogrel[4]  and aspirin during the initial 7 days after acute coronary syndromes in patients referred for early invasive strategy.  The study design consisted of a 2×2 factorial design to investigate if doubling the loading and initial maintenance doses of clopidogrel (600mg followed by 150mg daily for 6 days) is superior to standard dosing (300mg followed by 75 mg daily for 6 days) and whether high dose aspirin (300-325mg) is superior to low dose aspirin (75 to 100mg) for 30 days after ACS.  Full dose aspirin was given to both groups on day one and both clopidogrel groups received 75mg of clopidogrel daily for the remainder of the 30 day treatment period.  At 30 days, results showed no difference in cardiovascular death, myocardial infarction or stroke between high and low dose clopidogrel groups, though an increased risk of major bleeding was seen in the high dose group.  During subgroup analysis, double-dose clopidogrel was associated with a significant reduction in the rate of stent thrombosis in the subset of patients who underwent PCI.  In the aspirin comparison group, no significant benefit was seen between high and low doses and no significant difference was seen with regard to risk of major bleeding events; however, a nominally significant increase in minor bleeding and a slight increase in the incidence of major GI bleeding was seen in the high dose group.  The authors concluded that treatment with either high or low dose aspirin for the first 30 days appears to be acceptable, and given the increased risk of major bleeding, this study suggests standard dosing of clopidogrel is the preferred regimen, except perhaps in patients undergoing PCI.

 A retrospective study of 100,000 Swedish patients presenting with a first acute myocardial infarction [5] (MI) demonstrated that patients presenting with STEMI were younger, had less prior cardiovascular disease and had used fewer medications prior to presentation.  Prior use of aspirin, beta-blockers, ACE inhibitors or statins were all independently associated with a lower risk of presenting with a STEMI vs an NSTEMI.  Use of one medication was associated with a decreased risk of presenting with a STEMI, with a further risk reduction of 15-25% when 2 and 3+ medications were taken.  However, 30 day mortality was not affected by the number of medications taken.  The study emphasizes the benefit of preventive medications, in this case decreasing the risk of STEMI in patients presenting with a first acute MI.

 Several articles this week featured the topic of medical education and training.

This weeks New York Times featured NYU in an article on new changes to the standard medical school curriculum.[6]  Instead of waiting for their third-year, medical students were introduced to patients on their first day of class, prior to receiving any medical knowledge.  The curriculum at NYU and at other medical schools across the country have been revised to increase clinical exposure during the first two years of school with the aim to foster more personal relationships earlier on between patients and students.  Some say these changes, taking place at NYU and at other national medical schools, is in response to a fear among medical professions that today’s young physicians lack humanity and have a “loss of idealism, empathy, and morality.”  In fact a study published by Dr. Fitzhugh Mullen of George Washington University ranked NYU fifth worst in the nation at promoting socially conscious medicine.  It is unclear from this article what his study findings were based on.  Regardless of why the changes were instituted, NYU medical students will have a chance to improve their clinical skills and see pathology as it manifests itself while they learn the fundamental sciences behind disease. 

 In other education news, medical educators gathered at a forum entitled “Innovating and Updating the Medical School Curriculum.”  An article in Nature Medicine suggested that traditional cadaver dissection, a rite of passage for first-year medical students, and a staple of the traditional curriculum may become a thing of the past [7] as computer assisted simulations and three dimensional anatomical models or robotic patients take over in classrooms.  The shortage is attributed in part to the lack of cadavers as fewer people donate their bodies to medicine.

 What about that C+ in Organic Chemistry?

The Lancet featured a perspective article on the dangers of using performance in undergraduate science courses as a criteria for acceptance into medical school.[8]  The author states that instead of being a marker of future excellence as a physician, undergraduate grades have no correlation with the qualities that make a great physician: the ability to connect, communicate and empathize with patients.  His research showed that while performance in the premedical sciences does correlate with success in the preclinical years, it does not correlate with faculty evaluations of clinical performance and is “inversely associated with many of the personal, non-cognitive qualities so central to the art of medicine.”  He cites a series of psychological tests performed in the 1950s and ‘60s that states what many of us have experienced firsthand, that students who do better in science are “narrower in interests, less adaptable, less articulate, and less comfortable in interpersonal relationships.” 

 Lastly, JAMA features an article on new proposed rules on resident duty hours set forth by the ACGME.[9]  Some of the proposed rules include setting a 16 hour limit on first-year shifts, and requirements that interns are directly supervised by a physician, or the supervising physician remain on-site. 

Dr. Nayak is a first year resident at NYU Langone Medical Center

Peer reviewed by Cara Litvin, Executive Editor, Clinical Correlations

Image of  Caroline Wozniacki courtesy of Wikimedia Commons.

References:

 [1] Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C, Garber JE, Neuhausen SL, Matloff E, Eeles R, Pichert G, Van t’veer L, Tung N, Weitzel JN, Couch FJ, Rubinstein WS, Ganz PA, Daly MB, Olopade OI, Tomlinson F, Schildkraut J, Blum JL, Rebbeck TR.  Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010 Sept 1; 304(9): 967-975.  http://jama.ama-assn.org/cgi/content/full/304/9/967

 [2] Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang Y-K.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.  Lancet. 2010 Aug 28; 376:687-97.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61121-X/abstract

 [3]  Uchio EM, Aslan M, Wells CK, Calderone J, Concato J.  Impact of Biochemical recurrence in prostate cancer among US veterans.  Archiv of Intern Med.  2010 Aug 23; 170 (15): 1390-1395.  http://archinte.ama-assn.org/cgi/content/abstract/170/15/1390

 [4]  Mehta SR, Bassand J-P, Chrolvicius S, Diaz R, Eikelboom JW, Fox KA, Granger CB, Jolly S, Joyner CD, Rupprecht HJ, Widimsky P, Pogue J, Yusuf S.  Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Eng J of Med.  2010 Sept 2; 363 (10): 930-942.  http://www.nejm.org/doi/pdf/10.1056/NEJMoa0909475

[5]  Bjorck L, Wallentin L, Stenestrand U, Lapas G, Rosengren A.  Medication in relation to ST-segment elevation myocardial infarction in patients with a first myocardial infarction.  Arch Intern Med. 2010 Aug 23; 170(15): 1375-1381.   http://archinte.ama-assn.org/cgi/content/short/170/15/1375

 [6]  http://www.nytimes.com/2010/09/03/nyregion/03medschool.html?src=me&ref=general

 [7]  Palmer R.  Educators dissect the future of medical training.  Nature Medicine.  2010 Aug; 16(8): 836-837.  http://www.nature.com/nm/journal/v16/n8/full/nm0810-836a.html

 [8]  Barr DA. The art of medicine.  Science as superstition: selecting medical students.  Lancet.  2010 Aug 28; 376: 678-679.   http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61325-6/fulltext

 [9]  Kuehn BM. New rules call for more oversight, fewer hours for first-year residents.  JAMA. 2010 Sept 1; 304(9): 950-951.  http://jama.ama-assn.org/cgi/content/short/304/9/950

By Synphen H. Wu, PhD

Faculty Peer Reviewed

Mr. C is a 46-year-old Chinese immigrant restaurant worker who came to Bellevue Hospital after two weeks of fatigue, malaise, right upper quandrant (RUQ) abdominal pain, and progressive jaundice. He was referred from a Chinatown clinic, where his blood tests showed hepatitis B surface antigen, a hepatitis B viral load of 133 million copies, and elevated liver transaminases and bilirubin levels, consistent with acute hepatitis B reactivation and fulminant hepatic failure. When he arrived at the ER, his eyes were yellow, his skin was mustard-colored, and he was in a confused state.

Over his two-and-a-half-week stay at Bellevue, Mr. C’s encephalopathy subsided and his transaminase levels fell. However, his bilirubin levels remained high, and his jaundice did not improve. As his liver failure progressed, his legs became edematous and his abdomen taut and painful. While Mr. C’s condition would normally have qualified him for placement on the liver transplant list, this was impossible due to his lack of official documents. When nothing more could be done at Bellevue to change the course of his disease, Mr. C decided it was in his best interest to go back to China, where he could potentially receive the new liver he needed. He hadn’t gone back since he came to the United States 16 years ago. He hadn’t seen his wife and children in the many years he’d been gone.

Mr. C is from Fuzhou, the capital city of Fujian province, which in recent years has contributed heavily to the vast army of workers who stock the kitchens and dining rooms of the more than 40,000 Chinese restaurants doing business in America. That’s more restaurants than all the McDonald’s, Burger Kings, and Wendy’s combined.^[1,2]

Getting to the U.S. from Fuzhou to find work within this restaurant subculture is no small feat, and people can invest up to $70,000 to be smuggled in.[1] Mr. C is one of these thousands of undocumented workers who come to this country looking for an opportunity to earn a living and to provide for family still back in China. The center of this world, as far as the East Coast and Midwest is concerned, is Chinatown, New York. In Chinatown, it is possible to find work at restaurants through employment agencies clustered under the Manhattan Bridge. At these agencies, bulletin boards post jobs (waitress, chef, delivery man, driver) and include the salary, the area code of the city where the restaurant is located, and the number of hours by bus the city is from New York. For those who don’t read or speak English, the area codes are easy numerical markers that supplant actual geography. Thanks to the system of Chinese-run buses that link the various Chinatowns in cities across the country, traveling to a new-found job is as easy as turning the corner from the agency and boarding a bus marked with the right three digits.^[2] 

Work is typically 12-14 hours a day, 6 days per week, and owners provide room and board, often in apartments or buildings that function as dorms. In some towns, the workers at a restaurant may be the only Chinese people in town. There may be little chance to integrate into mainstream American society, and restaurant workers can live in the U.S. for many years, moving from job to job, without learning English. They are aliens in a foreign land, able to survive through the strong bonds of Chinese nationalism and common language that connect the overseas Chinese communities spread throughout the country. While these ties can provide undocumented workers with basic needs and shield them from legal difficulties, when serious health problems arise, these workers may have no recourse but to access healthcare institutions beyond their immediate communities.

Before Mr. C came to Bellevue, he was working as a cook in a Chinese restaurant somewhere in Florida in a town he could not name. His symptoms progressed quickly after they started, and within a few days, he was on a bus heading to New York to seek care, first in Chinatown and then at Bellevue. As much as Chinatown is the central hub for Chinese immigrant life, Bellevue stands as a main adjunct healthcare center for those in the Chinese immigrant community who need serious medical attention. Though he is a foreigner in the larger society, a person like Mr. C is no stranger to Bellevue, where an extraordinary confluence of people from all walks of life and different ethnic and economic backgrounds come for care. Since its inception in 1736, Bellevue has served the immigrant poor. For an extremely ill patient like Mr. C, an undocumented worker with little means, no institution compares to Bellevue in its ability to serve his needs.

Under the Emergency Medical Treatment and Active Labor Act instituted in 1986, undocumented immigrants who come to Bellevue are eligible for emergency care through Emergency Medicaid. This program and other public funding provide an estimated $1.1 billion in healthcare for undocumented adults in the United States every year.^[3] Emergency Medicaid covers medical conditions, which if not treated, could reasonably be expected to jeopardize the patient’s health, seriously impair bodily function, or cause serious dysfunction to any bodily organ or part. The hospitals are given the task of defining what constitutes an emergency, and procedures and treatments such as surgery, dialysis, and chemotherapy have all been covered under Emergency Medicaid. The one procedure for which Emergency Medicaid specifically excludes reimbursement is organ transplantation.

For all the care that he received at Bellevue, in the end there was no way to circumvent the fact that Mr. C would not be able to obtain a liver transplant in this country. So, after 16 years of working as a migrant restaurant worker and keeping in close contact with his family only by phone, Mr. C made a decision. “Now that I’m sick,” he said, “maybe it’s time to make a trip back to China. I think it’s time to see my family.”

For better or for worse, the limits of Bellevue’s and America’s healthcare provision for undocumented immigrants have sent Mr. C back to his family and to seek care in a country where he is part of the mainstream culture. After all the sacrifices he has made in America, Mr. C is finally returning home.

Commentary by Antonella Surbone, MD PhD, Clinical Correlations’ Ethics Editor.

The dramatic events of Mr. C’s illness and his final decision to return home to China for a liver transplant have been narrated by Dr. Wu in an extremely poignant way.

Because of the complexity of immigration’s individual, social and legal implications and of health care’s inevitable limitations, Dr. Wu finds the human and ethical thread that makes the story of Mr. C and of the hospital that took care of him a positive one.

We are so accustomed to analyze all private and public events from a detached critical perspective that very often, we lose sight of their human essence. Making sacrifices for loved ones, suffering physically and emotionally and being cared for with dedication and love are part of the human condition. It is our ethical duty to fight for a more equal society where all burdens do not fall on minorities but are alleviated through the efforts of the entire community, and it is also our ethical duty to see meaning and beauty in the good that we can do each day in our medical practice.

For Plato, ethics and aesthetics, the good and the beautiful, were interconnected, if not the same. There is good and beauty in this story, and that is inextricably connected with our personal commitment and social engagement as physicians.

 Dr. Wu is a fourth year medical student at NYU School of Medicine

Peer reviewed by Antonella Surbone, MD, Ethics Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

1. Adler, Margot. “Chinese Restaurant Workers in U.S. Face Hurdles.” NPR Morning Edition. May 8, 2007. http://www.npr.org/templates/story/story.php?storyId=10069448

2. Lee, Jennifer 8. Waiters and Cooks to Go. The New York Times. October 2, 2005. http://www.nytimes.com/2005/10/02/jobs/02lee.html

3.Goldman, Dana, et al. Immigrants and the Cost of Medical Care. Health Affairs 2006;25:1700-11. http://content.healthaffairs.org/cgi/content/abstract/25/6/1700

By

Faculty Peer Reviewed

 The onset of acromegaly is subtle, and its progression is usually very slow. In fact, the usual interval from the onset of symptoms until diagnosis is about twelve years.^[1] The manifestations of acromegaly result from excessive secretion of growth hormone (GH), which targets the liver, resulting in stimulation of hepatic secretion of insulin-like growth factor-1 (IGF-1), which causes many of the clinical manifestations of acromegaly.  The most common cause of acromegaly is a functional pituitary adenoma.^[2]  The effects of excess GH and IGF-1 secretion include the growth of many tissues, including skin, connective tissue, cartilage, bone, viscera, and many epithelial tissues.  There are also metabolic consequences such as insulin antagonism and lipolysis. The local mass effect of the adenoma can lead to symptoms of headache, cranial nerve defects, and visual field defects, specifically bitemporal hemianopsia.^[3]  The mortality rate of patients with acromegaly appears to be increased and is primarily from cardiovascular disease, a risk that may be reversed by curing the disease.^[2]

The GH/IGF-1 axis has a direct endocrine effect on the myocardium, resulting in hypertrophy, enhancement of contractile performance, and elongation of the action potential of cardiac fibers.^[4]  Ultimately, the involvement of the heart in acromegaly is characterized by concentric biventricular hypertrophy. Structural changes of the heart can even occur in patients briefly exposed to GH hypersecretion.^[5]  This remodeling is further enhanced by the hypertension and glucose intolerance commonly present in the acromegalic patient.  The evolution of cardiomyopathy in acromegaly is characterized by significant worsening of the heart’s ability to function as an efficient pump.  In patients with short disease duration, there is initial cardiac hypertrophy with increased heart rate, contractility, and cardiac output, termed the hyperkinetic syndrome.^[4]  This is a result of the stimulatory effects of GH and IGF-1 on myocardial contractility as mediated by changes in intracellular calcium.^[4]  As hypertrophy becomes more prominent, diastolic dysfunction may develop, leading to the development of heart failure with preserved ejection fraction.  Fortunately, the clinical syndrome of heart failure is uncommon (~3%) in patients with acromegaly with either a normal or reduced ejection fraction.^[6]  However, at the advanced stages of untreated disease, cardiac abnormalities may rarely result in systolic dysfunction with manifestations of congestive heart failure.

Cardiovascular disease is not limited to structural abnormalities in patients with acromegaly.  There is also valvular disease, including mitral regurgitation, aortic regurgitation and tricuspid regurgitation seen in the late stages of acromegaly as a result of ventricular remodeling, as well as increased potential for arrhythmias.^[4]  The mechanism behind the predisposition for dysrhythmic events involves phenotypic changes in membrane proteins, conduction system disease,^[4] and structural uncoupling of cardiac myocytes resulting in an increased number of re-entrant events.  Compared to controls, individuals with acromegaly have a higher prevalence of ectopic beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia, and bundle branch blocks.^[7]  

The data regarding a direct relationship between the development of coronary artery disease and acromegaly are limited.  Given the frequency of hypertension and diabetes seen with the syndrome, it is likely that patients with acromegaly are at increased risk for developing atherosclerosis.  In terms of the direct effect of GH and IGF-1 on atherosclerosis development, the evidence suggests that it is largely the hypertension and diabetes  associated with acromegaly that predispose patients to the development of atherosclerotic disease.  It is known that GH and IGF-1 cause direct endothelial dysfunction with subsequent decreased vasodilatory capacity, which may have implications for susceptibility to vascular events.^[5]   In terms of the reversibility of acromegalic cardiomyopathy, suppression of GH and IGF-1 has been shown to be efficacious in improving diastolic function by virtue of reducing left ventricular mass.  However, the effect on systolic function and exercise tolerance are variable and depends largely on the length of exposure to GH and IGF-1, as well as the co-morbidities of acromegaly, including hypertension and diabetes.^[8]

It is important to note that the cardiac implications of acromegaly are a result of excessive secretion of GH and IGF-1 and that these hormones play an important role in cardiac development when present at normal physiologic levels.  In fact, patients with GH deficiency, whether childhood- or adult-onset, suffer from structural cardiac abnormalities, including narrowing of cardiac walls and functional impairment, with resultant reduction in diastolic filling and reduced left ventricular response to peak exercise.^[9]  As in the acromegalic heart, these cardiac abnormalities are partially reversible with GH supplementation.^[9]  Additionally, attention has been focused on the efficacy of GH to increase cardiac mass and function in chronic non-endocrine-related heart failure including ischemic and idiopathic cardiomyopathies, thereby illustrating the dichotomy between the potential beneficial effects of exogenous GH in carefully selected patients and the disadvantageous effects of excess GH secretion in patients with acromegaly.

Dr. Pollack, Class of 2010, NYU School of Medicine

Peer reviewed by Alex Reyentovich, MD, Cardiology, NYU School of Medicine

Image courtesy of Wikimedia Commons.

References:

 [1]  Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004; 25(1):102-152.

[2]  Melmed S. Medical progress: Acromegaly. N Engl J Med. 2006;355(24):2558-2573.

[3]  Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am. 1992;21(3):597-614.

[4]  Lombardi G, Galdiero M, Auriemma RS, Pivonello R, Colao A. Acromegaly and the cardiovascular system. Neuroendocrinology. 2006;83(3-4):211-217.

[5]  Vitale G, Pivonello R, Lombardi G, Colao A. Cardiac abnormalities in acromegaly: pathophysiology and implications for management.  Treat Endocrinology. 2004;3(5):309-318.

[6]  Bihan H, Becker KL, Snider RH, Nylen E, et al. Long-term outcome of patients with acromegaly and congestive heart failure. J Clin Endocrinol Metab. 2004;89(11):5308-5313.

[7]  Kahaly G, Olshausen KV, Mohr-Kahaly S, et al.  Arrhythmia profile in acromegaly.  Eur Heart J. 1992;13(1):51-56.

[8]  Colao A, Cuocolo A, Marzullo P, et al. Is the acromegalic cardiomyopathy reversible?  Effects of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance.  J Clin Endocrinol Metab. 2001;86(4):1551-1557.

[9]  Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart.  Clin Endocrinol (Oxf). 2001;54(2):137-154.

By Han Na Kim, MD

Faculty Peer Reviewed

In the national news, a ruling came from Washington DC that shocked NIH scientists and researchers across the nation’s universities. Chief Judge Royce Lamberth of Federal District Court for the District of Columbia ruled against President Obama’s stem cell policy and stopped federal funding of embryonic stem cell research that destroys embryos, claiming that this violates the Dickey-Wicker Amendment regarding federal spending bills. Lamberth commented, “The Dickey-Wicker Amendment unambiguously prohibits the use of federal funds for all research in which a human embryo is destroyed.” Current projects may continue, but the ruling, if upheld, would force many experiments in areas from diabetes to Parkinson’s disease to be suspended. The Obama administration will appeal.

Remember those Bellevue clinic patients who come in with total body pain and fatigue that you’ve brushed off as “somatization”? Perhaps we need to take them more seriously. The New York Times this week reported a study^[1]published in the Proceedings of the National Academy of Sciences linking chronic fatigue syndrome to murine leukemia virus (MLV). The study found MLV-related virus gene sequences in the blood samples of 32 out of 37 chronic-fatigue patients but only 3 out of 44 healthy patients. Many experts remain skeptical, as there are several studies with conflicting results regarding the association, but in the meantime the American Association of Blood Banks recommended that people with chronic fatigue syndrome be discouraged from donating blood.

