PrimeCuts

PrimeCuts: This Week in the Journals

March 1, 2010

sedonaIshmeal Bradley MD

Faculty peer reviewed

As America enters Year Two of the current economic recession, unemployment and underemployment still remain incontrovertibly high. Not surprisingly, doctors, like other Americans, are working fewer hours these days, too. The New York Times published the result of a study from JAMA this week about the decline in the number of hours that physicians put in per week (1, 2). In their population survey study, they queried over 27,000 doctors from 1977 to 2007 about how much they worked in the preceding week. What they found was rather surprising.Between 1977 and 1997, the average number of weekly hours remained relatively constant at about 55 hours per week. This included both resident and non-resident physicians. However, for the next ten years, that weekly average began to drop. Between 1996 and 2008, the number of hours declined from 55 to 51, or 7.2%. This reduction was rather dramatic. For non-resident physicians, the decline in hours was 5.7%, while that for residents was 9.8% (partly due to work hour regulations implemented in 2003).

Although the advent of work hour regulations did cause resident work hours to decrease, it was not the driving force behind the cut in work hours. The study authors cite several other potential, but non-significant factors, like the increase in female physicians and younger doctors going into more “lifestyle” fields with smaller time commitments. But none of these other factors could fully explain the downward trend.

Perhaps the most significant reason was the decrease in real wages for physicians during this time period. Adjusted for inflation, the average doctor saw a 25% decrease in fees in 2006 compared to 1995. This drop in income has made doctors less likely to work longer hours if their time is not going to be compensated. Further supporting this claim are data showing that those metropolitan areas that saw the largest decline in physician salaries were also the areas that had the largest decline in physician work hours, and vice versa.

What this study highlights is the impending crisis in healthcare. Out of 630,000 physicians in the U.S., this decline in hours worked per week is equal to the net loss of 36,000 physicians. The current healthcare reform debates taking place in Washington may ultimately provide coverage for more patients, stressing an already over-burdened and understaffed system, and unfortunately, making the shortage of primary care physicians even more acute.

Since we are working fewer hours than before, what are we really doing with our time in the hospital? A study from the Archives of Internal Medicine examined the amount of time that internal medicine residents spend on documentation and clerical duties. (3) The authors surveyed nearly 86% of all U.S. internal medicine residents in 2006 about the amount of time they spend on clinical documentation and clerical duties (including notes, forms, orders, dictations) versus face-to-face patient contact time. Two-thirds of respondents said that they spend >4 hours per day doing documentation compared with 39% who said that they spend >4 hours in face-to-face patient contact. The amount of time used for non-direct patient contact continues to grow and can affect the educational impact of residency training. With rules regarding how many hours a resident can work, providing more clerical services to help with the marginal duties can allow residents more time to hone their clinical skills, which really is the purpose of training.

While on the subject of hospital-based medicine, there was plenty of discussion in the journals this week about the optimum management of critical care and surgical patients. As internal medicine housestaff rotate through the ICUs and ER, they become intimately familiar with early goal-directed therapy for sepsis management, the main principle of which is to reestablish adequate tissue perfusion as quickly as possible. Early trials have, so far, focused mainly on central venous oxygen saturation as a marker of tissue perfusion. However, continuous measurement of ScvO2 has proven difficult to incorporate into the sepsis guidelines because of the specialized equipment and technical expertise needed to place and monitor the intravenous catheter. Measuring serial serum lactate levels, though, is much easier to do. In a randomized controlled trial published in JAMA, the authors report on a non-inferiority study to see if following serum lactate levels was as effective as following ScvO2 in the management of severe sepsis and septic shock. (4)

They randomized 300 patients presenting to the emergency department into a ScvO2 group and a lactate group. All patients received the same early goal-directed care, including aggressive fluid resuscitation, ionotropic support if needed, and blood transfusion if needed. The primary endpoint was in-house mortality, with several secondary endpoints (ICU length of stay, hospital length of stay, ventilator-free days, and new onset multiorgan failure). Using intention-to-treat analysis, absolute in-hospital mortality for the two groups was 23% for the ScvO2 group versus 17% for the lactate, a difference of 6%, below the predefined -10% non-inferiority threshold. Their results add to a growing body of literature suggesting that other markers of tissue perfusion (which can be more easily obtained) other than central venous saturation can be used to monitor our septic patients.

Another possible change in critical care management may be coming. Although those of us at NYU are familiar with team ICU rounds with an intensivist, nursing, and sometimes a clinical pharmacist, that is by far not the national norm. The Archives published a retrospective study looking at the effect of multidisciplinary care teams on ICU mortality. (5) The researchers looked at medical ICU admissions and discharges at two-thirds of the non-federal acute care hospitals in Pennsylvania. Their primary outcome was 30 day mortality. Not surprisingly, they found that intensivist staffing and multidisciplinary care teams were more common in teaching hospitals and those with critical care fellowships. Multidisciplinary care teams were associated with a 16% reduction in odds of death (OR-0.84). Intensivist staffing was also associated with a 16% reduction. Together, having both an intensivist and a multidisciplinary care team resulted in a 22% reduction in the odds of death. Given the shortage of critical care physicians, their study shows that having a multidisciplinary care team can also be used to optimize medical care in the ICU and to improve patient survival.

Finally, another new trend in hospital care is worth mentioning. More and more surgical patients are being managed by internists. (6) Another study in the Archives this week examined the growth in medical hospitalist management of surgical patients between 1996 and 2006. The retrospective cohort study examined patients that were admitted for the fifteen most common surgical procedures (including cholecystectomy, CABG, hip replacement, among others). They noticed an increase of 20.5% to 31.3% of surgical patients having an internist co-managing their care over this time period. Much of this was due to the increase in hospitalist care, with an increase from 1.7% in 1996 to 12.5% in 2006. Older patients, women, and patients with more medical comorbidities were all more likely to have an internist on board. This study highlights the expanding role of the hospitalist today, namely perioperative management. This has implications for the future of residency training. Currently, the ACGME does not mandate competency in perioperative medicine. The growth in co-management of these patients may ultimately cause a shift towards more formalized education of perioperative medicine during residency. And what could this mean? More medical consult shifts at Bellevue? That’s just quite possible.

Dr. Bradley is a 3rd year resident in internal medicine at NYU Medical Center.

Sources:

1. Associated Press. Docs Cut Work Hours as Primary Care Shortage Looms. New York Times. 2010 February 24.
2. Staiger, Douglas O., David I. Auerbach, and Peter I. Buerhaus. Trends in the Work Hours of Physicians in the United States. JAMA 2010;30(8)3:747-753.
3. Oxentenko, Amy S. et al. Time Spent on Clinical Documentation. Arch Intern Med 2010;170(4):377-380.
4. Jones, Alan E. et al. Lactate Clearance vs Central Venous Oxygen Saturation. JAMA 2010;303(8):739-746.
5. Kim, Michelle M. et al. The Effect of Multidisciplinary Care Teams on Intensive Care Unit Mortality. Arch Intern Med 2010;170(4):369-376.
6. Sharma, Gulshan et al. Comanagement of Hospitalized Surgical Patients by Medicine Physicians in the United States. Arch Intern Med 2010;170(4)”363-368.

Primecuts-This Week in the Journals

February 22, 2010

vancouver-olympics-2010-language-test-onlineEmily Taylor, MD

Can your case of seasonal affective disorder be cured by a healthy dose of the Vancouver Olympics?  A commentary in this week’s JAMA addressed the Winter Olympics as a prime opportunity to promote safety helmets for alpine sports.  There are approximately 600,000 ski-slope injuries a year, of which 15-20% include traumatic brain injury. The US Consumer Product Safety Commission is quoted as claiming that 44% of these injuries are preventable by wearing a safety helmet, but despite these strong recommendations, helmets are worn by only 12% of skiers and snowboarders. So if, inspired by Shaun White, you head out to the slopes during our next blizzard, please wear your safety helmet.

Olympic fever brings us to another article in JAMA about a more deadly fever in a young ruler who has been the subject of countless movies, books, conspiracy theories and even a particularly memorable SNL skit. King Tutankhamen’s death at the age of 19 has been a mystery to Egyptologists, but a two-year investigation has uncovered the DNA markers identifying Plasmodium falciparum in his mummified remains.  The authors concluded that the most likely cause of death to be an acute illness, possibly after a fall which caused him to fracture his leg; this illness became life-threatening in a boy whose immune system was already ravaged by malaria.

Malaria may soon become a problem for some of Haiti’s earthquake survivors.  As reported by the NY Times, the displaced citizens of Port-Au-Prince are gathering in make-shift tent camps, and the city officials are unable to properly dispose of the resulting human waste. Donated latrines overflowed recently during a rainstorm, but a more important need is for waste removal systems to be upgraded. Overcrowding is leading to shigella and typhoid and unless the current conditions improve, a cholera outbreak may cause many otherwise preventable deaths. Some health care workers have suggested breaking up the current tent-cities and relocating people in smaller groups to more remote locations just outside the city to prevent a large scale outbreak when the rainy season comes.