 Now for the headlines in the medical journals…

 This week in medical world, there were three interesting studies in cardiology:

 JAMA featured the Balloon Pump-Assisted Coronary Intervention Study (BCIS-1),^[2] which showed that routine intra-aortic balloon pump (IABP) insertion before high-risk percutaneous coronary intervention does not reduce the incidence of major adverse cardiac and cardiovascular events (MACCE) in patients with severe left ventricular dysfunction and extensive coronary disease. There have been observational studies that reported improved outcomes with elective IABP insertion, but these have been retrospective, underpowered studies with selection bias. No randomized controlled trial investigating routine IABP use in high-risk procedures had been reported prior to BCIS-1. MACCE was defined as death, MI, stroke, or further revascularization at hospital discharge. Three hundred and one patients were enrolled in this prospective RCT conducted between December 2005 and January 2009 in 17 tertiary referral cardiac centers in the UK. Patients awaiting high-risk single-vessel or multi-vessel PCI to native coronary arteries or bypass grafts were included. Patients were randomized either to no IABP insertion or elective IABP insertion prior to PCI. The primary endpoint was MACCE at 28 days and secondary endpoints were 6-month all-cause mortality, major procedural complications, bleeding complications, TIA, and duration of hospital stay. The groups had similar baseline characteristics: mean age of 71, LVEF of 24%, and BCIS-1 Jeopardy Score of 10. Intention-to-treat analysis was applied and MACCE at hospital discharge occurred in 15.2% of the elective IABP and 16.0% of the no planned IABP groups (P =.85; OR 0.94 [95% CI, 0.51-1.76]). Of note, rescue IABP was inserted in 12% of the no-IABP group, mainly for prolonged hypotension. Patients who received rescue IABP placement had worse in-hospital outcomes than patients who received elective IABP. All-cause mortality at 6 months was 4.6% in the elective IABP group and 7.4% in the no-IABP group; the difference was not statistically significant. Major procedural complications occurred less with elective IABP insertion compared to no planned IABP (1.3% vs. 10.7%, P <0.001; OR, 0.11 [95% CI, 0.01-0.49]. Major or minor bleeding occurred in 19.2% in elective IABP group and 11.3% of no IABP group (P = .06; OR, 1.86 [95% CI, 0.93-3.79]). Overall, the study showed that elective IABP insertion did not reduce MACCE following PCI and therefore does not recommend routine elective IABP insertion before high-risk PCI. However, given that 12% of no IABP patients needed rescue IABP, standby IABP should be always available.

 Wanna know the secret to a long life? Keep reading.

 This week’s Circulation featured a study^[3] showing exercise capacity as an independent predictor of all-cause mortality in older men. The study identified 5390 male veterans aged 65-92 who completed exercise tolerance tests (ETT) between 1986 and 2008. There were 2137 deaths during the median follow-up period of 8.1 years. Baseline exercise capacity among survivors was 6.3±2.4 metabolic equivalents (METs) compared to 5.3±2.0 METs in the group that died (P<.001), suggesting poor exercise capacity as a predictor of mortality. Patients were further categorized into fitness groups; compared with the least fit group (≤4 METs), hazard ratios of mortality were progressively lower with each 1-MET increase from a MET level of 5. Regardless of the age group, the mortality risk was 38% lower (hazard ratio=0.62; 95% CI, 0.54 to 0.71) in patients who achieved 5.1 to 6.0 METs compared to the least fit group, and further declined to 61% (hazard ratio=0.39; 95% CI, 0.32 to 0.49) in patients who achieved >9 METs. The data suggest that for any significant health benefit, exercise capacity of >5 METs may be necessary. The study further examined the association between change in fitness and mortality in 867 individuals by repeating the ETT at least 6 months after the initial test. Analysis showed that survival improved significantly when unfit patients became fit, with 35% lower mortality risk (hazard ratio=0.65; 95% CI, 0.46 to 0.93; P = 0.019) compared with subjects who were unfit during both ETTs. The relationship between exercise capacity and mortality may not demonstrate causality due to residual confounders, and interventional studies are needed to confirm. Nonetheless, the study strongly supports inverse and graded association between fitness and mortality risk.

 Another article in Circulation investigated the association between birth weight and incident atrial fibrillation (AF) among women, mainly white. This prospective study^[4] followed 27 982 women aged >45 who were free of cardiovascular disease, cancer, and AF at baseline. Based on self-reported birth weights, patients were categorized into 5 birth weight groups: <2.5 kg, 2.5 to 3.2, 3.2 to 3.9, 3.9 to 4.5, and >4.5 kg. Median follow up period was 14.5 years.  The primary outcome was time to incident AF. During the follow-up period, 735 confirmed AF events occurred. Age-adjusted AF incidence rates increased with increasing birth weight: 1.45, 1.82, 1.88, 2.57, and 2.55 events per 1000 person-years. Relative risks of developing incident AF with increase in birth weight category were 1.27 (95% CI: 0.95-1.71), 1.31 (CI: 1.00-1.72), 1.75 (CI: 1.27-2.41) and 1.76 (CI: 1.16-2.67). Additionally, several statistical analyses with multivariable adjustments were performed. Adjusting for body-mass index, blood pressure, and history of diabetes did not affect the association between birth weight and incident AF, but when further adjusted for adult height, the association was substantially attenuated and became nonsignificant. Further adjustment for maximum body weight between 18 to 30 years of age attenuated the relationship between birth weight and AF even more: relative ratios 1.27 (CI: 0.94-1.71), 1.10 (CI: 0.83-1.46), 1.41 (CI: 1.01-1.96), 1.29 (CI: 0.84-1.98). The study concluded that increased birth weight is significantly associated with incident AF among women. Although early life determinants may play a role in incident AF, it seems that adult height and/or cumulative lifetime exposure to elevated body mass have greater impact on modifying the risk of AF.

 Do you have a pregnant patient with genital herpes or herpes zoster? Read on.

 JAMA published the largest study^[5] to date investigating the risk of birth defects with the use of acyclovir, valacyclovir, and famciclovir (FDA pregnancy-risk category B drugs) in the first trimester of pregnancy. The study found that there was no increased risk of major birth defects with exposure to these antivirals. Prior to this study, there were no published data on valacyclovir, and famciclovir use was limited to 4 reported pregnancies. This was a population-based historical cohort study examining 837,795 live-born infants in Denmark between 1996 and 2008. Infants with chromosomal aberrations, genetic disorders, birth defect syndromes with known causes, or congenital viral infections were excluded. Nationwide registries were used to identify the cohort and gather data regarding dispensed antiviral drugs, major birth defects, and potential confounders. The primary objective of the study was to investigate the risk of any major birth defects diagnosed within the first year of life due to exposure to antiviral drugs during the first trimester. Among 1804 pregnancies with exposure to acyclovir, valacyclovir, or famciclovir in the first trimester, 40 infants (2.2%) were diagnosed with major birth defects compared to 19,920 (2.4%) infants in the unexposed group (adjusted prevalence odds ratios [POR], 0.89; 95% CI, 0.65-1.22). Despite the significance of the study, the result should be interpreted with several study limitations in mind: (1) defects diagnosed after one year of age would have been missed, (2) the study did not include abortions, (3) maternal comorbidity was incomplete, and (4) nonadherence to the dispensed medications would lead to underestimation of teratogenic effects. All in all, it seems that acyclovir, valacyclovir and famciclovir will still remain pregnancy category B drugs.

 Dr. Kim is a second year resident at NYU Langone Medical Center

Peer reviewed by Michael Tanner, MD, Section Editor – Class Act, Clinical Correlations

Image courtesy of Wikimedia Commons: President Obama speaks before signing the Stem Cell Research Executive Order on March 9, 2009.

References:

[1]  Lo S-C, Pripuzova N, Bingjie L, et al.  Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. www.pnas.org/cgi/doi/10.1073/pnas.1006901107.

 [2]  Perera D, Stables R, Thomas M, et al. Elective intra-aortic balloon counterpulsation during high-risk percutaneous coronary intervention: a randomized controlled trial. JAMA. 2010;304(8):867-874.

 [3]  Kokkinos P, Myers J, Faselis C, et al. Exercise capacity and mortality in older men: a 20-year follow-up study. Circulation. 2010;122(8):790-797.

 [4]  Conen D, Tedrow U, Cook NR, Buring JE, Albert CM. Birth weight is a significant risk factor for incident atrial fibrillation. Circulation. 2010;122(8):764-770.

 [5]  Pasternak B, Hviid A. Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. JAMA. 2010;304(8):859-866.

By Aditya Mattoo, MD

Faculty Peer Reviewed

Not too long ago, a patient came to my clinic and said (I’m paraphrasing of course), “I never cared for alcohol, doctor, so I haven’t had much to drink since my college days.  Maybe champagne or wine on the rare special occasion, but I keep hearing about how wine is good for your heart, so I am thinking I should start drinking regularly.”  For years I have been telling patients don’t drink, don’t smoke, don’t do drugs, don’t eat fatty foods, exercise more, and lose weight.  I have become quite accustomed to playing the role of “Dr. Buzzkill” with my patients (the actual name given to me by a patient).  Yet, we have all heard about the potential benefit to light drinking.  Still, I felt a little uneasy about telling someone to start drinking everyday. To ease my discomfort, I decided to review the data behind alcohol and cardiovascular mortality for the current installment of Myths and Realities.

Alcohol and its affects on cardiovascular disease has been studied as far back as 1904, when Dr. Richard Cabot published an article in JAMA attempting to draw a relationship between alcoholism and arteriosclerosis.[1]  The recent reemergence of this discussion has been prompted by the observation that French people, although eating a diet relatively rich in saturated fats, had a relatively lower incidence of cardiovascular disease and mortality from cardiovascular events.  This so called “French Paradox”, coined in 1992 by Dr. Serge Renaud, a scientist from Bordeaux University in France, has been attributed to the higher consumption of wine.

Several mechanisms for the protective effect of alcohol in cardiovascular disease have been proposed.  For example, alcohol related antiatherogenic alterations in plasma lipoproteins, particularly elevations in high-density lipoprotein cholesterol, are thought to offer cardiovascular protection.  Additionally, alcohol associated increased activity of endothelial-type nitric oxide synthase, leading to increased levels of nitric oxide and maintenance of blood vessel patency, has also been implicated.  Finally, the potential anticoagulant and antiplatelet properties of polyphenols, found in wine, may contribute as well.  Some studies have suggested that red wine, because of the disproportionately higher levels of polyphenols as compared to other forms of alcohol (i.e. white wine, liquor and beer), is more protective from a cardiovascular standpoint.

Many clinical studies over the last three decades have attempted to validate this phenomenon.  In 1991, Rimm et al published a study of 51,529 male health professionals followed prospectively for two years.[2]  A questionnaire was distributed at the beginning of the study asking about alcohol intake in the previous 10 years, along with coronary risk factors, diet, etc.  Follow-up questionnaires asked about newly diagnosed coronary disease, and a statistically significant inverse relationship was seen, suggesting a lower incidence of coronary disease in men with increased alcohol consumption.

In 1995, a prospective study of cardiovascular mortality in middle-aged women was published by Fuchs et al.[3]   In this study, a dietary questionnaire was sent to 85,709 nurses beginning in 1980 and continuing for a 12 year follow up period.  A J-shaped relationship was observed, i.e., light-moderate drinking was associated with a decreased risk of death, however, heavier drinking was associated with an increased risk of death from other causes, particularly breast cancer and cirrhosis.

In 1997, Thun et al published a study following 490,000 men and women for nine years.[4]  A similar questionnaire was used to assess alcohol consumption and then cause of death was observed.  As one would expect, excessive alcohol consumption was associated with increased rates of death from cirrhosis, as well as cancers of the mouth, esophagus, pharynx, larynx and liver.  In contrast, the risk of cardiovascular death was 30-40% lower in both men and women who reported one drink daily compared to nondrinkers.

Castelnuovo et al performed a meta-analysis reviewing 26 studies on the relationship of beer and wine and cardiovascular mortality.[5]  Published in 2002, a total of 417,454 persons were studied and a 32% risk reduction of cardiovascular death with moderate wine consumption was observed, whereas a 22% risk reduction was observed with moderate beer consumption.

Finally, in April of this year, the Journal of the American College of Cardiology, published an article by Mukamal et al supporting this growing body of evidence that alcohol consumption prevents cardiovascular disease.[6]   Data from the National Health Interview Survey, which surveyed approximately 245,000 U.S. adults annually between the years 1987 and 2000, showed that light and moderate drinkers had a 31% and 38%, respectively, lower risk of death due to heart disease than abstainers.

Overall, large epidemiological findings have consistently demonstrated a cardiovascular benefit of light alcohol consumption.  Although no head-to-head prospective studies have been conducted to compare cardiovascular outcomes of different types of alcohol, the literature suggests that red wine seems to be the most protective.  However, skeptics note that these studies do not take into account the different drinking patterns of wine, beer and hard liquor drinkers.  Another potential confounder is lifestyle.  Studies have shown that light, particularly wine, drinkers may have different demographics and behavior patterns as compared to the rest of the population.  They have a tendency to eat healthier, exercise more and come from higher socioeconomic backgrounds (which may imply they have better access to medical care).  The contribution of the direct effect of alcohol or the common lifestyle choices of light moderate drinkers is a difficult confounder to tease out from survey-based, uncontrolled data.

So bringing it all back home, how should you counsel your patients?  Although detractors often complain that the data is largely based on patients answering questionnaires reliably, the literature is has reproduced the benefits of light alcohol consumption time and time again.  Furthermore, there is an undeniable paucity of studies that demonstrate light drinking is harmful.  Armed with this, Dr. Buzzkill would probably advise patients to have a glass of wine nightly with dinner.  aybe now my patients will start calling me Dr. Feelgood.

Until the next installment of Myths and Realities–the first round is on me.  Cheers!

Dr. Mattoo is a second year fellow in Nephrology, NYU Langone Medical Center

Peer reviewed by Barbara Porter, Section Editor, Myths and Realities, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

[1] Cabot, RC. The Relation of Alcohol to Arteriosclerosis. JAMA. 1904; 43(12):774-775.

[2] Rimm, EB. Prospective study of alcohol consumption and risk of coronary disease in men. The Lancet. 1991; 338(8765):464-468.

[3] Fuchs, CS. Alchohol consumption and mortality among women. NEJM. 1995; 332(19):1245–1250.

[4] Thun, MJ.  Alcohol consumption and mortality among middle-aged and elderly U.S. adults. NEJM. 1997 Dec 11;337(24):1705-14.

[5] Di Castelnuovo, A.  Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002 June 18;105:2836-2844.

[6] Mukamal, KJ.  Alcohol Consumption and Cardiovascular Mortality Among U.S. Adults, 1987 to 2002.  J Am Coll Cardiol. 2010; 55:1328-1335.

By Robert Donnino, MD

Faculty Peer Reviewed

The 59^th Annual Scientific Sessions of the American College of Cardiology (ACC) took place in Atlanta on March 14-16, 2010. Despite inclement weather in the northeast causing the cancellation of many flights, a large number of NYU faculty, fellows, and others made it to Atlanta to give talks, presentations, or simply attend the conference.

As usual, the Sessions presented us with many important studies from around the world, some of which may change our clinical practice for years to come. While it is obviously impossible to cover even a small portion of the many important works that were presented, I would like to highlight a few “late-breaking trials”.

The first official day of the meetings was referred to by some as “Negative Sunday” because of the many “negative” trials that were presented. As some pointed out, however, a “negative” trial may be very positive for our patients (and their treating physicians) by providing essential information for their care.

Two trials relating to the Action to Control Cardiovascular Risk (ACCORD) trial were presented: the ACCORD lipid [1]and the ACCORD BP [2] trials.

First, the accord lipid trial investigated the effects of adding fenofibrate to a statin (simvastatin) in all patients with type 2 diabetes at “high risk” for cardiovascular disease with a mean follow-up of 4.7 years. 5,518 diabetics were randomized to statin plus placebo (control group) or statin plus fenofibrate. The study results showed no significant difference in cardiovascular (CV) events—major fatal and nonfatal CV event rates/year were 2.2 in fenofibrate group and 2.4 in control group (p=NS). In a subgroup analysis, a trend toward benefit of fenofibrate was shown in the group of diabetics that had a significant dyslipidemia (low HDL and high triglycerides). Additional subgroup analysis showed a trend toward harm in women (but not men) in the fenofibrate group.

Comment: This trial, while providing very important information, will likely not change current clinical practice as fibrates are generally not used routinely in this population. Given the results from the subgroup analysis in those with elevated triglycerides and low HDL, addition of fibrates in this group of diabetics is reasonable (which is often done currently in clinical practice). The trend toward harm in women is of obvious concern, and should be investigated in future studies.

 The second ACCORD trial was the ACCORD blood pressure (BP) trial. This was the first of 2 trials presented on Sunday regarding BP control in diabetics.

This trial randomized 4,733 type 2 diabetics to “intensive” (goal systolic BP <120 mmHg) vs. “standard” (goal systolic BP <140mmHg) BP control arms. Surprising to many, there was no benefit of intensive BP control over standard control regarding the primary endpoint of major fatal and nonfatal cardiovascular (CV) events. There was a reduction in strokes in the intensive control arm, however since the incidence of stroke was very low (less than 0.5% per year), the number needed to treat to prevent one stroke would be 89 patients over 5 years. In addition, the intensive group suffered significantly more adverse effects related to anti-hypertensive treatment than the standard group (3.3% vs. 1.3%).

The second trial presented on Sunday was a retrospective analysis of the INVEST trial [3] which originally investigated the effects of a calcium channel blocker versus beta-blocker (in addition to other BP meds) in 6,400 diabetics with coronary disease, with a goal BP of 130/85. It is important to point out that INVEST did not randomize patients into BP control “strategy” arms, so this analysis was done by dividing the patients into groups based on what BP was achieved with treatment (retrospectively). In this analysis, the investigators found that those patients with uncontrolled BP (>140mmHg) suffered the most cardiovascular events, however those in the “usual” control group (130-140mmHg) did not suffer any more events than those in the “tight” (<130mmHg) control group. And, in fact, there was an increased risk for mortality in the tight group compared to the usual control group, which on further analysis appears to be only significant in those achieving BP of <115mgHg.

Comment: These trials provide extremely valuable clinical information and may impact clinical practice for many physicians. The data suggest that BP control in diabetics is extremely important to a level below 140mmHg. However, a goal lower than 120mmHg may not carry significant benefit and may even cause harm in high risk diabetics. Given the difficulty in clinical practice of pushing BP below 120mmHg and the growing problem of polypharmacy, this is welcome news for physicians and patients alike. Still, some may argue that the stroke benefit in ACCORD was significant and that certain subgroups of diabetics might benefit from tighter control as opposed to a strategy for all diabetics, however further analysis of these trials and others will be necessary to confirm these hypotheses.

 Another trial presented on Sunday was the Everest II trial [4] which randomized 279 patients with severe mitral valve regurgitation to either surgery (repair or replacement) or percutaneous repair using the “MitraClip”. Investigators found that the 30 day adverse event rate was significantly lower in the percutaneous group, although the majority of this reduction was related to blood transfusions, which some argue should not be considered a major event. Clinical success, defined as freedom from mitral surgery/reoperation and mitral regurgitation less than or equal to 2+ at 12 months, was 72% in the percutaneous group and 88% in the surgery group (p = 0.0012).

Comment: The results from this trial are very encouraging regarding the potential use of percutaneous valve repair, but they must be interpreted with caution. This study does show that this new percutaneous technique is safe and relatively effective out to 1 year. This is a very short follow-up time, however, and extrapolating this technique over a longer term is not warranted from these data, especially given the fairly high number of patients with residual mitral regurgitation after this procedure. One of the most important pieces of information that we will need to examine in the future will be whether mitral valve repair (as opposed to replacement) will still be feasible if the MitraClip device fails. With a short term failure, we know repair is usually possible, however after the clip has been in place for 1 or more years the effect of scar tissue, etc. on valve repair is unknown. Nonetheless, with this safety and efficacy data, this study gives us a new treatment option for severe mitral regurgitation, which may become especially important in those who would otherwise not be candidates for surgical repair. FDA approval for this device is pending.

 Another late-breaking trial presentation set out to answer a very important and controversial question in the cardiology community: how long to continue clopidogrel after the implantation of a drug-eluting stent (DES). This study combined 2 Korean trials (REAL-LATE and ZEST-LATE) [5] in which all patients received both aspirin and clopidogrel following implantation of a DES for 12 months. After 12 months, patients were then randomized to either continue this dual anti-platelet regimen or continue aspirin alone without clopidogrel. After a 19.2 month median follow up, the investigators found no significant difference in the two groups relating to the primary endpoint of nonfatal MI or cardiac death (1.8% in dual drug group vs. 1.2% in aspirin alone group, p=NS).

Comment: This study is very important, but does suffer several limitations. In addition to methodological concerns of combining 2 trials, the event rate was markedly lower than expected, thus reducing the power of the study results. Another limitation was the fact that some patients were randomized after 18 months of dual anti-platelet therapy instead of 12. And finally, the duration of follow up was relatively short. Despite all of these shortcomings, this trial provides evidence that continued dual antiplatelet therapy beyond 1 year in patients with DES may not be warranted (although this is still frequently done in clinical practice). Fortunately, larger trials looking at this question are underway currently and should help to clarify the evidence presented here.

 The last trial I will mention is the RACE-2 trial [6].  This trial randomly assigned 614 patients with permanent atrial fibrillation (AF) to 2 different rate control strategies: the “strict” control group (resting heart rate [HR] < 80 bpm and <110 bpm on limited exercise) and the “lenient” control group (resting HR <110 bpm). The primary outcome was a composite of cardiovascular death, stroke, hospitalization for heart failure, systemic embolic event, pacemaker/ICD implantation, life-threatening arrhythmic event, bleeding and adverse events of rate-control drugs. The results demonstrated no significant difference in the primary endpoint between the two treatment groups after 3 years follow-up, with 12.9% vs. 14.9% in the lenient vs strict group, respectively. Health care provider visits were much higher in the strict group (684 vs 75 visits).

Comment: Given the difficulty in achieving strict HR control, these results are again good news for both patients with atrial fibrillation and their providers. While the results may be surprising to some, it is important to point out that post-hoc analysis from previous trials (AFFIRM and RACE) suggested this lack of benefit to stricter HR control in atrial fibrillation. As with all of these trials, however, it is important to keep in mind that care must be individualized and those that remain symptomatic or are at higher risk of heart failure may indeed require tighter rate control. Further analysis and details of this data including quality of life measures will be very important in fine tuning any conclusions from this study.

 Final thoughts: Several of the above presentations, while “negative” are actually extremely important for the treatment of our patients. They remind us that, while aggressive patient management is essential to preventing serious clinical events, there is a point at which we reach diminishing returns and may even cause harm with overtreatment. One reason for this almost certainly involves polypharmacy, which is becoming an increasingly important point of concern for all of our patients, especially the elderly and those with multiple co-morbidities. It should also be pointed out that treating (or overtreating) patients with a “one-size-fits-all” approach may not be appropriate and may explain the lack of benefit seen in some of the above presentations. Determining the subset of patients, if any, that might benefit from more intensive control (e.g. of BP, HR, glucose, etc.) will be the goal of future clinical research.

 Dr. Donnino is a Section Editor, Cardiology, Clinical Correlations

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image of blood pressure exam courtesy of Wikimedia Commons.

References:

[1]  ACCORD study group. Effects of combination lipid therapy in type 2 diabetes mellitus. NEJM 2010 (published online http://www.nejm.org/)

[2]  ACCORD study group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. NEJM 2010 (published online www.nejm.org)

[3]  Presented by Rhonda Cooper-DeHoff at the ACC.10/i2 Summit, Atlanta, GA, March 2010

[4]  Presented by Dr. Ted Feldman at the ACC.10/i2 Summit, Atlanta, GA, March 2010

[5]  Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. NEJM 2010 (published online http://www.nejm.org/)

[6]  Van Gelder CI, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. NEJM 2010 (published online http://www.nejm.org/)

By Joshua Smith, MD

Faculty Peer Reviewed

As I am sure many of my fellow interns can attest, choosing to begin one’s year on the wards and as a night float at  Bellevue Hospital has resulted in two predictable outcomes: an unbelievable appreciation for free time and an utter lack of knowledge regarding anything occurring outside the 10 block radius of NYU’s three hospitals.  Therefore, it is with great enthusiasm that, thanks to an elective block, I have once again been able to open my mind to the rest of New York City and the world at large.

 In world news, the devastating floods in Pakistan have now left an estimated 4.6 million people homeless and have claimed the lives of as many as 1600.  Despite the US pledging  60 million dollars in aid, Pakistan continues to struggle due to the lack of additional monetary aid from around the world.  Unfortunately , many countries are facing economic hardships of their own as a result of the seemingly endless stream of disasters that have occurred  this year [1]. 

 Closer to home, in a blow to civil rights activists in California on Monday, an order from the 9th Circuit Court of Appeals set aside a federal judge’s decision earlier this month that would have permitted same-sex marriages to resume in California as early as Wednesday [2].  It appears that the battle for civil rights in California and the country at large continues to take two steps forward and one step back.

 In popular medical news this week, a massive egg recall began after cases of Salmonella were linked to consumption of eggs from a particular egg producer in Iowa.  There have been no reported deaths but estimates for the number affected are now in the thousands [3]. 

 Turning to the medical literature, several themes have emerged this week including end-of-life care, doctor-patient communication, as well as several new studies investigating renal transplantation.

 Palliative Care

 Major media outlets including the  NY Times this week reported the results of a study on palliative care that was published in the New England Journal of Medicine [4][5].  This randomized, controlled study was performed on a group of individuals with newly diagnosed metastatic small-cell-lung cancer, a group that typically has a substantial symptom burden and in whom aggressive measures are often taken near the end of life.  The participants in the study were randomly assigned to either early palliative care (as adapted from the National Consensus Project for Quality Palliative Care) along with standard oncologic therapy or to oncologic therapy alone.  Quality of life and mood were assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and the Hospital Anxiety and Depression Scale, respectively, at the onset of therapy and again after 12 weeks.  The primary outcome was change in quality of life at 12 weeks.  The results of the study showed that patients assigned to early palliative care had a better quality of life than did patients assigned to standard care (FACT-L score of 98 vs. 91.5, p=0.03) and fewer patients in the palliative care group than in the standard group had depressive symptoms (16% vs. 38%, P=0.01).  Furthermore, though patients in the early palliative care group received less aggressive end-of-life care, their median survival was significantly longer than in the group receiving standard care (11.6 months vs. 8.9 months, P=0.02).  Though this study had several important limitations including the fact that it was performed at a single tertiary center with limited patient diversity and was not blinded, I think that the findings in this study are extremely important to take note of in our current medical culture where  we pursue futile aggressive measures regardless of cost abd palliative care is not begun until the very end of life.

 Doctor-Patient Communication

 Two articles this week focused on the importance of communication between doctors and their patients and the outcome of that communication (or lack thereof). 

 The Archives of Internal Medicine reports the results of a study by Olsen, et al. aimed at identifying communication discrepancies between physicians and hospitalized patients [6].  The participants in the study included a wide variety of hospitalized patients and the house staff that cared for them.  Patients were given two standardized questionnaires.   The study produced some very interesting findings including a significant discrepancy between the percentage of patients who appropriately reported their diagnosis (43%), named the physician in charge of their care (18%), and were informed of side effects of new medications (10%) versus what the physician felt that they had communicated to the patient.  Though this study is rife with limitations including being performed at a single institution with a limited amount of patient diversity, the results are striking.   Physicians should be reminded of the rift that exists between what we perceive that our patients understand and what they actually understand about their conditions.

 Though it is generally accepted that it is in our patients’ best interest that we disclose medical errors surrounding their care , the fear of legal repercussion has often stood in the way of this becoming a standard practice.  Kachalia, et al looks at the question of these types of communications in the most recent Annals of Internal Medicine [7]. The study was designed to compare liability claims and costs before and after implementation of a disclosure-with-offer program.   It was performed using data from the University of Michigan Health System (UMHS), a system which has fully disclosed and offered compensation to its patients for medical errors since 2001.  The patients enrolled in the study were those inpatients and outpatients involved in claims made to UMHS.  The results showed a significant decrease in new legal claims, number of lawsuits per month, time to claim resolution, and costs after implementation of the program of disclosure with offer of compensation.  The results of this study should be analyzed with caution as malpractice claims declined throughout Michigan during the study period in general and UMHS’s unique approach to offering compensation may lead to lack of generalizability.  However, despite these limitations, this study does suggest that a medical center can implement a disclosure-with-offer program without increasing its malpractice costs.  As this is undoubtedly in our patients’ best interest, it would be a shame for other hospital systems to not follow suit.

 Renal Transplantation

 For reasons unbeknownst to this writer, renal transplantation was a hot topic in the medical literature this week…

 Historically, the data regarding medical outcomes in living kidney donors has been obtained almost exclusively from white patient populations.  To address this racial discrepancy, Lentine, et al. performed a study analyzing racial variation in medical outcomes among living kidney donors.  The results were published in this week’s New England Journal of Medicine [8].   The individuals included in the study were chosen by linking identifiers from the Organ Procurement and Transplantation Network (OPTN) with administrative data of a private U.S. health insurer.  This resulted in a database of 4650 individuals who were living kidney donors that had also been patients under the given health insurance.  The data were then compared with prevalence patterns for the general population.  The patient demographics in this study were much more diverse than in previous studies (76.3% white, 13.1% black, 8.2% Hispanic, and 2.4% another race or ethnic group).  The results showed that black and Hispanic donors had a significantly increased risk of hypertension, diabetes mellitus requiring drug therapy, and chronic kidney disease which could not be explained by socioeconomic factors.  Most of these results were in line with the racial disparities seen in medical conditions in the general population and were not unique to living kidney donors.  The limitations of this study including the limited available data and sampling approach using data from an insurance plan do decrease its applicability, however the results support long-standing data that indicate that non-white populations in the U.S. tend to suffer worse health outcomes in general and the living kidney donor population is no exception.  Therefore, increased attention to health outcomes in these populations is warranted.  

 Also in renal transplant news, a cohort study by Summers, et al. published in The Lancet investigated factors that affect outcome after transplantation of kidneys donated after controlled cardiac death in the UK [9].  The study was undertaken due to the fact that 1/3 of all kidneys from deceased donors in the UK are donated after cardiac death, but concerns had been raised as to the outcome of such transplants as compared to donors who suffered brain death.  The study included a large number of kidney transplants (9134), 8289 which were donated after brain death and 845 after controlled cardiac death.  The results showed no significant difference in graft survival or eGFR up to 5 years after transplant in the two groups.  The results from this well-designed, large, multi-center study indicate that kidneys from controlled cardiac-death donors demonstrate equivalent graft survival and function when compared with kidneys donated from brain-death donors for at least 5 years post-transplant.

 To conclude our busy week in renal transplantation research, a study by Kainz, et al. published in The Annals of Internal Medicine looked into steroid pretreatment of organ donors to prevent post-ischemic renal allograft failure [10].  Post-transplantation acute renal failure (ARF) occurs in an estimated 25% of recipients of organs from deceased donors, and inflammation in the donor organ is associated with an increased risk for ARF.  Therefore, this prospective, randomized controlled multi-center trial was designed to determine whether administering corticosteroids to donors reduces the incidence and duration of ARF in organ recipients.  Incidence of ARF, defined as greater than 1 dialysis session in the first week after transplantation, was the primary end point.  The results of the study showed no significant difference in incidence of ARF between the steroid-treated donors and the placebo-treated donors.  Though the study may lack generalizability due to its mainly-white patient population and the limited geographic diversity of its centers, these findings suggest that pre-treatment of donors with steroids is not indicated in renal transplantation.

Dr. Smith is a first year resident at NYU Langone Medical Center

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image of Bellevue Ambulatory Care Center courtesy of Wikimedia Commons

 References:

[1]      http://www.nytimes.com/2010/08/20/world/asia/20pstan.html?_r=1&ref=world

[2]      http://www.cnn.com/2010/US/08/17/same.sex.marriage/index.html?npt=NP1

[3]      http://www.nytimes.com/2010/08/19/business/19eggs.html?ref=health

[4]      http://www.nytimes.com/2010/08/19/health/19care.html?ref=health

[5]      Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med 2010;363:733-42. http://www.nejm.org/doi/full/10.1056/NEJMoa1000678

[6]      Olson DP, Windish DM.  Communication discrepancies between physicians and hospitalized patients. Arch Intern Med 2010;170(15):1302-1307.    http://archinte.ama-assn.org/cgi/content/short/170/15/1302

[7]      Kachalia AK, Kaufman SR, Boothman R, et al. Liability claims and costs before and after implementation of a medical error disclosure program. Ann Intern Med 2010;153(4):213-221.    http://www.annals.org/content/153/4/213.abstract?aimhp

[8]      Lentine KL, Schnitzler MA, Xiao H, et al. Racial variation in medical outcomes among living kidney donors. N Engl J Med 2010;363:724-732 http://www.nejm.org/doi/full/10.1056/NEJMoa1000950

[9]      Summers DM, Johnson RJ, Allen J, et al. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK. Lancet 2010, early online publication, doi:10.1016/S0140-6736(10)60827-6 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960827-6/abstract

[10]   Kainz A, Wilflingseder J, Mitterbauer C, et al. Steroid pretreatment of organ donors to prevent postischemic renal allograft failure. Ann Intern Med 2010;153(4):222-230   http://www.annals.org/content/153/4/222.abstract

By Todd Cutler

Faculty Peer Reviewed

A 31-year-old woman presents to the clinic with chronic fatigue. She was diagnosed with iron  deficiency anemia when she was 25 years old and has since taken oral contraceptives to limit bleeding during menstruation which she describes as minimal. She has a family history significant for an older brother with celiac disease. She is thin and her exam is significant for conjunctival pallor. Her laboratory findings are significant for a hemoglobin of 9.7 g/dL, a mean corpuscular volume of 72.3 fL, an iron level of 26 mcg/dL and a ferritin of 18 mcg/L.

 How should the diagnosis of celiac disease be pursued as the possible etiology of her iron deficiency anemia?

 Celiac disease is an immune disorder characterized by chronic inflammation of the gastrointestinal tract which can manifest clinically with diarrhea, abdominal discomfort and complications of malabsorption including weight loss, osteoporosis and iron deficiency anemia. These findings are classically seen, although they are neither sensitive nor specific for celiac disease.[1]

 Atypical presentations such as generalized fatigue are common, resulting in delays in diagnosis and misdiagnosis. For example, many patients ultimately found to have celiac disease are first diagnosed with irritable bowel syndrome.[2]

 In the last few decades, however, a greater understanding of the pathogenesis of celiac disease has led to the development of new tools to assist in detecting this disease. Along with these advances has come the recognition that celiac disease, once believed to be rare, has a prevalence of 1% in most populations and morbidity much greater than was originally appreciated when the disease was first described.[3]

 Celiac disease is a unique autoimmune syndrome in that the environmental antigen, gliadin, has been identified and treatment involves avoidance of that precipitant. Gliadin is a digested fragment of gluten, a storage protein present in wheat, barley and rye.[4]  In susceptible patients, the enzyme tissue transglutaminase (TTG) induces deamidation of gliadin peptides, initiating an inflammatory response mediated by gliadin-reactive CD4+ T-cells.

 In 1997, Dieterich and colleagues identified TTG as the primary autoantigen in celiac disease.[5] Elevated serum levels of IgA antibodies against TTG, as well as anti-endomysial antibody IgA, are directly correlated with celiac disease although their respective roles in disease pathogenesis are unknown.

 Most guidelines for the diagnostic evaluation of a patient suspected to have celiac disease recommend serologic titers in conjunction with a small bowel biopsy. Biopsy typically shows blunting of the villa and endothelial lymphocytic infiltration. However, these findings are nonspecific and may be seen in other disease entities such as lactose intolerance, HIV and Crohn’s disease. For these reasons, the European Society for Pediatric Gastroenterology and Nutrition, in 2004, called for a non-invasive method for diagnosing celiac disease.[6]

 In contrast, Green and Cellier, in their 2007 review of celiac disease, wrote, “The diagnosis of celiac disease requires both a duodenal biopsy that shows the characteristic findings…and a positive response to a gluten-free diet.”[7] In light of these shortcomings, there is no universally accepted algorithm for the diagnosis of celiac disease.

 The high sensitivity and specificity of anti-EMA IgA (90% and close to 100%) and anti-TTG IgA (98% and 90%)[8]^,[9] has prompted outpatient providers to initiate investigation of celiac disease[10] and more patients are being started on empiric gluten-restricted diets based solely on the results of blood tests. The wisdom of this practice is a topic of ongoing debate. Hadziselimovic and Burgin-Wolff reported that 99.8% of patients who test positive for the combination of anti-TTG IgA, anti-endomysial IgA and gliadin IgA and IgG antibodies have small bowel biopsies that show mucosal injury consistent with celiac disease.[11] A related study found that 98% of patients with anti-TTG serum levels >100U ultimately had positive biopsy results.[12]

 hese findings suggest that for patients in whom the clinical suspicion is high and serum titers are elevated, the empiric initiation of a gluten-free diet can be confidently recommended without a biopsy. The population of patients with intermediate serologic titers should be evaluated further with small bowel biopsies. Ultimately, a clinical response to the diet would confirm the diagnosis.

 Furthermore, as antibody titers are directly correlated with the severity of disease, serologic markers can be used to monitor the response to therapy. A poor response to diet may necessitate endoscopic investigation to rule out processes associated with celiac disease like intestinal T-cell lymphoma and adenocarcinoma of the small intestine. In these patients, serologic testing provides no information about the state of the intestinal epithelium and these patients are often diagnosed when clinical symptoms persist despite adherence to a gluten-free diet.[13]

 A caveat to this approach is that even a very low incidence of false positivity would expose many patients to unnecessary dietary changes.[14] As the American Gastroenterological Association technical guidelines point out, if one assumes a 1% prevalence in the general population, for the positive predictive value to be greater than 95%, the pre-test probability of a patient having celiac disease would have to be at least 35%.[15] Considering the notoriously nonspecific presentations of celiac disease, this goal may be difficult to achieve.

 In related studies, patients with mild celiac disease by histology had significantly decreased anti-TTG antibodies sensitivity and up to 60-70% of patients with celiac disease would not be identified by serologic screening with anti-TTG alone.[16],[17] These studies, however, included patients with a low suspicion of celiac disease and some argue that, in the correct population, judicious use of autoantibody testing would obviate the need for intestinal biopsy.[18]

 There is no gold standard for the diagnosis of celiac disease. The diagnosis is most confidently made with the support of a clinical picture consistent with celiac disease, elevated autoantibody levels, positive biopsy results and, ideally, an improvement with dietary changes. Perhaps, as serology testing improves, in a patient with a highly suspicious presentation and a positive antibody test, a trial of a gluten-free diet would offer only marginally less evidence as the same clinical findings with the additional support of a positive intestinal biopsy. Larger studies are needed to elucidate the feasibility of diagnosis based on serologic testing alone. For now, however, a multi-disciplinary approach to the diagnosis of this disease is recommended.

Dr. Cutler is a third year resident at NYU Langone Medical Center

Peer reviewed by Dr. Ilseung Cho, Division of Gastroenterology, NYU Langone Medical Center

Image of gluten-free cookies courtesy of  Wikimedia Commons.

References:

[1] Celiac sprue. Farrell RJ, Kelly CP. N Engl J Med. 2002 Jan 17;346(3):180-8. Review.

[2] Characteristics of adult celiac disease in the USA: results of a national survey. Green PHR, Stavropoulos SN, Panagi SG, Goldstein SL, Mcmahon DJ, Absan H, Neugut AI. Am J Gastroenterol. 2001 Jan;96(1):126-31.

[3] NIH Consensus Development Conference on Celiac Disease. NIH Consens State Sci Statements. 2004 Jun 28-30;21(1):1-23.

[4] Investigation and management of coeliac disease. Rodrigues AF, Jenkins HR. Arch Dis Child. 2008 Mar;93(3):251-4. Epub 2007 Sep 19. Review.

[5] Identification of tissue transglutaminase as the autoantigen of celiac disease. Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, Schuppan D. Nat Med. 1997 Jul;3(7):797-801.

[6] Celiac disease and other immunologically mediated disorders of the gastrointestinal tract: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition.

Troncone R, Bhatnagar S, Butzner D, Cameron D, Hill I, Hoffenberg E, Maki M, Mendez V, de Jimenez MZ; European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

[7] Celiac disease. Green PH, Cellier C. N Engl J Med. 2007 Oct 25;357(17):1731-43. Review.

[8] Celiac disease: risk assessment, diagnosis, and monitoring. Setty M, Hormaza L, Guandalini S. Mol Diagn Ther. 2008;12(5):289-98. Review.

[9] Serological testing in screening for adult celiac disease. Gillett HR, Freeman HJ. Can J Gastroenterol. 1999 Apr;13(3):265-9. Review.

[10] Changing patterns of coeliac serology requests. Evans KE, Malloy AR, Gorard DA. Aliment Pharmacol Ther. 2009 May 15;29(10):1137-42. Epub 2009 Feb 23.

[11] Celiac disease. Hadziselimovic F, Bürgin-Wolff A. N Engl J Med. 2008 Feb 14;358(7):747-8; author reply 748-9.

[12] Can tissue transglutaminase antibody titers replace small-bowel biopsy to diagnose celiac disease in select pediatric populations? Barker CC, Mitton C, Jevon G, Mock T. Pediatrics. 2005 May;115(5):1341-6.

[13] Malignant complications of coeliac disease. Brousse N, Meijer JW. Best Pract Res Clin Gastroenterol. 2005 Jun;19(3):401-12. Review.

[14]. Diagnosing celiac disease with a positive serological test and without an intestinal biopsy. Rashid M. Pediatrics. 2005 Oct;116(4):1054-5; author reply 1055.

[15] American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Rostom A, Murray JA, Kagnoff MF. Gastroenterology. 2006 Dec;131(6):1981-2002. Review.

[16] Autoantibodies and histogenesis of celiac disease. Rostami K, Mulder CJ, Stapel S, von Blomberg BM, Kerckhaert J, Meijer JW, Peńa SA, Heymans HS. Rom J Gastroenterol. 2003 Jun;12(2):101-6.

[17] Autoantibodies in celiac disease. Alaedini A, Green PH. Autoimmunity. 2008 Feb;41(1):19-26. Review.

[18] Two-step approach for diagnosing celiac disease. Bürgin-Wolff A, Hadziselimovic F. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1173; author reply 1173-4.

By Ami Jhaveri, MD

Faculty Peer Reviewed

In the headlines this week, The New York Times featured an article describing a test capable of identifying biomarkers in cerebrospinal fluid to diagnose patients with Alzheimer’s disease.^[1]  This article is based on a study that was published this week in the Archives of Neurology.  Previously, Alzheimer’s disease could only be diagnosed based on clinical suspicion until a definite diagnosis was available with autopsy.  In the study by De Meyer et al., researchers measured levels of A1-42, total tau, and P-Tau_181P and used mixture modeling approaches to apply these markers in the diagnosis of Alzheimer’s disease.  Reduced levels of A1-42 and increased levels of P-Tau_181P were considered hallmarks of Alzheimer’s disease.  This data was first validated on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, which includes normal participants, patients with mild cognitive impairment, and patients with a diagnosis of early Alzheimer’s disease^.[2]  In the ADNI database, the biomarkers were identified not only in 90% of patients with Alzheimer’s disease and 72% of patients with moderate cognitive impairment, but also in 36% of normal participants.  Analysis showed that these biomarkers had 90% sensitivity and 64% specificity for an Alzheimer’s diagnosis.  Validation of the findings was achieved using both a Belgian database of autopsy-proven Alzheimer’s disease and another group of patients initially diagnosed with mild cognitive impairment who later developed Alzheimer’s disease.  Sensitivity was 94% in the autopsy-verified Alzheimer’s disease specimens.  In the prospectively studied chort, the markers showed 100% sensitivity in patients with moderate cognitive impairment who were clinically progressing towards Alzheimer’s disease over a 5-year follow-up period.  However, this group of patients does not have a pathology-confirmed diagnosis of Alzheimer’s disease.  The authors suggest that this test may be used in patients prior to the development of clinical features of Alzheimer’s disease.  The New York Times feature of this study brings up the issue of using a diagnostic test for a disease with limited treatment options, significant consequences, and no cure.