In infectious disease news, Science discussed a new antibiotic created by chemists in Switzerland that shows promise in the treatment of Pseudomonas aeruginosa. Pseudomonas is a common hospital-acquired pathogen that can lead to pneumonia, skin infections and sepsis. The researchers, lead by John Robinson, created a synthetic molecule called a petidomimetic that binds to LptD, a protein found only in Pseudomonas. Because the molecule is synthetic, it is not broken down as quickly as other peptides; it binds to the LptD which protrudes from the bacterial wall, damaging the wall’s integrity and allowing other antibiotics to enter the cell. The degradation of the strong cell wall also reduces the bacteria’s ability to rid itself of antibiotics by actively pumping them out.

In other pharmaceutical news, The New York Times reported that there are confidential government documents, as yet unreleased, recommending that Avandia be pulled from the market. Many doctors have chosen other alternatives since a 2007 meta-analysis was published in The New England Journal of Medicine showing an association between the use of Avandia and increased risk of myocardial infarction. The NY Times reports that, as early as 2003, the World Health Organization had alerted GlaxoSmithKline, the makers of Avandia, to a possible link between the use of the drug and cardiac disease.  GlaxoSmithKline is attempting to assess this risk by running the TIDE trial, an FDA-approved, randomized, double blind, safety/efficacy trial comparing Avandia, Actos and placebo in patients with diabetes and heart disease. Since a previous study described risks of MI in patients on this medication, the trial has come under fire for being too risky. A Senate investigation is expected to be released on Feb 22.

This week the FDA did issue warnings about Long-Acting Beta Agonists (LABA), supporting this decision with studies that showed an increased risk of symptom progression, hospitalization, and mortality in patients taking these medications. Specific instructions state that this class of drug should only be started in asthmatics that cannot be managed on a controller medication alone, and that it should not to be used without concurrent use of an asthma controller medication. When prescribing it, physicians should choose a combination product that also contains inhaled corticosteroids rather than a LABA alone. For patients currently on these medications, it is recommended that they be weaned off in a timely manner and that the LABAs be used for the shortest amount of time possible.

The American Gastroenterological Association published a statement on colorectal cancer screening for IBD in Gastroenterology. They continue to recommend colonoscopy within 8 years of the onset of disease and more frequent surveillance in patients with extensive or left sided colitis. Colectomy is reserved for patients with biopsy-proved dysplastic lesions that are not consistent with adenomas. Other colon cancer risk factors include primary sclerosing cholangitis and a positive family history.

The CDC issued an almost 600 page annual report on the general health of Americans this week. Highlighted points are found in the more manageable “In Brief” edition, which shows not only that life expectancy in the US continues to increase (77.7 years for 2006), but that life expectancy of black Americans is increasing at a faster rate. In 1990 the gap in life expectancy at birth between white and black men was 8 years; but by 2006 the gap had narrowed to 6 years. A similar trend is also seen in women, though the gap in the case of women is narrower. All cause mortality continues to decline, with decreases in death from heart disease and stroke most evident since the 1950s; however, chronic lower respiratory diseases and diabetes as cause of death are climbing. The prevalence of diabetes, cardiac disease and hypertension among middle aged Americans was found to correlate with poverty. Cigarette smoking rates continue to decline, especially among high school students. Obesity rates have increased from 15% to 35% of the population in the last 25 years, while the rate of Americans that are overweight but not obese has remained the same.

Lastly, as far as our own microcosm of American medicine, life in Bellevue Hospital has been memorialized in an essay by Danielle Ofri, MD, in the LA Times. The article captures a snapshot of life on Bellevue floors, and encourages physicians to always continue learning from their patients. Her recent book, “Medicine in Translation: Journeys with My Patients”, is available in bookstores now.

 Emily Taylor is a third year internal medicine resident at NYU Medical Center

Faculty Peer Reviewed by Neil Shapiro, MD, Editor-in-Chief, Clinical Correlations

Bibliography

1. Cusimano MD, Kwok J. Skiers, Snowboarders, and Safety Helmets. JAMA. 2010; 303(7): 661-662.

2. Hawass Z, Gad YZ, Ismail S, Khairat R, Fathalla D, Hasan N, Ahmed A, Elleithy H, Ball M, Gaballah F, Wasef S, Fateen M, Amer H, Gostner P, Selim A, Zink A, Pusch CM. Ancestry and Pathology in King Tutankhamun’s Family. JAMA. 2010; 303(7): 638-647.

3. Romero S. Poor Sanitation in Haiti’s Camps Adds Disease Risk. The New York Times. 2010 Feb 19.

4. Wogan T. Fighting Back Against a Superbug. Science Now: Up to the Minute News from Science. 2010 Feb 18.

5. Harris G. Research Ties Diabetes Drug to Heart Woes. The New York Times. 2010 Feb 19.

6. U. S. Food and Drug Administration. FDA Announces New Safety Controls for Long-Acting Beta Agonists, Medications Used to Treat Asthma. 2010, Feb 18.