An article in JAMA addressed the increasing incidence of diabetic retinopathy as our population ages and the prevalence of diabetes increases.^[3]  Zhang et al. analyzed data from 2005-2008 to summarize the prevalence and risk factors associated with diabetic retinopathy among adults aged 40 years and older.  This retrospective review used National Health and Nutrition Examination Surveys 2005-2008 (NHANES), which are surveys of 6797 adults aged 40 years and older from the National Center for Health Statistics.  The surveys were of the general US population, and the diagnosis of diabetes was defined from self-reporting of a previous clinical diagnosis or hemoglobin A1c 6.5% or greater.  Participants of NHANES 2005-2008 had photographs of their eye to diagnose diabetic retinopathy.  The study found that the prevalence of diabetic retinopathy among US adults with diabetes was 28.5% (CI 24.9-32.5%).  Further analysis found higher rates of diabetic retinopathy in non-Hispanic, black individuals.  Male sex, higher hemoglobin A1c, longer duration of diabetes, insulin use, and higher systolic blood pressure were independent risk factors for diabetic retinopathy in multivariate analysis.  The authors concluded that the high prevalence of diabetic retinopathy should encourage population-based public health interventions for eye care.

The Lancet featured an epidemiological study describing a new mechanism for antibiotic resistance in India, Pakistan, and the UK^.[4]  Given our experiences with the problems of MRSA, VRE and ESBL-producing bacteria, there is now concern for new Enterobacteriaceae resistance to carbapenem antibiotics. The New Delhi Metallo-beta-lactamase 1 (NDM-1) is responsible for the resistance of this family of gram negative rods including Escherichia coli, Klebsiella pneumoniae, and Proteus spp. to carbapenems.  Researchers identified Enterobacteriaceae isolates from India, Pakistan, Bangladesh, and UK and found that NDM-1 was present in E. coli and K. pneumoniae isolates that were resistant to all antibiotics except tigecycline and polymyxin.  The study found that 1% of all carbapenem-resistant Enterobacteriaceae from Chennai were NDM-1 positive.  In the UK, 37 Enterobacteriaceae isolates with the NDM-1 enzyme were found; an additional 73 isolates were analyzed from different parts of India and Pakistan.  With the surge of ESBL producing gram negative bacteria, we continue to depend on carbapenems for antibiotic therapy so resistance to this class of antibiotics would present a significant global health problem. This study represents yet another alarm about the perils of indiscriminant antibiotic usage.

 Also addressing antibiotic resistance, an article in JAMA assessed the current state of health care-associated invasive MRSA infections, including MRSA bacteremia, pneumonia, skin or soft tissue infection, bone or joint infection, urinary tract infection, and endocarditis.^[5]  This large retrospective review used data from the CDC’s Emerging Infections Program/Active Bacterial Core surveillance system between 2005 and 2008.  This program tracks data from 9 different metropolitan areas.  On a positive note, this study found decreased rates of invasive health care-associated MRSA with a 28% and 17% decrease in hospital-onset and health care-associated community onset MRSA infections during this time period.

In this week’s NEJM, a Perspective article by Dr. Ofri of NYU School of Medicine addressed the growing use of quality measures to assess physician performance.^[6]  Dr. Ofri explains that providing medical care involves many factors including aspects of a doctor-patient relationship that lab results may not take into account.  

 Dr. Jhaveri, MD is a third year resident at NYU Langone Medical Center

Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations

Image of Dr. Alois Alzheimer courtesy of Wikemedia Commons.

References:

[1] Kolata G. Spinal-Fluid Test is Found to Predict Alzheimer’s. The New York Times. 2010 Aug 9. http://www.nytimes.com/2010/08/10/health/research/10spinal.html?scp=2&sq=alzheimer’s&st=cse”&HYPERLINK

[2]  De Meyer G, Shapiro F, Vanderstichele H, et al. Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People. Arch Neurol. 2010;67:949-956.  http://archneur.ama-assn.org/cgi/content/abstract/67/8/949

[3]  Zhang X, Saaddine JB, Chou CF, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304:649-656.  http://archneur.ama-assn.org/cgi/content/abstract/67/8/949

 [4] Kumarasamy KK, Toleman MA, Walsh TR, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010.  http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(10)70143-2/abstract

[5]   Kallen AJ, Mu Y, Bulens S, et al. Health care-associated invasive MRSA infections, 2005-2008. JAMA. 2010;304:641-648.  http://jama.ama-assn.org/cgi/content/full/304/6/641

 [6]  Ofri D. Quality Measures and the Individual Physician. NEJM. 2010;363:606-608.   http://www.nejm.org/doi/full/10.1056/NEJMp1006298

By Ishmeal Bradley

 Faculty Peer Reviewed

In the first two parts of this article, we explored the historical and legal contexts of direct-to-consumer (DTC) advertising, the effects of these ads on prescribing behavior, and the economic incentives to advertise. In this final installment, we will examine what patients and physicians really think about these ads and offer one possible way to minimize the potentially harmful effects of DTC advertising.

 Perceptions about DTC Advertising

 Patient perceptions about DTC advertising are dynamic and have become less favorable over time. The FDA carried out a series of surveys in 1999 and 2002 to determine what patients thought about consumer advertising.^{[1 ]} In both years, the agency interviewed more than 900 patients. Overwhelmingly, in both surveys the most common source of DTC advertising was television (>90%). Over the course of three years, patients’ attitudes about DTC became less positive. The percentage of patients who said that they liked seeing prescription drug advertisements fell from 52% in 1999 to 32% in 2002. Also, the percentage of patients who thought that advertisements helped them to make better decisions about their health fell from 47% to 32%. And finally, when asked if advertisements helped them to have better discussions with their doctors, 62% of patients agreed in 1999 compared to 43% in 2002. The lobbying group, Pharmaceutical Research and Manufacturers of America (PhRMA), claims that its ads are beneficial because they help patients to make better healthcare decisions.^[2] However, given these survey results, this does not appear to be true.

 The FDA results are not unique. Another survey study from Colorado in 2004 also examined patients’ and physicians’ opinions about DTC advertising. In their study, only 29% of patients felt that DTC advertising was a positive trend in healthcare.^[3] Furthermore, only a fraction of consumers (28.6%) felt that DTC ads made them better informed about their health. Of note, these patient surveys were conducted during and immediately after the Vioxx scandal. A more recent survey is needed to see if these attitudes have held up over time.

 Physicians had more mixed views about DTC advertising. Whereas 29% of patients thought DTC ads were a positive trend, only 9.8% of physicians agreed. Despite this negative opinion, data from the FDA physician survey in 2002 showed that physicians actually thought that DTC ads improved the clinical encounter. Half of the surveyed physicians (53%) felt that these ads allowed them to have better discussions with their patients. Also, 73% thought that patients who had seen these ads asked more thoughtful questions, and 45% felt that the time they spent with their patients was used more effectively as opposed to 35% who disagreed. The discrepancy between patient and physician perceptions about the utility of these ads demonstrates that there is a fundamental gap between what patients want and what they actually receive in the clinical encounter. Given the mixed results from these survey studies, it remains unclear how much impact, if any, these advertisements actually have on the doctor-patient relationship and effective clinical decision-making.

 “Advertising is Information”: Pros and Cons of DTC Advertising

 DTC advertising is inherently controversial, with business interests on one side and consumer groups and physicians cautiously on the other. DTC ads do make patients more aware of available treatments and may indeed improve communication between patients and doctors. On the other hand, though, these ads do cause an increase in prescription writing that may or may not be beneficial, do not fully illustrate the risks alongside the benefits, and may confuse patients about what are acceptable standards of care.

 On the eve of the FDA’s remarkable reversal to allow broadcast DTC ads in 1997, Nancy Buc, a spokeswoman for Wyeth-Ayerst Laboratories (makers of Zosyn, Protonix, and Ativan) was quoted as saying, “Advertising is information.”^[4] Is this information educational and valuable? PhRMA agrees. In their 2008 press release on the matter, the organization contended that without the “active dissemination of information about medicines to both physicians and consumers,” the gap between necessary care and the care that patients actually received would widen.²

 So what information are consumers getting from these ads? According to the FDA surveys, not much. When consumers were asked if advertisements provided enough information about risks, only 31% agreed in 1999 and 32% in 2002. Regarding information about benefits, a selling point that one would think would be over-emphasized, only a minority of consumers agreed that DTC ads gave enough (39% in 1999 and 41% in 2002). The paucity of substantive information about drug indications, side effects, duration of treatment, or alternative non-medical therapies is glossed over with images of celebrities, cartoons, and ex-presidents all encouraging us to “talk to our doctors.”

 Perhaps the biggest criticism of DTC advertising is that the bulk of these ads air within a year of FDA approval. The approval process, based on small studies involving only hundreds of patients over weeks to months, may not detect infrequent adverse events. However, clinical trials conducted over longer time frames with larger groups of patients are not feasible and are prohibitively expensive. As a result, the FDA relies on post-marketing surveillance to ensure that a drug that was considered safe actually is. Scott Lassman, senior assistant general counsel of PhRMA said that “when a drug is approved, the FDA has already made an assessment that it is safe.”^[5]

 One only has to look at the Vioxx scandal to see how wrong that statement is. When the FDA approved Vioxx in May 1999, Merck heralded the drug as a godsend for patients with osteoarthritis. Within a year, the $161 million marketing campaign began. However, early in 2000, the results of the VIGOR study (VIoxx GI Outcomes Research) were published, which showed an increase in cardiovascular events associated with Vioxx. Later, in 2001, the APPROVe study (Adenomatous Polyp PRevention On Vioxx) also showed a similar increase in patients taking Vioxx for more than eighteen months. Amidst these two trials were allegations that Merck had intentionally withheld poor outcomes data from the FDA to make the drug appear safer than it really was. In September 2004, Merck voluntarily withdrew the drug. Shortly thereafter, the lawsuits began.

 The Future of DTC Advertising: A Way Out?

 Direct-to-consumer advertising is here to stay and will most likely only increase in the coming years. Advertising has been afforded First Amendment protection under the doctrine of commercial free speech, and there are few in the public or in Congress who are willing to challenge that. Attempts by individual members of Congress, notably Rep. Henry Waxman and Senators Edward Kennedy and Michael Enzi, to give the FDA more regulatory power, have so far been unsuccessful. One potential solution would be a moratorium on advertising for the first few years that a drug is on the market. This would allow time for post-marketing data collection on adverse events before the drug is widely advertised to the public. There is support for this idea, both in the federal government and in industry. However, whereas the FDA would prefer a two-year limit, individual pharmaceutical companies are asking for only six months to one year.

 The bottom line: drug companies are businesses. They make a product that impacts the health of the consumer and they can charge a premium for that product. We should not expect drug companies to be altruistic in their motives or in their advertising. As a medical profession, we should be wary of exaggerated claims and should place the same amount of scrutiny on ads for prescription drug as we would on any other advertisements. Also, as physicians, we should not be hesitant or annoyed to discuss these ads when patients bring up the topic in our offices. They may have genuine concerns and questions about their health that we should honor. Yes, prescription drug ads are far from perfect, but they can serve a purpose in the larger context of patient education if they are indeed fair, balanced, and honest. Hopefully, DTC advertising will make consumers not just more informed, but better informed.

Dr. Bradley is a Section Editor, Clinical Correlations

Peer reviewed by  Scott Sherman, MD, MPH Associate Professor of Medicine and Psychiatry at NYU Langone Medical Center

 References:

[1]  Food and Drug Administration. “Patient and Physician Attitudes and Behaviors Associated with DTC Promotion of Prescription Drugs: Summary of FDA Survey Research Results.” Final Report November 19, 2004. Available at http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm109593.htm. Accessed July 22, 2009.

[2]   Pharmaceutical Research and Manufacturers of America. “Pharmaceutical Marketing in Perspective: Its Value and Role as One of Many Factors Informing Prescribing.” July 2008. Available at http://www.phrma.org/files/PhRMA%20Marketing%20Brochure%20Influences%20on%20Prescribing%20FINAL.pdf. Accessed July 22, 2009.

 [3]   Robinson, Andrew R. et al. “Direct-to-Consumer Pharmaceutical Advertising: Physician and Public Opinion and Potential Effects on the Physician-Patient Relationship.” Arch Int Med 2004;164:427-432.

[4]   Zuger, Abigail. “Drug Companies’ Sales Pitch: ‘Ask Your Doctor.’” New York Times. August 5, 1997.

[5]  Weintraub, Arlene. “Putting Drug Ads Back in the Bottle.” BusinessWeek. August 13, 2007.

By Emily Slater

Faculty Peer Reviewed

Mr. R is a 46-year-old man with a past medical history of polycythemia vera on hydroxyurea and chronic hepatitis B and C who presented with acutely worsening left upper-quadrant abdominal pain.  This occurred in the context of 3 months of worsening abdominal pain and 1.5 years of increasing abdominal distension.  His physical exam was remarkable for massive splenomegaly (18cm span) and a non-palpable liver. 

Laboratory findings are significant for microcytic anemia with an elevated RDW, thrombocytopenia, elevated PT, PTT, and INR, elevated D-dimer, normal AFP, and normal liver enzymes.  CT of the abdomen and pelvis, MRV, and MRI suggested chronic portal vein thrombosis with cavernous transformation, splenic vein thrombosis, massive splenomegaly, esophageal varices, and liver cirrhosis.  No focal liver or splenic lesions were noted. Polycythemia vera is a clonal disorder of multipotent hematopoietic progenitor cells, and is characterized by the accumulation of phenotypically normal red blood cells, granulocytes, and platelets in the absence of a recognizable physiologic stimulus.  As the most common chronic myeloproliferative disorder, polycythemia vera presents in patients as an elevated hemoglobin or hematocrit, and can be further defined with laboratory evaluation as an increase in red cell mass.  The definition of polycythemia  vera as a disease of panmyelosis encompasses both its primary features and complications, including splenomegaly, pruritis, erythromyalgia, bleeding, and hypercoagulability with arterial and venous thrombosis. 

In 2005 a chromosomal clue to the molecular basis of polycythemia  vera was elucidated.  Certain patients with myeloproliferative disorders, including polycythemia vera, essential thrombocythemia, and myelofibrosis, can manifest a loss of heterozygosity on the short arm of chromosome 9.  Subsequent microsatellite mapping of a cohort of these patients identified a somatic, dominant, gain-of-function mutation in a region that included the pseudokinase domain of the JAK2 gene.  The JAK2 V617F mutation was then described as a base pair transversion that results in a single amino acid substitution of phenylalanine for valine on the short arm of chromosome 9.1  

Not all patients with polycythemia vera have a loss of heterozygosity at the 9p locus; rather, this 9p locus merely identifies the location of the JAK2 allele, and patients with polycythemia may be heterozygous or homozygous for the JAK2 V617F mutation.  It is the JAK2 V617F mutation, however, regardless of its homozygous or heterozygous presentation on a chromosomal level, that is seen in almost all polycythemia vera patients.  Over 95% of patients with this myeloproliferative disorder have this mutation in one of these two forms; the other 5% have other JAK2 mutations with functional consequences similar to those noted for JAK2V617F.2  The JAK2 mutation, therefore, is virtually pathogneumonic for polycythemia vera.

JAK2 functions as a cytoplasm tyrosine kinase that transduces signals from hematopoietic growth factors in both normal and euplastic multipotent hematopoietic progenitor cells.  Because the characteristic JAK2 mutation occurs in hematopoietic progenitor cells, the circulating erythrocytes, granulocytes, and platelets that derive from these euplastic precursors also harbor the mutation.  This results in a panmyelosis, with marked qualitative and quantitative dysfunction that affects all three lineages. 

Polycythemia vera, however, is classically characterized by neoplastic erythroid cells that proliferate in the absence of erythropoietin because of constitutive signaling by the mutated JAK2 protein.  While this results in the increased red blood cell number and mass that are part of the diagnostic criteria for polycythemia vera, this hyperviscosity is not the sole mechanism of the hypercoagulability that also seen in the disease.  While high whole blood viscosity due to high hematocrit certainly contributes to the hypercoagulable state of polycythemia vera, phlebotomy reduces but does not eliminate the increased risk of thrombotic events. Hence, hypercoagulability in polycythemia vera is a multifactorial process.

Hypercoagulable states include both primary inherited and secondary acquired disorders associated with increased risks of thromboembolism.  While the mechanism of hypercoagulability in these inherited states, such as factor V Leiden, antithrombin III mutation, and protein C or S deficiency, can be summarized as abnormal regulation of the coagulation cascade, the pathophysiology of increased thrombotic events in the acquired disorders is more variable.  Several heterogeneous disease states, including cancer, myeloproliferative disorders, antiphospholipid antibody syndrome, and heparin-induced thrombocytopathy may predispose to thrombosis; the mechanisms of hypercoagulability in these diseases, however, differ vastly. 

What is especially intriguing about the myeloproliferative disorders, and specifically polycythemia pera, is that the same mutation that defines the neoplastic, clonal proliferation of tri-lineage myeloid precursors in the bone marrow and their descendants in the blood is also responsible for the hypercoagulable state of the disease.   This JAK2 mutation of polycythemia vera not only defines the molecular basis for the disease, but is also responsible for its sequelae, including increased red blood cell number and mass, hypercoagulability, and pruritis, as well as its response to hydroxyurea, the current mainstay of therapy.

Although the myeloproliferative disorders have been linked to splanchnic venous thrombosis, such as Budd-Chiari syndrome and portal vein thrombosis for many years, the mechanism of hypercoagulability has only recently been elucidated. 

Early research, later proven to be incorrect, proposed that splanchnic veno-occlusive disease was caused by direct damage to sinusoidal endothelial cells in the portal circulation, resulting in local embolism by sinusoidal lining cells and subsequent circulatory blockage.3  Subsequent studies hypothesized roles for decreased natural anticoagulants, increased plasma homocysteine, anticardiolipin antibodies, or inherited thrombophilic genotypes (such as factor V Leiden, prothrombin mutation, and protein C deficiency) in promoting arterial disease and splanchnic venous thrombosis in patients with polycythemia vera. 

Although portal and hepatic venous thrombosis are most often the result of more than one thrombotic risk factor and are not due to single, isolated events,4 thrombophilic genotypes or deficient functional natural anticoagulants are equally prevalent among polycythemia vera patients with arterial disease, splanchnic venous thrombosis, or no thrombotic events at all.5  These observations suggested that an additional process – one that was independent of the classically inherited mechanisms that increase the risk of thromboembolism -was responsible for the hypercoagulable state of polycythemia vera. 

The hypercoagulable state of polycythemia vera is the direct result of the JAK2 mutation.  As a consequence of mutated JAK2 function, there is a generalized hypersensitivity to cytokines, with over-expression of procoagulant factors and adhesion molecules at the vascular wall.  Specifically, there is activation of hemostasis, with increased expression of platelet-associated tissue factor microparticles and resultant increased formation of platelet-neutrophil aggregates.6  The JAK2 mutation also results in platelet hypersensitivity to these prothrombotic signals, as they undergo spontaneous activation, product secretion (i.e., thromboxane A2), and aggregation mediated by von Willebrand factor.  Platelet plugs then transiently occlude the microvascular circulation, deaggregate, and recirculate in a defective form.7  The quantitative and qualitative dysfunctions of platelets in polycythemia vera, as well as the hypersensitivity to cytokines at the level of the endothelial wall, explain the hypercoagulable state of the disease. 

The defective circulating platelets also, however, explain the bleeding diathesis that is another, seemingly paradoxical, characteristic of the disease.  Leukocytosis, due to hyperproliferation from JAK2 kinase activity, also contributes to increased thrombotic risk and cardiovascular endpoints.  White blood cell counts over 15 x 10⁹ are positively correlated with increased risk for cardiovascular death, stroke, transient ischemic attack, myocardial infarction, peripheral arterial thrombosis, deep venous thrombosis of the leg or abdominal veins, and pulmonary embolism.8  While the molecular mechanism for this increased thrombotic risk due to leukocytosis has yet to be definitively elucidated, one may hypothesize that increased neutrophil numbers promote enhanced interactions with transient platelet plugs and a prothrombotic endothelial wall, thereby increasing the probability of significant vascular occlusive events.

The JAK2 mutation is also likely responsible for the intense pruritis that did not affect Mr. R, but that affects up to 85% of polycythemia vera patients.  Granulocytosis, a component of the JAK2 mutation-associated panmyelosis, results in increased circulating numbers of both basophils and mast cells.  Although no formal mechanism has been described for basophil hyperactivation and subsequent degranulation, mast cells of polycythemia patients are not only more numerous, but also functionally different from those of normal individuals.  Mast cells from polycythemia vera patients are more resistant to apoptosis and release quantitatively more puritogenic cytokines than do normal mast cells.9  The sequelae of polycythemia vera, therefore, including hypercoagulability and pruritis, are direct results of the JAK2 mutation; it induces both panmyelosis and hypersensitivity of increased circulating numbers of erythrocytes, platelets, and granulocytes to cytokines. 

It is perhaps only fitting, therefore, that the JAK2 mutation also predicts the response of patients with polycythemia vera to chemotherapy.  The presence of the JAK2 mutation and, specifically, its allele burden, is inversely correlated with the daily dose of hydroxyurea needed for adequate bone marrow suppression.  Hydroxyurea inactivates ribonucleotide reductase, thereby inhibiting DNA synthesis and DNA repair, and inducing cell death in S phase.  Higher allele burdens of the JAK2 mutation required smaller daily doses of hydroxyurea, suggesting that the antiproliferative effect of hydroxyurea is most potent in patients with higher levels of JAK2-associated stem cell myeloproliferation.10  The presence of this JAK2 mutation in multipotent hematopoietic stem cells and their tri-lineage descendants dictates the molecular mechanism, hyperviscosity, hypercoagulability, pruritis, and current treatment approach to polycythemia vera. 

It is tempting to speculate, however, about how the therapeutic approach to patients like Mr. R. will evolve in the future. With this focused, well-defined target providing a source for most, if not all, manifestations of polycythemia vera, perhaps specific targeting of the pathophysiologic effects of the V617F chromosomal mutation and its resultant gain-of-function JAK2 cytoplasmic tyrosine kinase may alleviate the manifestations of this myeloproliferative disease.  Small molecule inhibitors of JAK2 are currently under development and in early phase clinical trials.11  While the results of these studies may be neither timely nor conclusive enough to alter the therapy or the course of Mr. R.’s disease, they will take the first step toward investigating the clinical efficacy of JAK2 inhibitors, both specifically in patients with polycythemia vera and more generally in those with other myeloproliferative disorders. 

Commentary By Bruce Raphael, MD, Clinical Professor of Medicine, Division of Hematology NYU Langone Medical Center:

This a very good review of the complications of polycythemia vera and the proposed molecular basis of the disease with its consequent changes in numbers and function of all the hematopoietic cells derived from a stem cell that has a JAK2 mutation. This mutation, unlike many hematologic malignancies with complex cytogenetic and molecular changes, would appear to be solely responsible for the disease state. That said, the same mutation can manifest as essential thrombocythemia while other patients in the heterozygote or homozygous state have similar presentation as p. vera despite the different allelic load. Hence, there is probably a host cellular response to the mutation that affects the phenotypic presentation. The hope that inhibition of the JAK2 derived tyrosine kinase will cure this disease as in BCR/abl positive CML has not been evident in the early studies further complicating the hypothesis of JAK2 driven hematopoiesis.

Emily Slater is a 4th year medical student at NYU School of Medicine

Peer reviewed by Bruce Raphael, MD, Clinical Professor, Department of Medicine Division of Hematology, NYU Langone Medical Center

References:

1.  Kralovics R. et al.  “A gain-of-function mutation of JAK2 in myeloproliferative disorders.”  NEJM 352(2005): 1779-1790. 

2.  Tefferi, A.  “Polycythemia Vera – molecular mechanisms and clinical applications.”  NEJM 356(2007): 444-445.

3.  Poreddy V. and DeLeve, L.D.  “Hepatic circulatory diseases associated with chronic myeloid disorders.”  Clinics in Liver Disease 6(2002): 909-931. 

4.  Denninger M.H., Chait Y., Casadevall N., et al.  “Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors.”  Hepatology 31(2000): 153-159.

5.  Amitrano, L. et al.  “Thrombophilic genotypes, natural anticoagulants, and plasma homocysteine in myeloproliferative disorders: relationship with splanchnic venous thrombosis and arterial disease.”  American Journal of Hematology 72(2003): 75-81.

6.  Falanga A., Barbui T., and Rickles, F.R.  “Hypercoagulability and tissue factor upregulation in hematologic malignancies.”  Seminars in Thrombosis and Hemostasis: Tissue Factor and Cancer 34(2008): 204-210.

7.  Michiels J.J. et al.  “The paradox of platelet activation and impaired function: platelet-von Willebrand factor interactions, and the etiology of thrombotic and hemorrhagic manifestations in Essential Thrombocythemia and Polycythemia Vera.”  Semin Thromb Hemost 32(2006): 589-604.

8 . Landolfi R. et al.  “Leukocytosis as a major thrombotic risk factor in patients with Polycythemia Vera.”  Blood 109(2007): 2446-2452.

9.  Mesa, R.A.  “Itchy mast cells in myeloproliferative neoplasms.”  Inside Blood 113(2009): 5697-5698.

10.  Sirhan S. et al.  “The presence of JAK2V617F in primary myelofibrosis or its allele burden in Polycythemia Vera predicts chemosensitivity to Hydroxyurea.”  Hematology 83(2008): 363-365.

11.  Pardanani A.  “JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical studies and ongoing clinical trials.”  Leukemia 22(2008): 23-30.

 Image courtesy of Wikimedia Commons.

By Caprice Cadacio, MD

Faculty Peer Reviewed

Last month my fellow interns and I were enveloped by the fury that is known as July, the month infamous for shocking young interns into realizing they are now doctors.  I was fortunate to have started on Ambulatory Care meaning my evenings and weekends were still mine to enjoy and in the midst of this August elective, I continue to hold on to my summer.  In a few weeks, however, I will say goodbye as I am literally escorted into the night when I begin a night float rotation.  Until then, I can share my summer reading with you.

In local news, outrage erupted in lower Manhattan this week when the New York City Landmarks Preservation Commission made room to build a mosque near Ground Zero (1).  Interestingly, the structure that the Commission denied landmark status already houses a Muslim prayer site.  Moving west, a federal judge overturned California’s controversial Proposition 8, giving many Golden Staters a reason to rejoice (2).  It seems that America continues to struggle with issues of civil liberties and rights.  We still have a long way to go, America.

World politics is going to get interesting as musician Wyclef Jean declared his candidacy for Haitian president (3).  Speaking of politics, a few politicians’ children made some noteworthy headlines this week.  Rudolph Guliani’s daughter, Caroline, was caught shoplifting in the Upper East Side (4).  Bristol Palin and Levi Johnson called off their engagement again (5).  And Chelsea Clinton wed in Rhinebeck, New York (6).

Lastly, BP is fairly confident that it has the Deepwater Horizon oil rig permanently under control after engineers poured thousands of barrels of mud and cement into the oil well (7).  Amen.

Now onto some medical headlines…

The Annals of Internal Medicine featured CARDIA, a prospective study showing that individuals aged 18-30 with suboptimal LDL levels (>100 as defined by ATP III) had a greater risk of developing coronary calcium, an early marker of coronary artery disease, 15 to 20 years later (prevalence of 44% with LDL scores >160 compared to 8% with LDL scores <70, p<0.001) (8, 9).  Putting the two extremes head-to-head would of course show a hefty difference in coronary calcium levels but there was an increase in odds ratio and proportion of patients with coronary calcium as cumulative LDL scores increased.  Thus, aggressive lifestyle modification early on for patients with suboptimal but not high LDL (100 to 159) has utility in promoting future coronary health.  This study also highlights the discrepancy between ATP III and USPSTF lipid screening guidelines.  ATP recommends starting screening at age 20 while USPSTF recommends starting at 35 for men unless a patient has risk factors (9, 10).  Maybe the CARDIA study will sway some physicians towards using the ATP III guidelines.  The Lancet featured more on lipids, specifically HDL, with Ridker et al’s study using the population and data from the JUPITER trial (11).  HDL is known to be cardioprotective and Ridker et al confirmed that low HDL is a risk factor for vascular events in the placebo group.  This inverse relationship, however, was not observed in the rosuvastatin treatment group.  The authors daresay that residual risk of vascular events even after aggressive statin therapy may not be attributable to low HDL.  Does this mean patients with optimal LDL on statins but low HDL levels should not receive adjunct HDL promoting therapy?  Unlikely.  This study seems to suggest that a patient’s baseline HDL before statin therapy is a better predictor of cardiovascular risk.

Type II diabetes has made major news in the last few weeks with Avandia but let us shift our attention from medication to the role of nutrition in treating diabetes.  Diet modifications are known to improve and slow the progression of diabetes.  The LOADD study in BMJ, examined the effect of intensive nutrition counseling on diabetics with A1Cs over 7% who were already on optimized medication regimens (12).  93 patients were enrolled and randomized to either routine care or routine care with nutritional intervention over 6 months.  After six months the intervention group showed a 0.4% decrease in A1C while the control group showed no change (p = 0.007).  The absolute reduction in A1C may have been even greater with more follow up time.  Thus, let us not be afraid to refer our patients to nutritionists or counsel on nutrition more aggressively when A1Cs won’t budge.

Speaking of diet we turn to the age old debate of low carbohydrate versus low fat diets for weight loss.  The Annals of Internal Medicine featured a study that randomized 307 obese patients to abide by either a low carbohydrate or low fat diet (13).  The primary endpoint was weight loss after 2 years on the assigned diet regimen and group behavioral treatment including self monitoring and relapse management.  After two years there was no significant difference in weight loss between the low carbohydrate and the low fat diet arm, -7.37 (-9.10 to -5.63) and -6.34 (-8.06 to -4.63) respectively (p=0.41).  Although there was an overall weight reduction in both treatment arms, weight loss peaked at 6 months and both groups gained some weight back in the latter part of the study.  In summary, when patients ask about one macronutrient driven diet over the other for weight loss, we can say the debate is still out but there continues to be no proven difference.

This week’s NEJM featured three articles on the treatment of hereditary angioedema (HAE).  About 1 in 50,000 individual are affected by this condition, characterized by low or nonfunctioning C1 inhibitor, a complement pathway inhibitors (14).  Clinical manifestations include painful attacks of mucosal swelling in the skin, GI tract, and upper airway.  For acute HAE attacks, C1 inhibitors have been available in Europe for years now but have only recently been available in the US since 2009 with the drug Berinert.  Cinryze, also a C1 inhibitor, was approved for HAE prophylaxis in 2008 but Zuraw et al. wanted to examine Cinryze’s utility as an agent for acute HAE attacks (15).  In their placebo controlled trial, 68 patients were randomized to receive either placebo or 1000U of C1 inhibitor during an acute attack.  The median onset of relief in the placebo group was over 4 hours compared to 2 hours in the treatment group (p=0.02) but 40% of the treatment group did NOT have relief within 4 hours.  More robust data is likely needed to convince the FDA to bestow another clinical indication upon Cinryze.

Androgens and anti-fibrinolytics were the only available short and long term prophylactic agents for HAE in the US until 2008 when Cinryze was approved.  Zuraw et al included a second set of data from a crossover study confirming the efficacy of C1 inhibitors as prophylaxis for HAE.  The treatment arm received injections of 1000U of C1 inhibitor every three to four days for 12 weeks.  Participants crossed over and received the treatment from the other study arm for another 12 weeks.  Average normalized attack rates for the C1 inhibitor group during both 12 weeks periods were 6.26 compared to 12.73 for the placebo group, (p<0.001).  One caveat against C1 inhibitors: they are expensive. C1 inhibitors may not be cost effective first line agents for long term HAE prophylaxis.

Briefly, icatibant and ecallantide for acute HAE attacks were discussed in two separate articles.  To better understand the effects of these drugs, we can very lightly touch upon the mechanism behind HAE’s clinical manifestations. C1 inhibitor plays a regulatory role in several pathways including the complement, coagulation, fibrinolytic and kallikein-kinin pathways (16).  All of these pathways are interconnected and their relationship ultimately leads to the release of bradykinin.  Bradykinin, the true culprit, mediates pain and leads to vasodilatation and vessel permeability causing the edema of HAE.  In the FAST-2 trial, Cicardi et al showed that icatibant, a bradykinin B2 receptor antagonist, significantly reduced the median time to clinically significant relief compared to tranexamic acid, an anti-fibrinolytic agent (p<0.001).  In the FAST-1 trail, however, Cicardi et al showed that there was an insignificant reduction in median relief time from icatibant versus placebo (p=0.14).  Icatibant is currently only available in Europe but with no significant benefit over placebo, icatibant may not fly in the US unless more placebo-controlled data becomes available.  Wrapping up this discussion on acute HAE treatment, Cicardi et al’s EDEMA 3 study showed that ecallantide, a kallikren inhibitor, had significantly better median treatment outcome scores than placebo at four hours (p=0.004), (14).  Ecallantide received its FDA nod in December 2009 but it was slapped with a black box warning regarding the risk of anaphylaxis.  EDEMA 3, a follow up to EDEMA 1 and 2, reported no anaphylaxis in their participants.

Expect to see more HAE treatment data in the future as the FDA continues to review follow-up studies.  This is great news for sufferers of this rare but debilitating condition.  Future research can focus on self-administration of C1 inhibitors for acute attacks as well as comparing the different treatment modalities to one another.

Ending with some local medical news, 3 cases of the West Nile Virus were confirmed in the NYC area (17).  All three were hospitalized and over the age of 45 and one individual had meningitis.  The war continues against the vector of this virus: those pesky mosquitoes.

Dr. Cadacio is a first year resident at NYU Langone Medical Center

Peer reviewed by Barbara Porter, MD, Section Editor, Clinical Correlations

Picture of Static Kill released by Coast Guard Unified Command, courtesy Wikimedia Commons

References:

1.  http://cityroom.blogs.nytimes.com/2010/08/03/mosque-near-ground-zero-clears-key-hurdle/?scp=1&sq=mosque&st=cse

2.  http://www.nytimes.com/2010/08/05/us/05prop.html?hp

3.  http://blogs.wsj.com/speakeasy/2010/08/04/wyclef-jean-on-his-decision-to-run-for-the-presidency-of-haiti/

4.  http://www.nytimes.com/2010/08/05/nyregion/05giuliani.html?hp

5.  http://www.npr.org/templates/story/story.php?storyId=128960758

6.  http://www.nytimes.com/2010/08/01/nyregion/01chelsea.html?scp=4&sq=clinton&st=cse

7.  http://www.nytimes.com/2010/08/06/us/06spill.html?scp=2&sq=bp&st=cse (BP oil) (BP oil)

8.  Pletcher MJ, Bibbins-Domingo K,  Liu K, Sidney S, Lin F, Vittinghoff E, Hulley S. Nonoptimal Lipids Commonly Present in Young Adults and Coronary Calcium Later in Life: The CARDIA (Coronary Artery Risk Development in Young Adults) Study. Ann of Int Med. 2010 August 3;153(3): 137-146.  http://www.annals.org/content/153/3/137.abstract

9.  http://www.nhlbi.nih.gov/guidelines/cholesterol/atp_iii.htm

10.  http://www.ahrq.gov/clinic/uspstf/uspschol.htm

11.  Ridker PM, Genset J, Boekholdt, SM, Libby P, Gotto AM, Norestgaard BG, Mora S, MagFadyen JG, Glynn RJ, Kastelein JJP. 2010 July 31. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. The Lancet. 2010 July 31. 376 (9738): 333 – 339.  http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960713-1/abstract

12.  Coppell KJ, Kataoka M, Williams SM, Chisholm AW, Vorgers SM, Mann JI. Nutritional intervention in patients with type 2 diabetes who are hyperglycaemic despite optimised drug treatment-Lifestyle Over and Above Drugs in Diabetes (LOADD) study:randomised controlled trial. BMJ. 2010 July 20. 341:3337.  http://www.bmj.com/cgi/search?fulltext=loadd&sortspec=date&x=0&y=0

13.  Foster GD, Wyatt HR, Hill JO, Makris AP, Rosenbaum DL, Brill B, Stein RI, Mohammed BS, Miller B, Rader DJ, Zemel B, Wadden TA, Tenhave T, Newcomb CW, Klein S. Weight and Metabolic Outcomes After 2 Years on a Low-Carbohydrate Versus Low-Fat Diet A Randomized Trial. Ann of Int Med. 2010 August 3;153(3): 147-157.s  http://www.annals.org/content/153/3/147.abstract

14.  Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M, Horn PT, Pullman WE. Ecallantide for the Treatment of Acute Attacks in Hereditary Angioedema. N Engl J Med. 2010 August 5. 363:523-531.  http://www.nejm.org/doi/full/10.1056/NEJMoa0905079

15.  Zuraw BL, Busse PJ, White M, Jacobs J, Lumry W, Baker J, Craig T, Grant JA, Hurewitz D, Bielory L Cartwright WE, Koleilat M, Ryan W, Schaefer O, Manning M, Patel P, Bernstein JA, Friedman RA, Wilkinson R, Tanner D, Kohler G, Gunther G, Levy R, McClellan J, Redhead J, Guss D, Heyman E, Blumenstein BA, Kalfus I, Frank MM. Nanofiltered C1 Inhibitor Concentrate for Treatment of Hereditary Angioedema. N Engl J Med. 2010 August 5.363:513-522  http://www.nejm.org/doi/full/10.1056/NEJMoa0805538

16.  Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann K, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anné S, Björkander J, Bouillet L, Cillari E, Hurewitz D, Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hébert J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Fernández Romero DS, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Wing-Tze Fan WT. Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema. N Engl J Med. 2010 August 5.363:532-541.  http://www.nejm.org/doi/full/10.1056/NEJMoa0906393

17.  http://www.nytimes.com/2010/08/07/nyregion/07nile.html?_r=1&scp=1&sq=west%20nile&st=cse

Image courtesy of Wikimedia Commons.

By Ishmeal Bradley

Faculty Peer Reviewed

 In the first installment, we looked at the history behind consumer advertising of prescription drugs. We also explored the concept of commercial free speech and why this form of advertising is legal. To fully appreciate the controversy about direct-to-consumer (DTC) advertising, we must now examine the commercial effects of these ad campaigns. Do these ads really increase prescription volume and drug costs? Are both physicians and patients affected by the commercials they see on television? In this installment, we will delve into the economics and commercial impact of DTC advertising.

 The Economic Motive behind Pharmaceutical Advertising

 Prescription drugs are a big business in America. There will always be sick patients and doctors ready to treat them. This inevitability has not been lost on the pharmaceutical industry. Like any other business, drug manufacturers seek to minimize costs and maximize profits. One proven way to ensure that your product is more likely to be bought is through advertising. By sidestepping healthcare professionals and advertising directly to consumers, though, some critics argue that drug companies are creating demand for prescription drugs that may not be appropriate. Regardless of whether the increased prescription writing is appropriate, one cannot deny the fact that advertising works. Shannon Brownlee, senior fellow at the New America Foundation, in her book Overtreated: Why Too Much Medicine Is Making Us Sicker and Poorer, quoted a statistic that shockingly showed that every dollar the pharmaceutical industry spends on advertising generates $4.20 in increased sales.¹

 One only has to look at marketing and sales data to see how profitable advertising can be. In 2000, the top ten most heavily advertised drugs (including blockbusters like Vioxx, Paxil, and Claritin) cost $926 million to promote to consumers. In a market where there were 9,880 other drugs also advertised, these ten drugs took up 37% of the advertising dollars. The drug companies were handsomely rewarded for their investment in ads; sales of these ten drugs alone topped $16 billion.²

 Effects of DTC Advertising

 The central question behind the DTC ad controversy is what effects (if any) do these ads have on physician prescribing behavior and drug costs? As noted above, advertising plays a tremendous role in increasing the number of prescriptions written. But is this increase appropriate?

 Regarding the growth in prescriptions, Pharmaceutical Research and Manufacturers of America (PhRMA), the industry lobby, argues that a positive effect of DTC advertising is that more patients are seeking medical care and are consequently being screened for common conditions.³ Although this argument has an element of truth, it does not match reality. Yes, better primary care and preventive screening will catch more patients with hypertension, depression, diabetes, and dyslipidemia. And yes, these newly diagnosed patients will require medications, sometimes indefinitely. PhRMA would have more credibility, though, if the DTC ads actually focused on medications used to manage chronic diseases, especially with hopes of reducing long term complications. When the top twenty advertised drugs in 2005 include Cialis ($110 million), Lamisil ($110 million), and Lunesta ($224 million), it becomes clear that drug companies are spending considerable resources to promote lifestyle drugs rather than public health.

 One considerable concern about DTC advertising is its potential effects on prescribing behavior. To better study this, Kravitz et al. performed a randomized control trial to see if patients’ requests for an advertised antidepressant, Paxil, affected which antidepressant, if any, the physician prescribed.⁴ In their study, they used standardized patients exhibiting symptoms of either major depression or adjustment disorder. These SPs presented to primary care physicians in New York and California. To determine if a patient’s request for a specific advertised medication effected which antidepressant the physician prescribed, the SPs were told to either ask for Paxil by name, ask for a general antidepressant, or neither. Paxil was chosen because, at the time of the data collection, it was heavily advertised ($92 million spent in 2000), priced higher than fluoxetine (which had become generic at that time), and was on the formulary of the large health insurance plans in these two states. Focusing on the major depression group, of those that asked for Paxil by name, 27% received it, while 25% received another antidepressant (and 47% received nothing). By comparison, of those that asked for any antidepressant, only 1% received Paxil and 74% received another drug.

 Their results showed that for those patients with symptoms of major depressive disorder and who asked for Paxil, they were more likely to receive it (OR-2.72). They also showed that even those patients who made only a general request were more likely to be started on treatment with any antidepressant, not just Paxil (OR-7.99).  The study authors did not examine whether Paxil was a legitimate first-line agent to use, but their results highlight the fact that patient requests do increase prescriptions for that particular drug, even when there are other (potentially cheaper) options available.

 Admittedly, the pressure to prescribe an advertised medication that a patient asks for by name can be great. Physicians may feel compelled to comply with the patient’s wishes. In an FDA survey published in 2004, the agency posed this question to both primary care physicians and specialists: “To what extent did the patient’s expectation influence your decision to prescribe or not prescribe?” For the primary care physicians, only a third felt that the patient’s expectations had no influence over them at all (34%). However, a majority thought that there was some pressure (a little bit to somewhat) to prescribe (52%). On the other hand, the specialty physicians felt that they were less influenced by patient requests (51% for no influence and 49% for some degree of influence); they also felt less pressured than the primary care physicians (58% felt no pressure to prescribe at all).⁵

 The Kravitz study gives more credence to the idea that DTC advertising increases prescription volume. Who ultimately pays for this advertising? The costs of drug marketing—along with research and development costs—are passed on to consumers. PhRMA counters, however, the popular belief that DTC advertising significantly increases drug costs.