7. National Center for Health Statistics. Health, United States, 2009.

8. Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA Medical Position Statement on the Diagnosis and Management of Colorectal Neoplasia in Inflammatory Bowel Disease. Gastroenterology. 2010; 138(2): 738-745.

9. Offri, D. At Bellevue, a hospital reflects its changing world. Los Angeles Times. 2010 Feb 15.

PrimeCuts: This Week in the Journals

February 15, 2010

Rachel Bond, MD

Faculty peer reviewed

August 12, 2003. Rosuvastatin aka Crestor becomes FDA approved in combination with diet and exercise to increase HDL cholesterol (HDL-C), reduce total cholesterol (TC), LDL cholesterol (LDL-C), apolipoprotein B, non-HDL cholesterol and triglycerides in patients with known hyperlipidemia and mixed dyslipidemia. [1] Additionally, guidelines propose the use of statins in patients with hyperlipidemia and diabetes and/or established vascular disease.[2] These effects have been shown to slow down the progression of atherosclerosis and ultimately reduce the risk of cardiovascular disease (CVD) such as myocardial infarction (MI), stroke and/or death from CVD.

All of this sounded great; however, recent research has shown that nearly half of all MI’s and strokes occur amongst apparently healthy men and women with levels of LDL-C that are below currently recommended thresholds for treatment with statins.[3] What are we to do now? Fast-forward to six years, five months and twenty seven days later…

February 8, 2010. The FDA approves a new indication, making Rosuvastatin the first and only statin to receive the additional indication for primary prevention of CVD in healthy adult patients with normal LDL-C levels, an increased risk for CVD based on age, elevated high-sensitivity C-reactive protein (hsCRP) levels and the presence of one additional CVD risk factor,[4] such as hypertension, low HDL-C, smoking or family history of premature heart disease.

As reported by Reuter’s in The NY Times Business Section “this clears the way for the drug to be used by millions of people who are not typically prescribed the drug now…likely increasing sales of the drug .”[5] This statement leads one to think: does this new approval help in the advancement of preventive medical research for the betterment of our patient population or is this just another way for pharmaceutical companies to make a whopping profit? Hmmm, maybe it’s a little bit of both.

After all, this novel approval stems from a clinical trial presented for the first time in 2008 at the American Heart Association’s Annual Scientific Sessions in New Orleans, sponsored by the actual makers of Crestor, AstraZeneca Pharmaceutical Company. The trial is referred to as the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). In JUPITER, which was a randomly controlled, double-blinded, placebo-controlled, multi-center trial, the use of Crestor was examined in approximately 18,000 older patients who did not have elevated LDL cholesterol levels but illustrated other risk factors for heart disease, such as an elevated hsCRP (3). All patients examined in the trial were men and women of at least 50 and 60 years of age respectively. All lacked clinical evidence of heart disease and high LDL cholesterol levels (inclusion criteria of LDL<130 mg/dL), but all had levels of hsCRP ≥ 2 mg/L.

HsCRP is a protein/inflammatory marker found in the blood stream. Inflammation has been shown to play a major role in the initiation and progression of cardiovascular disease at the cellular level. In studies involving large numbers of patients, CRP levels have been shown to correlate with levels of cardiac risk. In fact, CRP seems to be at least as predictive, if not more predictive, of cardiac risk when compared to cholesterol levels. The Physicians Health Study,[6] a clinical trial involving 18,000 apparently healthy men, was the first large scale study to show that elevated levels of CRP were associated with a threefold increase in the risk of MI. In accordance, the Harvard Women’s Health Study [7] showed that the CRP test was more accurate than cholesterol levels in predicting coronary problems and was the strongest predictor of risk. As such, women in the group with the highest CRP levels were more than four times as likely to have died from coronary disease, suffered a nonfatal MI or stroke or to have required a cardiac procedure.

In the current study, Ridker et al. selected a treatment population according to their hsCRP level, based on the logic explained above and that statins have been shown to reduce levels of both hsCRP and LDL-C. [8,9] The investigators proposed that the main benefit of Crestor in individuals with normal levels of LDL, but elevated levels of hsCRP would be a reduced risk of non-fatal MI, non-fatal stroke and arterial revascularization (iii). In fact, patients in the study who were randomly assigned to take Crestor at a dose of 20 mg daily experienced a 44% reduction in the trial primary end point of all vascular events (P<0.00001), a 54% reduction in myocardial infarction (P=0.0002), a 48% reduction in stroke (P=0.002), a 46% reduction in need for arterial revascularization (P<0.001), and a 20% reduction in all cause mortality (P=0.02) compared to patients given the placebo. Clearly, true clinical benefit. Treatment with Crestor did not have a significant effect on secondary endpoints, such as cardiovascular death or hospitalization for unstable angina.