 The rise in prescription drug costs and spending is multifactorial.⁶ As the American population ages, the prevalence of chronic conditions also increases. Treating chronic diseases, like depression, hypertension, and diabetes, is costly in the long term. Also, as professional organizations like the American Diabetes Association or the American College of Cardiology recommend tighter glycemic control or more stringent post-myocardial infarction goals, more medications will have to be prescribed to adhere to these ever-changing guidelines. Finally, as newer, more efficacious medications come to the market, the shift towards these better drugs will unfortunately increase the amount of healthcare dollars spent on prescription drugs. Better disease management, although good for the patient, will result in higher drug spending, be it through more prescriptions written per patient or price increases for individual drugs.

 Advertising, as expected, does play a profound role in increasing prescription volume, especially for newer medications. Drug manufacturers would hardly waste the money on multimillion dollar campaigns if this were not true. Furthermore, physicians, as stalwart as they may try to be, are not immune to the effects of advertising. The data do show that physicians are more likely to prescribe a medication (even though it may not be the one advertised) than not if a patient requests one. This is not necessarily bad. In the Kravitz study, those symptomatic patients that asked for any antidepressant were much more likely to receive adequate depression care than those that asked for nothing at all. As PhRMA points out, better medical care may actually be more costly and the increase in prescription drug costs may not be due solely to advertising. Regardless of the actual numbers, PhRMA still must counteract the public’s often negative perceptions about DTC advertising. In the final installment, we will examine how the public and physicians feel about advertising, the Vioxx debacle and its impact on the industry, and propose a potential solution to this controversy.

Dr. Bradley is a Section Editor, Clinical Correlations

Peer reviewed by  Scott Sherman, MD, MPH Associate Professor of Medicine and Psychiatry at NYU Langone Medical Center

References:

1. Weintraub, Arlene. “More Frequent Dose of Dollars for Drug Ads.” BusinessWeek. August 15, 2007.

 2. National Institute for Health Care Management. “Prescription Drugs and Mass Media Advertising, 2000.” Available at http://nihcm.org/~nihcmor/pdf/DTCbrief2001.pdf. Accessed August 18, 2009.

 3. Pharmaceutical Research and Manufacturers of America. “Pharmaceutical Marketing in Perspective: Its Value and Role as One of Many Factors Informing Prescribing.” July 2008. Available at http://www.phrma.org/files/PhRMA%20Marketing%20Brochure%20Influences%20on%20Prescribing%20FINAL.pdf. Accessed July 22, 2009.

 4. Kravitz, Richard L. et al. “Influence of Patients’ Requests for Direct-to-Consumer Advertised Antidepressants: A Randomized Controlled Trial.” JAMA 2005;293:1995-2002.

 5. Food and Drug Administration. “Patient and Physician Attitudes and Behaviors Associated with DTC Promotion of Prescription Drugs: Summary of FDA Survey Research Results.” Final Report November 19, 2004. Available at http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm109593.htm. Accessed July 22, 2009.

 6. Dubois, Robert W. et al. “Explaining Drug Spending Trends: Does Perception Match Reality?” Health Affairs 2000;19,2:231-9.

Image courtesy of Wikimedia Commons.

By Brad Pfeffer, MD

Faculty Peer Reviewed

Case: A 75- year-old non-smoking male with a history of type II diabetes, hypertension and hyperlipidemia comes to clinic with several months of stable anginal chest pain provoked by ten blocks of exercise with no change in exercise tolerance. He has seen you several times over the past year and has been placed on aspirin, beta blockers, calcium channel blockers and long acting nitrates with some relief of symptoms. In addition, he is on atorvastatin with an LDL of 77. His blood pressure is well controlled at 122/78 and his heart rate is 62.  His BMI is 25.   An EKG shows a normal sinus rhythm at 62 with no evidence of prior myocardial infarction. A transthoracic echo shows a normal ejection fraction with no wall motion abnormalities. An adenosine nuclear stress test was performed that showed a small reversible perfusion defect in the territory of the distal circumflex with a normal ejection fraction.  The patient asks if there are any further medical options or if it isnecessary for him to have a percutaneous intervention.   

Coronary artery disease continues to be a leading cause of death among both women and men. Angina pectoris is one of several syndromes that results from coronary artery disease. The symptoms of angina manifest as chest discomfort resulting from insufficient supply of oxygen to the heart with increasing demand.  In the United States, 16 million adults suffer from coronary artery disease and of those 9.1 million have angina. The total cost of coronary artery disease is 475.3 billion dollars [1]. Moreover, the number of patients suffering from and the health care cost of angina will continue to rise with a growing aging population.  

The traditional medical management of chronic stable angina attempts to balance oxygen supply and demand and prevent thrombosis while minimizing cardiovascular risk factors through smoking cessation, weight loss, blood pressure, cholesterol and diabetic management.  Medical management includes the use of beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy including aspirin or clopidogrel in patients intolerant of aspirin [2-3]. Beta-blockers should be titrated to reduce the resting heart rate to 55-60 beats per minute. In more severe cases of angina, beta-blockers can be titrated to a heart rate less than 50 if no adverse symptoms or heart block occur.  Sublingual nitroglycerin or spray nitroglycerin can be used for immediate relief of angina or prophylaxis prior to anginal causing activities. Long acting nitrates, such as isosorbide dinitrate, mononitrates, transdermal nitroglycerin patches, and nitroglycerin ointment can be used to prevent angina. Patients must have a nitrate free period of 8 to 12 hours in order to prevent nitrate tolerance [4].  Long acting nitrates can be titrated for prevention of symptoms as long as no hypotension or side effects such as headaches develop.

 There is little data to suggest that dual antiplatlet therepy is beneficial in patients with stable coronary disease. Data from the CHARSIMA trial has shown that dual antiplatelet therapy with aspirin and plavix does not reduce the rate of cardiovascular events but does increase the rate of bleeding when compared to aspirin alone [5]. However, in post hoc analysis the CHARISMA trial did show a significant reduction in cardiovascular events in patients with stable chronic angina with prior history of MI, stroke or symptomatic peripheral arterial disease [6-7]. As a result, dual antiplatelet therapy may be useful for patients at the highest risk for adverse events or who have recently undergone percutaneous coronary intervention (PCI).

Revascularization continues to be the routine treatment for refractory angina. According to the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Interventions patients continuing to have angina despite medical optimization (beta-blockers, calcium channel blockers, nitrates and antiplatelets therapy) should undergo PCI if there is a low likelihood of mortality and morbidity and high likelihood of success [8].  However, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) sought to compare clinical endpoints in patients receiving medical management alone verse medical management plus PCI.  

The COURAGE trial compared cardiovascular outcomes of PCI as an initial management for chronic stable angina to optimal medical therapy alone. In the COURAGE trial, 2287 patients with evidence of ischemia or significant coronary artery disease where randomized to receive PCI plus medical optimization therapy or medical optimization alone. All patients received ischemic therapy with beta-blockers, calcium channel blockers, long and short acting nitrates, as well as antiplatelet therapy with either aspirin or clopidogrel and aggressive lipid-lowering therapy, including administration of a statin with or without ezitimibe. In the initial follow up period, there was a statistically significant reduction in the number of anginal free patients in the PCI group, at one and three years (respectively 66% vs 58%, P< 0.001 and 72% vs 67%, P=0.02). The benefit of PCI persisted at five years. However, at five years, the number of patients that were free of angina, between the two groups, was not statistically significant (74% in the PCI group and 72% in the medical therapy group, P=0.35). It is important to note that 36.6% of all patients in the medical therapy group crossed over to the PCI group by five years. The study did not find any statistical difference between the PCI and medical therapy group in composite death, myocardial infarction and stroke (respectively 20% and 19.5%, P=0.62). [9]. This study supports the idea that PCI is not superior to optimal medical management in terms of death, myocardial infarction and stroke in patients with stable coronary artery disease. However, PCI continues to be beneficial for anginal symptom relief, but can be safely deferred in patients with stable coronary artery disease who are optimally medically managed.

How should you treat patients that continue to have anginal symptoms despite lifestyle and dietary modifications and the addition of anginal medications such as beta-blockers, calcium channel blockers, nitrates and antiplatelet therapy? Or how do you treat patients that have undergone catheterization with no known lesion or are not candidates for catheterization? Is there any medical therapy beyond the current guidelines?

 Ranolazine (Ranexa) was approved by the Food and Drug Administration for chronic stable angina in 2006. The use of ranolazine has been shown to be effective to improve anginal symptoms in several studies [9-10]. Ranolazine is a piperazine derivative that works through the inhibition of the late inward sodium current in cardiac cells.  Inhibition of late inward sodium current in cardiac cells leads to a decrease in intracellular calcium, increased myocardial relaxation during diastole and inhibits the rapidly activating component of the delayed rectifier potassium current (IKr). Although ranolazine inhibits the delayed rectifier potassium current and causes a modest increase in QTc, it is not associated with proarrhythmic activity [11]. However, given the possibility of prolongation of the QTc, a baseline EKG and EKG after initiation should be obtained. In clinical study, ranolazine does not statistically affect heart rate or blood pressure [12].

 The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, a multi-national, randomized, double-blind, placebo-controlled study, was the first trial of ranolazine SR 500, 1000 and 1500 mg BID  monotherapy in patients with chronic angina. The study population consisted of patients older than 21 years of age with well-documented coronary artery disease, angina pain for at least three months that responded to beta-blockers, calcium channel blockers and/or long acting nitrates. During the study, all patients discontinued their anti-anginal treatment.  Comparison of exercise stress testing before and after treatment showed that exercise duration increased with ranolazine 500, 1,000, and 1,500 mg twice daily by, respectively, 94, 103, and 116 seconds (P< 0.005).  The increase in exercise performance from monotherapy ranolazine is similar to those reported for maximal doses of nitrates, beta-blockers and calcium channel blockers. [12]

 The Combination Assessment of Ranolazine In Stable Angina (CARISA) trial examined the exercise tolerance, angina attacks and nitroglycerin use of 823 patients with symptomatic chronic angina taking standard doses of atenolol (50 mg), amlodipine (5 mg), or diltiazem (180 mg once daily) before and 12 weeks after being randomized to receive 750 mg or 1000 mg twice daily of ranolazine or placebo.  Ranolazine reduced the mean number of angina attacks per week from 3.3 ± 0.3 for placebo to 2.5 ± 0.2 for 750 mg (p = 0.006) to 2.1 ± 0.2 for 1000 mg (p < 0.001) ranolazine. It also significantly reduced nitroglycerin consumption (p < 0.02). Exercise duration increased significantly with ranolazine by 115.6 seconds from baseline in both ranolazine groups vs 91.7 seconds in the placebo group (P = .01).  The time to onset of anginal symptoms increased significantly in both the 750 mg and 1000 mg group (respectively 144 seconds, P=0.01 and 140.3 seconds, P=0.03).  There were no clinically significant changes in blood pressure or heart rate. These finding were independent of background therapy, and persisted for 12 weeks [10]. Similar reduction in angina symptoms were reported in the Efficacy of Ranolazine In Chronic Angina (ERICA) trial that examined the use of amlodipine (10 mg) and ranolazine (1000 mg twice daily) [13]. Post hoc analysis of diabetics in the CARISA trial showed a significant reduction in HbA1C levels [14].

Chronic angina is a debilitating disease that impacts millions of Americans. The mainstay of treatment involves dietary and lifestyle modifications along with beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy. Current guidelines reflect these mainstays of treatment. Ranolazine should be used as second line treatment when beta-blockers, nitrates and calcium channel blockers have failed to relieve symptoms. Unlike other anti-anginal medications ranolazine does not affect hemodynamics. As a result, ranolazine should be used in addition or alone when the titration or use of beta-blockers, calcium channel blockers or nitrates is limited by blood pressure or heart rate.  The most common side effects of ranolazine include dizziness (11.8%) and constipation (10.9 %). These symptoms led to discontinuation of ranolazine in 0.9% and 0.5% of patients, respectively [15].  Syncope and orthostatic hypotension has been seen in a minority of patients receiving 1000 mg twice daily. This may be due to alpha blockade with higher doses of ranolazine and possible drug interaction between higher doses of ranolazine and diltiazem [10]. As a result, it is recommended that clinicians start at the lowest possible dose of ranolazine and titrate up to effectiveness and tolerability. Ranolazine is contraindicated in patients with preexisting long QT prolongation intervals and should be used with caution with other medications that prolong QT intervals. It is also contraindicated in clinically significant liver disease. It should be used with caution in patients with Childs-Pugh class A or B liver impairment.  Ranolazine is a potent inhibitor of CYP3A4, thus it should be used with caution in combination with other drugs that utilize CYP3A4 such as diltiazem and verpamil. When used with medications that use CYP3A4 the dose of ranolazine should not exceed 500 mg twice daily.  Ranolazine also interferes with the metabolism of digoxin and simvastatin, thus dose reduction of these drugs may be necessary.

In conclusion, the addition of ranolazine to current guidelines may defer the decision for patients with chronic angina to go for PCI. It is likely that ranolazine may be part of future chronic angina management guidelines and should be considered in patients with chronic stable angina.

Commentary by Sohah Iqbal, MD, Division of Cardiology

As the above thoughtful review has highlighted, medical therapy for coronary disease and chronic stable angina continues to evolve. Ranolazine, anecdotally and in clinical trials, has been shown to improve exercise capacity in those with activity limiting angina. There are 2 key criteria that need to be met before adding ranolazine: (1) Identifying patients with chronic stable angina and (2) Ensuring that these patients are on optimal medical management.

Angina that progressively limits patient in their basic activities of daily living or angina changing in character and pattern need to be identified as unstable in nature and should be treated via a different algorithm. Also, before adding ranolazine, patients with coronary artery disease and chronic stable angina must be on medications that have been shown to reduce clinical end points such as aspirin, beta blockers, statins, and in certain subgroups, ace-inhibitors.  Once these two criteria have been met, ranolazine is an excellent additional agent to manage chronic stable angina.

 Dr. Pfeffer is Chief Resident at NYU Langone Medical Center

Peer reviewed by Sohah Iqbal, MD, Division of Cardiology, NYU Langone Medical Center

References:

1.         Rosamond, W., et al., Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008. 117(4): p. e25-146.

2.         Trujillo, T.C. and P.P. Dobesh, Traditional management of chronic stable angina. Pharmacotherapy, 2007. 27(12): p. 1677-92.

3.         Fraker, T.D., Jr., et al., 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation, 2007. 116(23): p. 2762-72.

4.         Gibbons, R., Abrams, J, Chatterjee, K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina.   [cited 2009 September 13]; Available from: http://www.acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.

5.         Bhatt, D.L., et al., Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med, 2006. 354(16): p. 1706-17.

6.         Bhatt, D.L., et al., Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol, 2007. 49(19): p. 1982-8.

7.         Bakhru, M.R. and D.L. Bhatt, Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin? Cleve Clin J Med, 2008. 75(4): p. 289-95.

8.         Smith, S.C., Jr., et al., ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation, 2006. 113(7): p. e166-286.

9.         Wilson, S.R., et al., Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol, 2009. 53(17): p. 1510-6.

10.       Chaitman, B.R., et al., Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 2004. 291(3): p. 309-16.

11.       Keating, G.M., Ranolazine: a review of its use in chronic stable angina pectoris. Drugs, 2008. 68(17): p. 2483-503.

12.       Chaitman, B.R., et al., Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004. 43(8): p. 1375-82.

13.       Stone, P.H., et al., Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol, 2006. 48(3): p. 566-75.

14.       Timmis, A.D., B.R. Chaitman, and M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J, 2006. 27(1): p. 42-8.

15.       Koren, M.J., M.R. Crager, and M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol, 2007. 49(10): p. 1027-34.

Faculty Peer Reviewed

One of the many advantages of being on elective this week was that I finally had the pleasure of spending time outside and experiencing the heat wave with millions of other sweaty, malodorous New Yorkers. Our sultry plight, however, was dwarfed by far graver weather problems in other parts of the world: record floods in Iowa, Pakistan, Afghanistan, and China have killed hundreds, if not thousands of people, while a destructive heat wave has swept over Russia, a country better known for its lethal winters (1)(2)(3)(4)(5).  Returning to news at the local level, New York veterans were left out of a decision by the Department of Veterans Affairs to allow patients treated at its hospitals and clinics to use medical marijuana (6). The decision does not apply to patients at our VA since medical marijuana is not legal in New York, but for once a small state west of the Hudson may save the day…medical marijuana is legal in New Jersey. Lest you start to feel depressed about the state of our state, Chelsea Clinton and Marc Mezvinsky chose to marry in the great state of New York this weekend even though neither are native New Yorkers (7). Mazel tov to the happy couple; may neither of you follow in your fathers’ missteps.

Medical news this week is a hodgepodge of topics as always, but several interesting oncology articles made headlines in major medical journals. In honor of this August being the 90^th anniversary of the passage of the 19th amendment (giving women the right to vote), this week’s Primecuts will continue in the tradition of gender equality by giving equal attention to developments in the diagnoses and treatment of prostate and breast cancers.

 Prostate Cancer

 And the controversy continues…

A large, retrospective study published in the Archives of Internal Medicine this week should raise the eyebrows of male patients and urologists alike (8). In this study, 66% of men ages 65 to 74 who had low-risk disease and PSA values below 4.0 ng/mL were treated with either a radical prostatectomy (RP) or radiation therapy (RT). However, these men with low risk disease…have low risk disease. If the side effects of RP and RT were minimal, such vigilance might be appropriate since early intervention has led to a significant decline in deaths from prostate cancer. Unfortunately, such procedures have serious, and not uncommon, side effects such as impotence and incontinence. While this article does not comment on whether men should still undergo annual PSA testing, it emphasizes the importance of counseling male patients appropriately regarding the risks and benefits of aggressive interventions. While this study does not cast doubt on the seriousness and potential lethality of high grade prostate cancer, it does strengthen the argument that prostate cancer as a whole is overdiagnosed and overtreated in this country. 

 Progress in prostate cancer care?

In other prostate-related news this week the New England Journal of Medicine published the results of a randomized, placebo-controlled trial of a therapeutic cancer vaccine for the treatment of treatment-resistant prostate cancer (9). The study enrolled over 500 men with minimally symptomatic, metastatic prostate cancer whose disease was refractory to androgen-deprivation therapy.  Men who received three rounds of the vaccine, known as sipuleucel-T, had a median survival of 4.1 months longer than those who received the placebo. While these results are exciting and may offer the hope of longer survival to a subset of prostate cancer patients, the feasibility of making this vaccine widely available is questionable. While the nitty-gritty details behind the vaccine’s procurement are enough to make a clinician’s head spin, it is important to note that making the vaccine is a labor-intensive process: each vaccine dose is patient-specific since it is made using the patient’s own antigen-presenting cells, and each round of vaccine takes two to three days to develop.  The cost of the vaccine remains to be seen, but it is likely to be very high. In an age of spiraling healthcare spending, particularly at the end of life, the cost of this vaccine may turn out to be a limiting factor in its use.

 Breast Cancer

 Ma’am, you may need that mammogram…in the future

What if a genetic test could stratify women into risk groups and tailor breast cancer screening recommendations accordingly? Such recommendations already exist for carriers of highly-penetrant BRCA1 and 2 genetic mutations, but such women make up a small minority of breast cancer patients.  A study published in JAMA this week attempted to identify the odds ratios for breast cancer associated with 14 individual single-nucleotide polymorphisms (SNPs) that have been linked to breast cancer in previous studies (10). This study compared the genotypes of over 10,000 women who had been diagnosed with breast cancer to those of over 10,000 women who had never been diagnosed with breast cancer. The study confirmed statistically significant, but not clinically significant, associations with breast cancer risk for 7 of the 14 SNPs examined.  When the effects of the 7 SNPs most strongly associated with breast cancer risk were combined using a polygenic risk score, the cumulative incidence of breast cancer among women in the top fifth was twice that in the bottom fifth, though still quite low (8.8% vs 4.4%). Although polygenic risk scores are not useful for stratifying breast cancer risk among women at this juncture, it is a tool that may prove clinically useful in the future.

 A PARP-inhibitor shows promise

A proof-of-concept trial published in The Lancet this week showed encouraging results for a new drug intended to treat advanced breast cancer in patients who carry a BRCA1 or 2 mutation (11). The drug, called Olaparib, is a member of a class of drugs known as poly(ADP-ribose) polymerase inhibitors, a.k.a. PARP-inhibitors. While a detailed description of Olaparib’s mechanism of action is beyond the scope of this article (and perhaps beyond the scope of its author), at a very basic level Olaparib is thought to induce synthetic lethality in BRCA-deficient cells by preventing PARP proteins from repairing single stranded DNA breaks. In this particular study, the primary endpoint was defined as the objective response rate (ORR) as measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Patients who received 400mg of Olaparib twice daily had an ORR of 41% and a median progression-free survival of 5.7 months, while those who received 100mg of Olaparib twice daily had an ORR of 22% and a median progression-free survival of 3.8 months.  The results of future phase 3 trial(s) will make or break the future of this potentially exciting new drug.

 Dr. Hemel is a first year resident at NYU Langone Medical Center

Peer reviewed by Mike Poles, Section Editor, Clinical Correlations

References:

1. http://www.nytimes.com/2010/07/26/us/26iowa.html

2. http://www.nytimes.com/aponline/2010/07/31/world/asia/AP-AS-Pakistan-Floods.html

3. http://www.reuters.com/article/idUSTRE66U0PM20100731

4. http://www.bbc.co.uk/news/world-asia-pacific-10784666

5. http://www.nytimes.com/2010/07/30/world/europe/30moscow.html

6. http://www.nytimes.com/2010/07/24/health/policy/24veterans.html

7. http://www.nytimes.com/2010/07/18/fashion/18CHELSEA.html

8. Shao YH, Albertsen PC, et al. Risk Profiles and Treatment Patterns Among Men Diagnosed as Having Prostate Cancer and a Prostate-Specific Antigen Level Below 4.0 ng/mL. Arch Intern Med. 2010;170(14):1256-1261.