The percentage of patients who suffered MI, stroke, revascularization, hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the Rosuvastatin arm and 2.8% in the placebo arm (iii), an absolute risk reduction of 1.2%. The proportion of participants with hard cardiac events in JUPITER was reduced from 1.8% (157 of 8901 subjects) in the placebo group to 0.9% (83 of the 8901 subjects) in the Rosuvastatin group; thus, 120 participants were treated for 1.9 years (actual duration of the study) to prevent one event.[10]

Side effects associated with Crestor in the JUPITER trial were generally similar to those previously associated with the statin class of medication and comparable in the Rosuvastatin and placebo group, with myalgia being one of the most frequently experienced adverse reactions. Of note, in the study, patients taking Crestor had higher rates of physician-reported diabetes than those taking placebo, including a higher increase in glycosylated hemoglobin (5.9% and 5.8%, respectively; P=0.001); however, it is important to note that an analysis of individuals in the JUPITER trial who had impaired fasting glucose at baseline did show a 34% reduction in major cardiovascular events with the use of Crestor. Once again, showing it to be of some clinical benefit.

Despite the positive findings, the question still prevails: patient beneficial, pharmaceutical moneymaker or a little of both? After all, there are many limiting factors that should be taken in to account in this trial. For one, scientists are still unsure whether the positive results of the trial are due to further reduction in LDL-C, hsCRP or both, since Crestor has been clinically shown to reduce both. As evaluated in the trial at twelve months there was a 50% lower median LDL-C and 37% lower median hsCRP in the Rosuvastatin group when compared to placebo (iii). This question cannot be answered in this study; however, it suggests that future studies should look specifically at the role of other anti-inflammatory medications as vascular therapeutic agents. Importantly, the absolute risk difference, a more clinically important factor, was found to be less impressive than the relative difference. Unfortunately, this point was overlooked in the discussion section of the trial. The study may also be limited due to its inability to adequately assess the potential risks of prolonged Crestor therapy in this population. The study was designed to last approximately four-years, but was stopped after only 1.9-years by an independent data monitoring board due to “meeting” predefined efficacy goals for the patients treated with Rosuvastatin. This short follow-up period raises concern of possible longer-term effects that could not be evaluated due to the shorter duration. In addition, lack of comparison of patients with low hsCRP levels (less than 2 mg/L) is a huge study limitation as there is not a pre-defined level goal. Further, since CRP is a nonspecific protein, elevated by a number of acute inflammatory conditions, it may not be reasonable to use it as a surrogate in the decision to initiate treatment with an expensive medication with associated adverse effects. Rosuvastatin, which roughly costs $3.45 per day, is much more expensive than that of generic statins (x). With this new FDA approval it should only be a matter of time before other pharmaceutical companies promote future studies comparing similar uses of other statins.

Based on these limitations, the FDA placed restrictions on their approval of Crestor for this indication. They state that physicians should take into account the clinical context of asymptomatic individuals who have evidence of clinical risk factors. As such, the FDA maintains Crestor should only be used as a preventative measure in individuals who have no clinical evidence of heart disease, but are at increased risk due to combined effect of older age (Men≥50, Women≥60), high hsCRP levels (≥2mg/L) and patient’s who illustrate one additional risk factor such as hypertension, low HDL-C, smoking or family history of premature heart disease. This makes the approval more conservative than may have been desired by the pharmaceutical company.

Regardless, debate will continue and AstraZeneca will continue to promote this medical breakthrough that has already increased its revenue. Crestor was AstraZeneca’s third-best selling product with estimated sales of $3.6 billion early last year. Since the publication of the JUPITER study in 2008, Crestor has increasingly been taking share away from competitors, including Pfizer’s Lipitor [11] which is expected to go generic in 2011. In fact, in the last quarter, revenue rose 29% to $4.5 billion, and now the FDA has cleared the way for an estimated six million more people in the US to buy the drug. Clearly, a true money maker.

In spite of the controversy, the study did succeed in its attempt to solve one piece of a vexing problem: not everyone who suffers a cardiovascular event has high cholesterol, and it’s next to impossible to predict who’s most likely to suffer from one imminently, even among people with some risks. Maybe hsCRP is the answer. Now with the new findings, a new question to ponder: to check hsCRP levels or not? I can only say physician discretion is advised.

Dr. Bond is a first year resident in internal medicine at NYU Medical Center.

Peer reviewed by Michael Poles MD, NYU Division of Gastroenterology

1. AstraZeneca Pharmaceuticals LP. Prescribing Information. Crestor: Rusuvastatin Calcium. Retrieved February 11, 2010 from http://www.crestor.com/c/home.aspx.

2.  Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: 227-239.

3. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto A, Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFayden JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ. Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein. New Engl J M 2008. 359: 2195-2207.