9. Kantoff PW, Higano CS, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010; 363:411-422.

10. Reeves GK, Travis RC, et al. Incidence of Breast Cancer and Its Subtypes in Relation to Individual and Multiple Low-Penetrance Genetic Susceptibility Loci. JAMA. 2010;304(4):426-434.

11. Tutt AT, Robson M, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. The Lancet. 2010;376(9737):235-244.

By Ishmeal Bradley, MD

Faculty Peer Reviewed

 Advertising is everywhere. That should come as no surprise to anyone who has lived in modern America. It is impossible to turn on the television, ride the subway, or even sort through the daily mail without coming across an ad for a new car, a soft drink, or the latest digital toy. These advertisements have only one goal: to entice you to buy their products. This is harmless enough when these ads refer to shoes, peanut butter, or shampoo. But what about drugs, especially prescription medications? Pharmaceutical companies and their hired advertising firms are increasingly marketing their wares directly to consumers and bypassing healthcare providers. Are drug companies really doing the public a service by disseminating this type of information? Can the motive to increase prescription volume (and profits) be reconciled with this goal of consumer education? Is this form of advertising really in the public’s best interest?

 To better explore direct-to-consumer (DTC) advertising in this three-part series, we must first examine the roots of commercial advertising of drugs, the role of the FDA in regulating advertising, and the legal protections surrounding commercial free speech. With that historical and legal context, we will then look at the economics and effects of DTC advertising. Finally, we will conclude with perceptions (both patient and physician) about DTC advertising and propose a possible solution to the controversy.

 Historical Trends in Direct-To-Consumer Advertising

 The stunning imagery of “the purple pill”, the bumblebee encouraging us to ask our doctors about Nasonex, or the “Viva Viagra” commercials, are relative newcomers to the public sphere. Not until 1997 did the FDA permit broadcast advertisements for prescription drugs. Currently, only two countries in the world, the United States and New Zealand, allow this type of advertising. Early print advertisements dating back to the 18^th century were only for over-the-counter medications. These ads made inflated claims that their products could cure everything from alcoholism and obesity to dyspepsia. Unfortunately, before the early 1900s, there was little governmental oversight over drug safety or efficacy. By the turn of the 20^th century, a glut of new products flooded the American pharmaceutical market, many with dubious claims of effectiveness. Congress, wanting to ensure that drugs on the market were safe for consumer use, passed the Food, Drug, and Cosmetic Act in 1938 which gave the FDA the authority to mandate that drug companies prove their products safe before marketing them. Congress later amended the original law in 1962 to grant the FDA additional authority to regulate advertisements of prescription drugs and to further require that pharmaceutical companies prove that their products were not only just safe, but also efficacious.¹

 During this time, pharmaceutical companies, while complying with federal regulations, advertised their products only to healthcare professionals. OTC medications were still advertised to the public, but advertising prescription medications over the heads of physicians was thought socially unconscionable. This changed in 1981 when Merck published the first DTC ad for a prescription medication, Pneumovax, in Reader’s Digest. Following Merck’s lead, several other companies began to print consumer-directed ads. Then in 1983 the first televised DTC ad, for Boots Pharmaceutical’s Rufen (prescription strength ibuprofen), aired. Given concerns about the possible negative—but  unproven—effects of DTC advertising of prescription medications, the FDA imposed a moratorium on advertisements later that year to further study the issue. After two years, the FDA suspended the moratorium in 1985. Although the agency felt that “direct to the public prescription advertising was not in the public interest”, it lifted the moratorium due to concerns over commercial free speech; it also believed that current guidelines regulating advertising were sufficient enough to protect consumers.² Furthermore, the agency explicitly warned that these DTC ads “should be held to the same standards as those directed to physicians.”³

 For the next twelve years, advertisements were primarily focused in print media. This was because of the “brief summary” requirement. The FDA required all prescription drug ads to disclose a brief summary which included all the warnings, precautions, contraindications, and adverse events of a particular drug. This was difficult to accomplish in a one-minute television or radio ad, essentially barring broadcast advertisements.⁴ Under pressure from the pharmaceutical lobby, the FDA conducted a series of public hearings in 1995 to reconsider its restrictions on DTC advertising. Then in August 1997 the FDA released a new set of guidelines entitled “Guidance for Industry: Consumer-Directed Broadcast Advertisements.” This statement, publicized more as a reinterpretation of current regulations, drastically changed the way that pharmaceutical companies were allowed to advertise. To make broadcast advertising easier, the new statement no longer mandated the lengthy brief summary and replaced it with the “adequate provision” clause. Adequate provision meant that since advertisements no longer had to present all the risks and precautions, they must provide consumers with alternative means of acquiring this information by referring them to a toll-free telephone number, a website address, a concurrently running print advertisement, or referral to a healthcare provider.⁴ Also, broadcast advertisements had to comply with a new “major statement” clause which required that only the major risks and most common adverse effects be disclosed. With these new rules, pharmaceutical companies could easily saturate the airwaves with ads, as long as the ads counseled patients to “talk to your doctor.”

 There are three types of DTC advertisements, only one of which is subject to regulation.⁵ The first are the so-called “help-seeking” advertisements. These advertisements describe a disease or condition, but they do not discuss specific treatments. Instead, they encourage the consumer to discuss the condition with their doctor. The second type are “reminder” advertisements. In these ads, the drugmaker can mention a particular medication, but cannot give information on the drug’s indication or make claims about efficacy.⁴ These first two types of ads are not required to disclose any risk information because they do not discuss benefits.

 The third type, the one from which the controversy stems, are the “product-claim” ads. These discuss both the drug and the condition for which is supposed to be used. The FDA requires drugmakers to include a “fair balance” of risks and benefits, and that the ads contain both the major statement and adequate provision according to the 1997 guidelines.⁴

Since the relaxation of advertising rules in 1997, there has been tremendous growth in the amount of money spent on DTC ads, both print and broadcast. In 1996, pharmaceutical companies spent $11.4 billion on all promotional spending (most of which was spent on advertising to healthcare professionals and free samples). Of this, 14.2%, or $985 million, was spent on DTC ads. By 2005, total promotional spending had nearly tripled to $29.9 billion, while the amount spent on DTC ads quadrupled to $4.2 billion.⁶ Indeed, by the year 2000, Merck was spending more money advertising its soon-to-be defunct painkiller, Vioxx ($160 million), than Budweiser ($146 million), Pepsi ($125 million), or Nike ($78 million).⁷ Those ads paid off; drug sales for Vioxx topped $1.5 billion that year.

 Role of the FDA

 Although Congress has afforded regulatory power to the FDA, the agency has faced serious challenges to its ability to ensure that DTC advertisements are accurate and reasonable. One hurdle that hampers the FDA is the lack of manpower . For example, the number of promotional pieces submitted to the FDA for review has ballooned from 32,000 in 1999 to nearly 53,000 in 2004.⁸ Despite this growth in the volume of consumer ads, staffing at the FDA’s Division of Drug Marketing, Advertising and Communications has been relatively stagnant. In 2002 when drug companies spent $2.9 billion on advertising, there were only three staff members to review these ads. By 2004 there were four staff members, even though spending on ads had increased to $4.5 billion.⁶ Furthermore, with the ever-increasing number of ads produced, the FDA has not been able to keep up with pre-market review. The percentage of broadcast advertisements that underwent FDA review before airing fell from 64% in 1999 to 32% by 2004.⁶

 Also, in this decade, there has been a change in the culture of the FDA. Under the conservative leadership of Secretary Tommy Thompson in 2002, the Department of Health and Human Services began requiring that all regulatory letters to industry about advertising violations first be approved by the FDA’s Office of Chief Counsel.⁶ This review process greatly increased the amount of time it took for warning letters to reach offending advertisers, so much so that by the time the letters were released, the ads were already off the air.

 Coupled with the declining real power of the FDA, is a general misconception by the public of the FDA’s role in regulation. According to one study, 50% of consumers thought that DTC ads had to be pre-approved by the government; 43% believed that only drugs that were completely safe could be advertised; and 21% thought that only extremely effective drugs could be advertised to the public.⁹ These misguided beliefs and the diminishing ability of the agency to wield regulatory authority over the pharmaceutical industry can create a false sense of security in the objectivity and truthfulness of drug advertisements.

 Commercial Free Speech and First Amendment Rights

 Legislatures, both state and federal, have also weighed in on the legality of direct-to-consumer advertising of prescription drugs. Two high-profile cases in the 1970s brought the idea of “commercial free speech” into the judicial vernacular. In the 1976 case of Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, the Supreme Court ruled that state laws could not block pharmacies from advertising prescription drug prices.¹⁰ When Justice Harry Blackmun, writing for the majority, declared that “the free flow of commercial information is indispensable,” he extended First Amendment protection to commercial advertising. The decision was not unanimous, though. Then- Associate Justice William Rehnquist, the lone dissenter, protested the notion that advertising was worthy of the same free speech protections afforded to political and social rhetoric. In his dissenting opinion, he wrote that “there are sufficient dangers attending [the] widespread use [of pharmaceuticals] that they simply may not be promoted in the same manner as hair creams, deodorants, and toothpaste.”¹

 To determine whether limits on commercial free speech are acceptable, the Supreme Court established the “Central Hudson Test.” These guidelines were based on the 1980 case, Central Hudson Gas & Electric Corp. v. Public Service Commission of New York, wherein the state of New York wanted to prevent utility companies from broadcasting ads encouraging consumers to use more electricity. The Central Hudson Test has three main criteria for determining whether a restriction on commercial free speech is permissible: is the speech misleading (if so, then the speech can be banned); does banning the speech advance a government interest (if not, then the government has no role in attempting to regulate the speech); and can that interest be advanced through less restrictive means (if so, then the less restrictive means should be undertaken). One could argue that a ban on prescription drug advertising may indeed serve a government interest, that of protecting consumers from potentially misleading ads, but neither industry nor consumer groups have brought forth a case, for fear of losing an incredibly murky constitutional battle. This did not stop U.S. Representative Henry Waxman (D-Calif.), however, from trying to attach a rider to a drug safety bill in 2007 that would have banned DTC ads for drugs that had been on the market for less than three years.¹¹ The bill passed without his amendment.

 Insights from the Medical Profession

 The American Medical Association issued its own statement on DTC advertising in 1999.¹² The AMA currently asks physicians to remain vigilant for advertisements that promise unfounded benefits and for those that do not comply with FDA standards. Furthermore, the AMA cautions physicians not to be biased against advertised drugs and to not feel pressured to prescribe these drugs against their better judgment. Instead, it urges doctors to foster a relationship with the patient that encourages an open dialogue about effective, individualized medical treatment.

 Direct-to-consumer prescription drug advertising has grown tremendously in the last decade. Furthermore, with the help of the Supreme Court, DTC advertising is protected under the doctrine of commercial free speech. The FDA, with its limited staff and resources, faces the enormous challenge of trying to police these advertisements to make sure that misleading information does not reach the public. If current trends continue, the growth in DTC advertising will only increase. What effects, if any, does advertising have on drugs costs and physician prescribing behavior? In the next installment, we will examine this question and the economic motives behind advertising. Can advertising really be as bad as we think it is?

Dr. Bradley is a Section Editor, Clinical Correlations

Peer reviewed by  Scott Sherman, MD, MPH Associate Professor of Medicine and Psychiatry at NYU Langone Medical Center

References:

1. Kesselheim, Aaron S. and Jerry Avorn. “Pharmaceutical Promotion to Physicians and First Amendment Rights.” N Engl J Med 2008;358:1727-32.

 2. Woloshin, Steven et al. “Direct-to-Consumer Advertisements for Prescription Drugs: What Are Americans Being Sold?” Lancet 2001;358:1141-46.

 3. Gellad, Ziad F. and Kenneth W. Lyles. “Direct-to-Consumer Advertising of Pharmaceuticals.” Am J Med 2007;120:475-80.

 4. Ostrove, Nancy M. “Testimony on Prescription Drug Promotion before the Senate Committee on Commerce, Science, and Transportation, Subcommittee on Consumer Affairs, Foreign Commerce, and Tourism.” (Date July 24, 2001). Text available at http://www.fda.gov/NewsEvents/Testimony/ucm115206.htm. Accessed July 18, 2009.

 5. Food and Drug Administration. “Keeping Watch Over Direct-to-Consumer Ads.” 2008. Available at http://www.fda.gov/consumer/updates/dtc_advertising093008. Accessed July 14, 2009.

 6. Donahue, Julie M, Marisa Cevasco, and Meredith B. Rosenthal. “A Decade of Direct-to-Consumer Advertising of Prescription Drugs.” N Eng J Med 2007;357:673-81.

 7. Rosenthal, M, ER Berndt, JM Donahue, et al. “Promotion of Prescription Drugs to Consumers.” N Eng J Med 2002;346:498-505.

 8. Behrman, Rachel E. “Testimony on Impact of Direct-to-Consumer Drug Advertising on Seniors’ Health and Health Care Costs before the Senate Special Committee on Aging.” (Date September 29, 2005). Text available at http://www.fda.gov/NewsEvents/Testimony/ucm112706.htm. Accessed July 18, 2009.

 9. Bell, Robert A., Richard L. Kravitz, and Michael S. Wilkes. “Direct-to-Consumer Prescription Drug Advertising and the Public.” J Gen Int Med 1999;14:651-7.

 10. Shuchman, Miriam. “Drug Risks and Free Speech – Can Congress Ban Consumer Drug Ads?” N Eng J Med 2007;356:2236-39.

 11. Weintraub, Arlene. “Putting Drug Ads Back in the Bottle.” BusinessWeek. August 13, 2007.

 12. American Medical Association. “Opinion 5.015 – Direct-to-Consumer Advertisements for Prescription Drugs.” AMA Code of Medical Ethics 1999. Available at http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion5015.shtml. Accessed July 14, 2009.

 Image courtesy of Wikimedia Commons

By Antony Q. Pham, Pharm.D. and Reena M. Tejura, Pharm.D.

Faculty Peer Reviewed

Recent publications have described a potential drug interaction between clopidogrel (Plavix®) and proton pump inhibitors (PPIs). Several retrospective studies have concluded that the use of PPIs can lower the effectiveness of clopidogrel and as a result, increase the possibility of cardiovascular events. Limited data from prospective trials have yet to show a clinical significance from this potential interaction. The Food and Drug Administration (FDA) released an early communication about the ongoing safety review of clopidogrel and omeprazole on January 26, 2009. Over the next 10 months, the FDA worked with Sanofi-Aventis/Bristol-Myers Squibb (the manufacturers of clopidogrel) to investigate this potential interaction. The follow-up report was released by the FDA on November 17, 2009, warning to avoid concomitant use of clopidogrel and omeprazole.¹ Subsequently, on December 10, 2009, a large, multicenter, observational study found no conclusive evidence of a clinically relevant interaction between PPIs and clopidogrel.⁶

Clopidogrel is a pro-drug that is activated only after metabolism via the cytochrome P450 system (mainly with the isoenzyme CYP2C19). It carries FDA approved indications for anti-platelet therapy post- myocardial infarction (MI), post-stroke and for peripheral artery disease. The use of PPIs is mainly for stress ulcer prophylaxis, treatment of gastrointestinal bleeds and acid reduction in gastroesophageal reflux disease; however there are no specific guidelines for the use of gastroprotective agents (like PPIs) in patients receiving clopidogrel. Certain PPIs are known to inhibit liver enzymes, including CYP 2C19. This inhibition can decrease the activation of clopidogrel, lowering its efficacy and thus increasing the risk of cardiovascular events. Omeprazole is known to be one of the strongest inhibitors of CYP2C19. ²

Juurlink et al. performed a retrospective case-control study that evaluated 734 post-MI patients (matched with controls) who were discharged on clopidogrel and a PPI.³ The combination of these agents was associated with a 27% increase for readmission for MI (odds ratio 1.27) versus the controls (clopidogrel only). Another retrospective cohort study by Ho et al examined 8,205 post MI/unstable angina patients who were readmitted for acute coronary syndrome or died.⁴  This study found that 30% of these patients were currently on clopidogrel + PPI versus 21% who were on clopidogrel alone. It was noted in both studies, however, that patients in the clopidogrel + PPI group had more co-morbid diseases such as diabetes, heart failure and/or renal insufficiency.  This illustrates the difficulties of controlling for confounding factors in retrospective studies.

Early prospective trials from TRITON-TIMI 38 did not show a clinically relevant interaction between clopidogrel and PPIs.⁵ The primary endpoints for this randomized study were a composite of cardiovascular death, myocardial infarction, or stroke in patients taking prasugrel vs. clopidogrel. Post-hoc analysis showed that 33% of enrolled patients were on a PPI at randomization. No association was found between PPI use and risk of primary endpoint in either group.

The COGENT trial was a randomized, double-blind, parallel group, phase 3 trial comparing the safety of clopidogrel + omeprazole (combination product) vs. clopidogrel alone. Despite early termination (due to sponsor bankruptcy), the early data from 3,627 patients (mean follow-up = 133 days) did not show any signs of increased cardiovascular events in the clopidogrel + omeprazole group. Although both of these prospective studies have limitations, they may offer reassurance that there is no clinically relevant interaction between clopidogrel and PPIs.

However, new pharmacokinetic data from Sanofi-Aventis/Bristol-Myers Squibb revealed a 47% reduction in anti-platelet activity when clopidogrel is given with omeprazole.^{1, 6}  Anti-platelet activity was measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation testing. Separating the administration times (12 hours apart) did not reduce this drug interaction. As a result, the FDA issued a follow-up to the early communication on Nov. 17, 2009 warning to avoid concomitant use of clopidogrel and omeprazole. The updated labels for clopidogrel will contain details of this drug interaction.

The FDA warnings are summarized below:¹

• The concomitant use of clopidogrel with omeprazole should be avoided. Patients receiving these interacting medications may not receive the full anti-platelet effect of clopidogrel.
• Separating the administration times of clopidogrel and omeprazole does not reduce this drug interaction.
• The current warnings pertain only to omeprazole and esomeprazole (the S-enantiomer of omeprazole) and other inhibitors of CYP2C19. At this time, there is insufficient data to conclude that other proton pump inhibitors interact with clopidogrel.
• Histamine 2 receptor antagonists (H2RA’s) are not known to interact with clopidogrel (except cimetidine). These agents can be used as alternatives for acid reduction.
• Health care providers are highly encouraged to ask patients about over-the-counter medications because both omeprazole and cimetidine are available commercially without a prescription.

 On Dec. 10, 2009, a subsequent study performed by Rassen et al⁷ evaluated the potential of an increased risk of adverse cardiovascular events among patients who took clopidogrel versus those who also concomitantly used PPIs.  Patients were evaluated in 3 cohorts based on geographical location and baseline characteristics were adjusted for confounding variables by applying a high-dimensional propensity score (hd-PS). Investigators evaluated the risk of primary event occurring in all PPIs together with clopidogrel and then specifically assessed omeprazole and pantoprazole with clopidogrel to evaluated aggregate versus agent specific interactions with clopidogrel.  A total 18,565 (of 64,561 patients) were evaluated and those who survived 7 days after percutaneous coronary intervention and were prescribed clopidogrel were enrolled in the study.  Although a slight increased risk of MI, hospitalization or death was observed in older patients on dual therapy of a PPI and clopidogrel; the risk was modest and investigators concluded there was no statistically significant PPI-clopidogrel interaction.⁷ The use of aspirin and over-the-counter medications such as generic omeprazole were not evaluated in the study. Additionally, this study only included those 65 years or older, so any modest increase risk of an event occurring can only be applied to older patients.  The data collected for patients’ drug usage were based on pharmacy claims data which may not be a true indicator of a patient’s actual drug usage.

The potential interaction between PPIs and clopidogrel is still currently under investigation. Despite conflicting conclusions between several observational and prospective studies, health care providers are encouraged to re-evaluate concomitant use of PPIs (especially omeprazole) with clopidogrel and adhere to the FDA warnings as closely as possible.

• During the publication of this manuscript, two additional studies were published in the medical literature. The first was a retrospective cohort study using automated data from 20,956 patients hospitalized for myocardial infarction, coronary artery revascularization or unstable angina.⁸ The results showed a reduced incidence of gastroduodenal bleeding with clopidogrel and omeprazole with no increase in serious cardiovascular disease. The second was an observational, retrospective study that included 588 consecutive patients undergoing coronary stenting. Primary outcomes of cardiac death or nonfatal myocardial infarction were not significantly different in clopidogrel plus omeprazole group and in clopidogrel only group after 1 year.⁹

 Peer reviewed by John Papadopoulos, B.S., Pharm D., Pharmacology Section Editor, Cinical Correlations

Image courtesy of  Wikimedia Commons user Trounce

References:

1.  Food and Drug Administration. Public Health Advisory: Updated Safety Information about a drug interaction between Clopidogrel Bisulfate and Omeprazole. http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm190825.htm. Accessed on November 20, 2009

2.  Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150mg clopidogrel maintenance dose: The PACA (proton pump inhibitors and clopidogrel association) prospective randomized study. J Am Coll Cardiology 2009;54:149-53

3.  Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8

4.  Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44

5.  O’Donoghue M, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton pump inhibitor: an analysis of two randomized trials. Lancet 2009;374:989-97

6.  Gilard M, Arnaud B, Cornily JC, et al. Influence of Omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA study. J Am Coll Cardiol 2008 Jan 22;51(3):256-60

7.  Rassen JA, Choudhry NK, Avorn J, et al. Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel With Proton Pump Inhibitors After Percutaneous Coronary Intervention or Acute Coronary Syndrome. Circulation 2009;120:1322-2329

8.  Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors. Ann Intern Med 2010;152:337-345

9.  Zairis MN, Tsiaousis GZ, Patsourakos NG, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. J Cardiol 2010;26(2):e54-e57.

Gratefully returning to daylight after a two-week stint assigned to the night float service, I’ve been observing the week’s events with great mirth.  It seems bedbugs have continued on their squirm-inducing rise to power and glory, causing panic on Park Avenue; the iPhone design flaw, dubbed “antennagate”, has threatened to undermine Apple’s ultimate superiority on the smartphone front (1); and Sarah Palin has found herself in yet another public snafu, this time mixed up with the unlikely likes of William Shakespeare. (2)  Things look like they are progressing nicely in the Gulf and in Washington, for a change.  BP is reportedly “days away” from finishing the highly-anticipated relief well that will – cross your fingers – kill its most unseemly gusher (although what’s with that brewing tropical storm?), and Obama has finally signed the sweeping financial regulation bill designed to protect main street consumers. (3)

Medical news this week has been equally interesting, and arguably as entertaining.  An anti-HIV microbicide shows exciting potential; doctors muse on what would happen if they open up their notes to patients’ scrutiny; pregnant closet coffee drinkers can breathe a sigh of relief (in moderation!); and a bit of light has been shed on the best therapy for ACL tears in young athletes.  Enjoy!

HIV Prevention

An ounce of prevention is worth a pound of cure, and nowhere is this more a propos than in the world of HIV.  A source of frustration for many, HIV infection prevention strategies have repeatedly come up short over the past several decades, and the few modalities that have been successful (male circumscision, vaccine combinations, and STI treatment clinics) have failed to squarely capitalize on that most explosive potential resource – women – with their efforts.  That is, until now.  Enter the CAPRISA 004 trial and its tenofovir 1% vaginal gel, recently made public in ScienceExpress. (4)  It was destined to be unique from the start, as one of the first gels to include an antiretroviral agent, and the results so far are making headlines around the world.  In a double-blind, randomized, placebo-controlled study of 889 HIV-uninfected sexually active women ages 18 to 40, researchers found that when applied within 12 hours of a sex act, the tenofovir gel reduced the incidence of new HIV infection by 39%.  In women whose adherence was considered high, using the gel decreased HIV acquisition by 54%.  To put that in perspective, the effectiveness of male circumcision in preventing HIV acquisition was found to be 57% (5,6,7), while an HIV vaccine combination tested in Thailand amounted to a 39% reduction in acquisition.  The numbers are promising, but alone do not tell the whole story; in a world where women often have no control over condom use or the fidelity of their sexual partners, tools like microbicides afford them a viable means of self-protection, and become a powerful addition to the anti-HIV arsenal that could well change the landscape of future HIV control strategy.  The study needs to be repeated on a larger scale to further assess safety, acceptability, and the role of varying adherence, but the results are encouraging and this is an area to keep an eye on.

In the Spirit of Patient Partnership

Now imagine yourself in a busy primary care practice.  Your 9:30 patient has arrived for his blood pressure follow-up visit and you enter the room to find him holding a copy of your note from his initial appointment.  You notice that beside most of the bulleted recommendations in your plan, he has written a checkmark. He looks up as you enter and asks, “Doc, I’ve been watching sodium in my diet like you said, and taking walks everyday too, but my blood pressure at home is still running 145/90’s . . . I saw that you wrote about starting hydrochlorothiazide if diet and exercise don’t work.  Is it time for that now?  Also, would you mind going over the results of my urinalysis? I want to make sure my kidneys are okay.”  In this scenario, your patient has had access to your clinic note so he understands your plan for treating his blood pressure and has signed on to do his part, in this case, participate in lifestyle changes in earnest and monitor his blood pressure at home.  You astutely realize that by giving your patients easy access to their own clinic notes, you have at once improved the health-literacy of your patients and heightened the efficiency and productivity of your clinic.  This dreamy scenario is what some researchers hope they might achieve with the OpenNotes project, a year-long observational study taking off in three hospitals in Massachusetts, Pennsylvania, and Washington state. ⁽⁸⁾Giving patients access to their medical records is not a new concept, but giving them easy access, and encouraging them to do so, is new.  The primary care physicians involved in the study hope it will improve patient-doctor communication, and ultimately clinic productivity, but at the same time voice concerns ranging from how the change will affect their time as administrative staff field calls from patients with numerous questions and corrections, to medicolegal implications, to how patients will react when called “SOB [short of breath].”  Some physicians question whether their notes will ever be fully understandable to patients.  At the end of the study, participants on both sides of the stethoscope will be asked about their experiences.  If the idea is palatable, the technology to make medical records widely and easy accessible through online portals is already in place.  The study is scheduled to begin this summer, and when the results come in, we may find ourselves entering into a new era of unprecedented patient-physician partnership.

A Cup a Day . . . Appears Okay in Pregnancy

I remember looking at one of my clerkship preceptors one morning.  She was bleary-eyed as she stared at her schedule, her right arm protectively held close to her 4-month pregnant belly. “Is everything alright?” I asked.  “Yes,” she said with a sigh, “it’s just -” and she looked at the ceiling, as if searching for some source of strength there, “ – no caffeine in pregnancy.”  Well, I hope she’s reading this next report!  This month in Obstetrics & Gynecology, the American College of Obstetricians and Gynecologists has released a committee opinion on the effects of caffeine consumption on spontaneous miscarriage and preterm birth.  (9)  After reviewing four large studies on the subject, the committee found no evidence to support an effect of moderate caffeine intake (less than 200 mg daily – a cup of coffee delivers 137 mg) on spontaneous miscarriage and preterm birth. There were discrepancies in outcomes with regards to higher caffeine intake (> 200 mg), possibly due to differences in patient population and study design, so the committee stopped short of commenting on the effects of larger amounts of caffeine, but today the take home message is that pregnant women can enjoy their morning cup of joe with peace of mind.

“Doc, do I need surgery?”

Musculoskeletal complaints are one of the most commonly cited reasons for outpatient provider visits.  As the quality and intensity of elite and non-elite athletic programs increases, the primary care physician will be faced with a growing number of athletes presenting with injuries sustained on the field.  This month in New England Journal of Medicine, a study by Frobel and colleagues sheds light on the proper management of anterior cruciate ligament (ACL) tears in young nonelite athletes. ⁽¹⁰⁾ In this randomized, controlled trial, 121 young, healthy adults with acute ACL injuries were entered into treatment regimens consisting of either structured rehabilitation plus early reconstruction of the ACL, or structured rehabilitation with the option of surgical repair if needed.  Investigators followed the young athletes for two years, assessing their status in terms a predetermined scale called the Knee Injury and Osteoarthritis Outcome Score designed to assess pain, functionality, symptoms, and knee-related quality of life.  At the end of the study, consistent with prior studies, early surgical reconstruction was not shown to be superior to rehabilitation with optional delayed surgery, and as only 40% of the delayed optional surgery group ever went on to seek surgical correction in the 2-year study period, a trial of rehabilitation prevented 60% of surgeries.   As surgery is expensive and the gateway to numerous complications, it would seem that the study would favor initial nonoperative management over early surgery.  However, the study does have some important limitations. For one, the follow up period only lasted 2 years.  It is possible that some participants may have elected to have surgery after the 2-year period due to persistent disability, thus reducing the magnitude of surgeries avoided.  Secondly, there was no sham surgery control group, so neither the subjects nor their assessors were blinded, potentially introducing bias.  And finally, the authors themselves note that the generalizability of this study is limited by the specificity of the rehabilitation program used.  It is possible that the results might not be reproducible with different rehabilitation programs.  In summary, this study shows that early reconstruction is likely not superior to initial nonoperative management with rehabilitation, and that the latter is a worthy therapeutic option when assessing patients.

Aimee Edell is a first year internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Danise Schiliro, Contributing Editor, Clinical Correlations

Picture Courtesy of Wikimedia Commons

1 http://www.bloomberg.com/news/2010-07-15/apple-engineer-said-to-have-told-jobs-last-year-about-iphone-antenna-flaw.html

2 http://www.washingtonpost.com/wp-dyn/content/article/2010/07/19/AR2010071904916.html

3 http://online.wsj.com/article/SB10001424052748704684604575381120852746164.html

4 Karim Q, Karim S, Frolich J, et al. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Sciencexpress. 19 July 2010. Available from: http://www.sciencemag.org/cgi/gca?gca=science.1193748v1&sendit.x=64 &sendit.y= 8&sendit=Get+all+checked+abstract%28s%29

5 Auvert B, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med 2.  2005 e298.

6  Bailey RC, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet.  2007 369, 643-656.

7 Gray RH, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet.  2007 369, 657-666.

⁸ Delbanco T, et al. Open notes: doctors and patients signing on. Ann Int Med. 2010. 153:121.

⁹ Committee on Obstetric Practice. Committee Opinion. Moderate caffeine consumption during pregnancy. Obstectrics and Gynecology. 2010. 116:467.

¹⁰ Frobell RB, et al. A randomized trial of treatment for acute anterior cruciate ligament tears. NEJM. 2010. 363:331.

Ramin Shayegan Hastings MD, Jonathan Willner MD, and Steven Sedlis MD

Introduction to Cases:

During the past several weeks, we have posted a series of cases addressing the appropriate treatment for patients with stable coronary artery disease. We have focused on indications for revascularization in stable angina. In all of the cases, the patients have been at high enough risk that stress tests and coronary angiography are performed.

There has been recent data and recommendations on the appropriate indications for revascularization in stable angina. These recommendations are based on clinical symptoms, non-invasive imaging, and catheterization findings. After reading through these cases, we hope you have a better understanding of what the appropriate indications are for revascularization, and the evidence behind them.

Review Case #1

Review Case #2

Review Case #3

Case #4

The patient from Case # 1 (see previous post) comes back to the clinic for a follow up visit.

In review, he is a 54-year-old male with hypertension and tobacco use who presented with anginal chest pain 1 year ago. He was found to have low-risk findings on stress testing, and a cardiac catheterization revealed 2 vessel disease (not affecting the proximal left anterior descending artery (LAD)). He was treated with medical therapy including blood pressure control, treatment of hyperlipidemia with a goal LDL of 100, long-acting nitrates, aspirin, tobacco cessation, and an exercise program.

However, the patient states that his angina has continued despite treatment. Over the past 3 months it has worsened, and now he is not able to continue his work as a plumber because of continuing pain. After walking only short distances, about 2 blocks or one flight of stairs, he develops chest pain. He still has not had any pain at rest, and physical exam is unchanged from previous. ECG is also unchanged from previous.

What is the appropriate next step in treatment?

A. No change in treatment

B. Increase the dose of long-acting nitrates

C. Repeat stress test with catheterization only if new abnormalities are noted

D. Repeat catheterization with subsequent revascularization only if new lesions are noted

E. Repeat catheterization with revascularization of lesions that correlate with areas of ischemia on previous stress or echocardiography

Answer: E

In this case, we have the same patient from the previous post who had low-risk findings on non-invasive testing, CCS class II anginal symptoms off medication, and 2 vessel disease on catheterization. See the previous post about why medical therapy was an appropriate initial treatment strategy for this patient. His symptoms have worsened despite medical therapy.

His symptoms can now be classified as CCS class III angina (1). In addition, his symptoms are now affecting his daily life as he is not able to work. He was started on medical therapy, however we would not consider it optimal medical therapy. Optimal medical therapy would include two or more anti-anginals (beta-blocker, calcium channel blocker, and/or angiotensin converting enzyme (ACE) inhibitor), along with lipid control, exercise program, smoking cessation, and blood pressure control. While recent studies have found there is no mortality benefit with revascularization for the majority of patients with similar findings as this patient (see previous posts), several studies have shown there is a reduction in symptoms of patients undergoing revascularization. Early randomized studies showed that patients often had significant improvements in anginal symptoms after revascularization utilizing coronary artery bypass grafting (CABG). In the Veterans Administration Cooperative Study 38.5% of patients who underwent revascularization were angina free at one year compared with 8.8% in medical therapy (2). However, this improvement was no longer apparent 10 years after randomization (3). Similar findings were noted in the Coronary Artery Surgery Study (CASS), as patients randomized to revascularization had significant improvements in chest pain through 5 years after randomization (63% chest pain free with CABG vs. 38% with medical therapy after 5 years) (4). These studies were before the advent of some newer medical therapies known to improve coronary artery disease.

Studies comparing revascularization with Percutaneous Transluminal Coronary Angioplasty (PTCA, balloon angioplasty) to medical therapy in patients with stable angina painted a similar picture. The Second Randomized Intervention Treatment of Angina (RITA-2) Trial randomized 1,018 patients with stable angina to PTCA or medical therapy. Although they found no mortality benefit with PTCA (see previous post), patients treated with revascularization had a significant improvement in anginal symptoms. 3 months after randomization 19.4% of the PTCA group had angina class II or worse compared to 35.9% of the medical therapy group. This difference remained for five years, however after eight years no significant improvement in symptoms were noted with the group treated with PTCA (4). Newer data shows the improvement in symptoms with revascularization may not be as great as once though. The most applicable study for this patient is the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial which randomized 2,287 patients with stable angina to percutaneous coronary intervention (PCI) with aggressive medical therapy or aggressive medical therapy alone (5). There was no difference in the primary outcome of death and myocardial infarction (MI, see previous post). Subsequent analyses found patients randomized to PCI had an improvement in symptoms at 1 year, although this was no longer present at 3 years (At 1 year 57% were free of angina with PCI vs. 50% free of angina in medical therapy; after 3 years that changed to 59% and 56% respectively).

Based on these data, the American College of Cardiology (ACC) and American Heart Association (AHA) recommend PCI or CABG “for patients who have not been successfully treated with medical therapy and can undergo revascularization with acceptable risk,” as a class IB recommendation (6). Medical treatment has failed this patient, as his symptoms have continued to worsen despite adequate medical treatment. In addition, he is having disabling angina and the appropriateness criteria for revascularization released by the ACC rated revascularization appropriate in patients with CCS class III or IV angina with almost any disease noted on angiography (except 1-2 vessel disease off treatment with low/intermediate risk findings on stress) (7). Revascularization with PCI or CABG would be appropriate in this patient, even if no further disease is noted on cardiac angiography. In addition, as stated above, an increase in his medical management with beta-blockers, calcium channel blockers, and ACEI is indicated as well.

As you can see, we have laid out two different indications for revascularization in patients with stable angina. The first is to improve survival, as may be the case in patients with high-risk findings on angiography or non-invasive testing (see previous post). The other is for symptom control in patients who have disabling angina or when symptoms are not adequately controlled with medical therapy alone.

References

1. Campeau L. The Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later. Can J Cardiol2002 Apr;18(4):371-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11992130

2. Peduzzi P, Hultgren HN. Effect of medical vs surgical treatment on symptoms in stable angina pectoris. The Veterans Administration Cooperative Study of surgery for coronary arterial occlusive disease. Circulation1979 Oct;60(4):888-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=113129

3. Eighteen-year follow-up in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Circulation1992 Jul;86(1):121-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1617765

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By Radhika Sundararajan, M.D., Ph.D

Faculty Peer Reviewed  

A healthy 18 year-old female presents to Urgent Care after slipping and falling this morning in the bathroom and hitting her head on the tile floor. She denies any loss of consciousness, vomiting, or current neurological deficits, but does have a mild occipital headache where she struck her head. She has heard a lot about recent research regarding concussions in young athletes and asks if you think she suffered a concussion and what this means for her.

 What is a concussion?

The term concussion has been used in the medical literature as a synonym for mild traumatic brain injury (TBI). Mild TBI is a common and typically benign type of injury, though there are risks of serious short- and long-term sequelae.

 In 1997, the Quality Standards Subcommittee of the American Academy of Neurology defined concussion as a trauma-induced alteration in mental status that may or may not involve loss of consciousness.¹ However, this term had been loosely applied to a range of presentations. In 2004, an international multidisciplinary conference on concussion convened to provide further clarification.² A concussion is therefore defined as a complex pathophysiological process affecting the brain, induced by traumatic forces and involving the following characteristics:

1) rapid onset of short-lived impairment of neurologic function that resolves spontaneously 

2) neuropathological changes, but with acute clinical symptoms largely reflecting a functional disturbance rather than structural injury

3) a graded set of clinical syndromes that may or may not involve loss of consciousness

4) resolution of the clinical and cognitive symptoms typically following a sequential course

5) grossly normal structural neuroimaging studies

 Pathophysiology

Mild TBI occurs with head injury due to contact and/or acceleration/deceleration forces and may result in cortical contusions with varying degrees of axonal damage depending on the force of the trauma. Disruption of axonal neurofilament organization can impair axonal transport and lead to swelling, Wallerian degeneration, and possible transection. In addition, the release of the excitatory neurotransmitters acetylcholine, glutamate, and aspartate, and generation of free radicals contribute to secondary injury.³

 Epidemiology

There are approximately 1.4 million reported incidents of TBI in the United States every year, with the overwhelming majority being mild.⁴ In the United States, estimates of the relative causes of TBI are as follows: motor vehicle accidents (45%), falls (30%), occupational accidents (10%), recreational accidents (10%), and assaults (5%). Mild TBI also occurs from contact; in American football alone, an estimated 10% of college and 20% of high school players sustain brain injuries each season.⁵ 

 Diagnosis

Patients who have sustained a concussion or mild TBI should be evaluated with a neurologic assessment and mental status testing. Clearly, patients who present with prolonged unconsciousness, persistent mental status alterations, or abnormalities on neurologic examination require urgent neuroimaging and neurosurgical consultation. The Standardized Assessment of Concussion (SAC) was developed as a tool for the sideline evaluation of athletes who suffer a head injury.⁶ The SAC includes measures of orientation, immediate memory, concentration, delayed recall, neurologic screening, and exertional maneuvers. Its efficacy has been studied in cohorts of high school and college athletes sustaining concussions where patients with concussion were found to have significantly lower scores as measured by the SAC than those without.

 The indication for neuroimaging depends primarily on the patient’s clinical presentation. Studies suggest a prevalence of CT scan abnormalities of 5% among patients presenting to a hospital with a normal Glasgow Coma Scale (GCS) score of 15, and of 30% for those presenting with a GCS  score of 13, with the incidence of abnormalities leading to neurosurgical intervention at 1%.⁷ The American College of Emergency Physicians has endorsed the New Orleans criteria for adult patients with suspected mild TBI.⁸ These criteria apply to patients with a GCS score of 15 and indicates CT scanning if there is headache, vomiting, age >60 years, drug or alcohol intoxication, persistent anterograde amnesia, or visible trauma above the clavicle. Evidence suggests that patients with a normal GCS score, normal examination and head CT, and no predisposition to bleeding are less likely to suffer subsequent neurologic deterioration.^8,9 Therefore outpatient observation may be permitted for the patient whose neurologic condition is very unlikely to deteriorate.

 Sequelae and Prognosis

Patients who have suffered a concussion are at risk for numerous short-term and long-term sequelae. Second impact syndrome describes diffuse cerebral swelling thought to occur if a second concussion takes place while an athlete is still symptomatic from an earlier concussion. This is a rare but potentially fatal complication of mild head injury caused by cerebrovascular congestion and edema with increased intracranial pressure.¹⁰ More commonly experienced is postconcussion syndrome (PCS), which generally includes symptoms such as headaches, dizziness, fatigue, irritability, anxiety, insomnia, loss of concentration/memory, and noise sensitivity. It is estimated that 30 to 80% of patients with mild to moderate brain injury will experience some symptoms of PCS.^2,6 Such symptoms typically develop in the first days after the trauma and generally resolve within a few weeks to a few months. Even more commonly occurring are post-concussion headaches, which occur in anywhere from 25 to 78% of patients after mild TBI, most often within one week of the injury.¹¹

  Case conclusion

Based on the New Orleans criteria, neuroimaging was not indicated for this patient. She was educated regarding the definition of a concussion, the fact that it is often diagnosed without neuroimaging, and the possible sequelae of postconcussion syndrome and headaches. She was also given strict instructions to return should her headache worsen or her condition deteriorate.

 Dr. Sundararajan is a recent graduate of NYU School of Medicine

Peer reviewed by Robert Staudinger, MD, Associate Professor, Department of Neurology, NYU Langone Medical Center

References:

 1. Practice parameter: the management of concussion in sports (summary statement). Report of the Quality Standards Subcommittee. Neurology. 1997;48(3):581-585.

2. McCrory P. Do not go gentle into that good night… Br J Sports Med. 2005;39(10):691.

3. Povlishock JT, Katz DI. Update of neuropathology and neurological recovery after traumatic brain injury. J Head Trauma Rehabil. 2005;20(1):76-94.

4. Centers for Disease Control and Prevention.  National Center for Injury Prevention and Control. “Traumatic Brain Injury in the United Sates: Emergency Department Visits, Hospitalizations, and Deaths,” May 2007. http://www.cdc.gov/ncipc/pub-res/TBI_in_US_04/TBI_ED.htm.  Accessed on December 16, 2009.

5. Kraus JF, McArthur DL. Epidemiologic aspects of brain injury. Neurol Clin. 1996; 14(2):435-450.

6. McCrea M, Kelly JP, Kluge J, Ackley B, Randolph C. Standardized assessment of concussion in football players. Neurology. 1997;48(3):586-588.

7. Borg J, Holm L, Cassidy JD, et al. Diagnostic procedures in mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J Rehabil Med. 2004;(43 Suppl):61-75.

8. Jagoda AS, Bazarian JJ, Bruns JJ Jr, et al. Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. Ann Emerg Med 2008;52(6):714-748.

9. Lawler KA, Terrigino CA. Guidelines for evaluation and education of adult patients with mild traumatic brain injuries in an acute care hospital setting. J Head Trauma Rehabil. 1996;11(6):18-28.

10. Kelly JP, Rosenberg JH. Diagnosis and management of concussion in sports. Neurology. 1997;48(3):575-580.

11. Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a systematic review. JAMA. 2008;300(6):711-719.

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