4. FDA US. Food and Drug Administration. Questions and Answers for Healthcare Professionals: CRESTOR and the JUPITER Trial. Retrieved February 11, 2010 from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm199891.htm

5. Reuters. Crestor Wins Approval as a Drug to Prevent Heart Disease. The New York Times: Business Section. February 8, 2010.

6. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979.

7. Ridker PM, Hennekens CH Buring JE, Rifai N. C reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-43.

8. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. Circulation 1999;100:230-5.

9. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the Pravastatin Inflammation/CRP Evaluation (PRINCE): a randomized trial and cohort study. JAMA 2001;286:64-70.

10. Hlatky M. Expanding the Orbit of Primary Prevention- Moving beyond Jupiter. N Engl J Med 2008. 359: 2280-2282.

11. AP. FDA Panel say Astra Zeneca’s Cholesterol Pill Crestor Can Curb Heart Problems. Health News. Retrieved February 11, 2010 from http://blog.taragana.com/health/2009/12/15/fda-panel-says-astrazenecas-cholesterol-pill-crestor-can-curb-heart-problems-17104/.

PrimeCuts: This Week in the Journals

February 8, 2010

Shortcut 3Rachana Jani, MD

Faculty peer reviewed

Women’s health stepped into the spotlight this week as the public and the media painted New York City red for cardiovascular awareness.  And appropriately so, as new information about heart disease in women continues to emerge. In the Annals of Rheumatic Diseases, a population-based study found that elderly women with gout were at increased risk of acute myocardial infarction compared to men with this ailment.  De Vera et al found that women were at an increased overall risk of 39% for MI, independent of age, comorbidities, and medications [1].  The exact mechanism eludes researchers at this time, but they speculate that women respond to hyperuricemia differently than men, leading to a more atherogenic and thrombogenic response.  

Diabetes and its complications were also alluded to this week. In JAMA, researchers found that three-year risk of death and myocardial infarction was increased in those with proteinuria despite differences in estimated glomerular filtration rate (eGFR).  The study showed an increase in relative rates of death, MI, and end-stage renal disease (1.22,1.18,1.92 respectively) independent of the level of eGFR[2].

The Journal of the American College of Cardiology touches on the need for enhanced communication between physician and patient this week by acknowledging what a large role homeopathic medicine plays in patient lifestyle [3].  Tachjian et al reviewed over 90 herbal medications and their cardiovascular effects, noting 15 in particular that increase the serum levels of common cardiac medications through cytochrome P450 enzymes.  Much of the time, physicians are unaware of all the supplements that patients are taking, partly because patients do not view herbal supplements as part of full disclosure and some fear judgment by their physicians.  These barriers in communication not only limit insight into patients’ medical history, but also serve as a barrier to teamwork and goal-forming that ideally exists between physician and patient.

The Journal of General Internal Medicine found that there is a discrepancy between the goals diabetics have for their health and quality of life and those that physicians hold for their patients, even though the ultimate goal is often the same.  This prospective cohort study found that while physicians rank hypertension as one of their most important concerns for patient welfare, only 18% of diabetics share this view [4]. This difference was partly attributable to patients being unaware of the importance of managing blood pressure and the priority that patients place on pain and depression.

Some good news is that during the American Academy of Pain Medicine’s meeting this week, there were some promising results for the treatment of pain.  Iyengar et al looked at four placebo-controlled trials of duloxetine in those who suffer from fibromyalgia and major depression.  They found a 50% improvement in pain in both low and high depression scores as compared to placebo, both of which were statistically significant [5].  

Biologics also continue to play new roles in pain management in those who suffer from autoimmune disease.  This week’s British Medical Journal looked at etanercept, a tumor necrosis factor-alpha inhibitor, and found a significant improvement in psoriatic skin manifestations when patients received etanercept twice weekly as opposed to weekly. This blinded, multicenter study found that 46% of patients on a twice-weekly regimen of etanercept completely cleared lesions as compared to 32% in the once-a-week group.  Unfortunately, there was not a significant effect on psoriatic arthritis, a manifestation that occurs in approximately one third of psoriasis sufferers [6].  It is unclear why the skin manifestations responded so well to treatment and not the arthritic symptoms.

This week’s New England Journal of Medicine also focused on immunomodulating agents for a different autoimmune process: multiple sclerosis [7].  MS is often treated with injectable medications, an obstacle for some patients.  In this double-blind randomized study, oral fingolimod, a sphingosine-1-phosphate-receptor modulator that inhibits lymphocytic exit from lymph nodes, showed a significant reduction in relapse rates as compared to placebo or intramuscular interferon beta-1a.  Another oral drug, cladribine, which targets specific lymphocyte subclasses, also showed a significant decrease in the relapse rate as compared to placebo [8].  Though exciting news, as with all immunomodulators, side effects were concerning. Fingolimod was associated with conduction defects and cladribine with leukocytopenia.  This week the FDA warned of a risk of progressive multifocal leukoencephalopathy with natalizumab, another immunomodulator used in multiple sclerosis.

Lastly, despite all the new therapies available, the CDC reminds us not to forget preventable illnesses. Adults are not receiving all of the recommended age-appropriate vaccinations. This is in part due to a lack of institutional access and to a lack of coverage by insurance companies, problems that may improve in the near future.  That being said, even rates for hot items such as the H1N1 influenza vaccine have declined as the majority of Americans assume the H1N1 pandemic is over, as noted in the New York Times [9]. Anne Schuchat, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases, warns that even with a decrease in activity over the last three weeks, the H1N1 strain is still circulating and poses a threat to those not vaccinated, so it may be time to visit your friendly neighborhood doctor.

Dr. Jani is 3rd year resident in internal medicine at NYU Medical Center.

Peer reviewed by Michael Tanner MD, Associate Editor, Clinical Correlations

References:

1. De Vera MA, Rahman MM, Bhole V, Kopec JA, Choi HK. Independent impact of gout on the risk of acute myocardial infarction among elderly women: a population-based study. Ann Rheum Dis. 2010; DOI: 10.1136/ard.2009.122770.

2. Hemmelgarn BR, Manns BJ, Lloyd A, et al. Relation between kidney function, proteinuria, and adverse outcomes” JAMA. 2010;303(5):423-429.

3. Tachjian A, Viqar M, Jahangir A. Use of herbal products and potential interactions in patients with cardiovascular diseases. J Am Coll Cardiol. 2010;55:515-525. doi:10.1016/j.jacc.2009.07.074

4. Zulman DM, Kerr EA, Hofer TP, Heisler M, Zikmund-Fisher BJ. Patient-provider concordance in the prioritization of health conditions among hypertensive diabetes patients. J Gen Intern Med 2010; DOI: 10/1007/s11606-009-1232-1.

5. Iyengar S, et al. Fibromyalgia and comorbid major depressive disorder: assessment of mood and pain response to duloxetine hydrochloride compared to placebo. AAPM 2010; Abstract 121.

6. Sterry W, Ortonne J-P, Kirkham B, et al. Comparison of two etanercept regimens for treatment of psoriasis and psoriatic arthritis: PRESTA randomized double blind multicenter trial. BMJ.  2010; 340: c147. DOI:10.1136/bmj.c147.

7. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-425.

8. Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416-426.

9. http://www.nytimes.com/2010/02/06/health/06flu.html?ref=health

 

PrimeCuts: This Week in the Journals

February 1, 2010

Shortcut 3Carolina Cabral MD

Faculty peer reviewed

As the world continues to witness the earthquake aftermath in Haiti, the stories and statistics become more unsettling. As the New York Times reported this week, after the devastating earthquake struck what was already one of the world’s most impoverished nations, Haiti saw the collapse or severe damage of 20,000 commercial buildings and 225,000 residences (1). The death toll has risen above 150,000 in the Port-au-Prince area alone, not to mention those who remain unaccounted for in both Port-au-Prince and its neighboring towns of Léogâne and Jacmel.

As rescue efforts have officially ceased, the focus has now shifted to providing aid to the more than 250,000 injured civilians and half a million people left homeless. Responding to the growing need for aid and medical assistance, a team of NYU doctors, led by Dr. Fritz Francois, of the Dept. of Medicine, Gastroenterology, helped to organize NYULMC-HEART (Haitian Effort and Relief Team). This team of healthcare providers included Prisca Bernard-Joseph, RN (Bellevue) Labor & Delivery/OR, David Feldman, MD, Pediatric Orthopaedics, Mary Ann Hopkins, MD, Surgery, Kenneth Mroczek, MD, Orthopaedic Surgery, Patricia Poitevien, MD, Pediatrics and Diana (Lucia) Voiculescu, MD, Anesthesiology. This team has just returned from a one-week mission to volunteer their time in a collaborative effort to provide surgical and medical services in Port-au Prince and most importantly to help out in any way they could. Their journey is detailed in a captivating blog that can be found at http://heart.med.nyu.edu/.

Recently highlighted in the BMJ as one of the worst natural disasters in recent years, the earthquake in Haiti wiped out much of the limited infrastructure of one of the world’s poorest countries (2). Margaret Chan, member of the World Health Organization and Director of its Department of Protection of the Human Environment, states: “We have every reason to be concerned about the health of survivors. Many of the problems we try to prevent after a disaster were already present in Haiti.” These problems include diseases associated with poor water and sanitation systems, low vaccination coverage, widespread malnutrition, outbreaks of infectious diseases, a high prevalence of HIV and tuberculosis, and “erratic delivery of medicines and care”. In times of such catastrophe, while emergency and critical care medicine are crucial, one must not forget the continued importance of preventative healthcare, as pointed out by Margret Chan, which are issues that affected Haiti long before the devastating earthquake.

In the spirit of preventative healthcare, we will discuss three articles published in the current issue of NEJM that look at the use of the rotavirus vaccine to prevent severe diarrhea and its other adverse health consequences. First, let’s discuss a study on the effect of the rotavirus vaccine on severe diarrhea in African infants (3). Rotavirus is the most common cause of severe gastroenteritis among children and is estimated by the World Health Organization (WHO) to account for approximately 527,000 deaths each year (4). Vaccines represent an invaluable resource in disease prevention. Previous studies have shown that two oral, live attenuated rotavirus vaccines, Rotarix (GlaxoSmithKline Biologicals) and RotaTeq (Merck), have excellent protective efficacy against severe rotavirus gastroenteritis (5,6,7). The current study is a randomized, placebo-controlled, multicenter trial in South Africa and Malawi conducted to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. The vaccine was used in about 4500 infants who were randomly assigned to receive either two or three doses of the vaccine or placebo. Severe gastroenteritis caused by circulating rotavirus was detected in 4.9% of the placebo group as compared with 1.9% in the pooled vaccine group, a difference that was significant. The vaccine showed efficacy against severe rotavirus gastroenteritis both in infants who received two doses of vaccine and in those who received three doses. Rotavirus gastroenteritis prevention was greater in Malawi as compared to South Africa, owing to the higher incidence of severe rotavirus gastroenteritis in Malawi. On the basis of this study and other supporting data, SAGE recently recommended that rotavirus vaccination of infants be included in all national immunization programs, in conjunction with other proven interventions for diarrheal disease.

NEJM also published a retrospective study on the effect of rotavirus vaccine on death from childhood diarrhea in Mexico (8). Data was obtained on deaths from diarrhea, regardless of cause, from 2003 through 2009 in Mexican children under the age of five. This time span encompasses both the pre and post-rotavirus vaccine eras. Vaccine coverage was estimated from administrative data. In 2008, there were 1118 diarrhea-related deaths among children younger than five years of age, a reduction of 675 from the annual median of 1793 deaths during the 2003-2006 period before the rotavirus vaccine. Diarrhea-related mortality fell from an annual median of 18.1 deaths per 100,000 children at baseline to 11.8 per 100,000 children in 2008. The reduction in the number of diarrhea-related deaths persisted through two full rotavirus seasons (2008 and 2009).

On the downside however, recent data showed vaccine-acquired Rotavirus in infants with severe-combined immunodeficiency (8). The vaccine is currently recommended for routine childhood immunization, and pre-licensure and post-licensure data indicate that the vaccine is efficacious and has a low risk of associated adverse events and that administering live rotavirus vaccine is not absolutely contraindicated in persons with compromised immune systems. While HIV positive children were included in the above studies, there have been 3 case reports of rotavirus disease detected after the administration of the vaccine in infants with severe- combined immunodeficiency.

Undoubtedly there is much work to be done in terms of financial and medical assistance to Haiti as well as in the sector of preventative health both domestically and abroad. However, amid the turmoil and tragedy, there are signs of hope. This week in the New York Times, David Harland, a senior United Nations official stated: “While reeling from the quake, Haitians had already managed to re-establish a cell phone network, get remittances flowing from relatives overseas and bring in produce from the countryside, all helping the country start ticking on its own.” (9).

Dr. Cabral is a 2nd year resident in internal medicine at NYU Medical Center.

Peer reviewed by Danise Schiliro-Chuang MD, Contributing Editor, Clinical Correlations.

References

1. The Associated Press. A Glance at Haiti Developments 16 Days After Quake. The New York Times. 2010 Jan 28.

2. Moszynski P. Damage to Haiti’s infrastructure is “almost unbelievable”. British Medical Journal. 2010 Jan 20; 340:c378.

3. Madhi S, et al. Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants. NEJM. 2010 Jan 28; 362:289-298.

4. World Health Organization. Rotavirus vaccines. Wkly Epi Rec 2007; 82:285296.

5. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. NEJM. 2006 Jan 5; 354:23-33.

6. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. NEJM. 2006 Jan 5; 354:11-22.

7. Araujo EC, Clemens SA, Oliveira CS, et al. Safety, immunogenicity, and protective efficacy of two doses of RIX4414 live attenuated human rotavirus vaccine in healthy infants. J Pediatr (Rio J) 2007; 83:217-224.

8. Richardson V, et al. Effect of Rotavirus Vaccination on Death from Childhood Diarrhea in Mexico. NEJM. 2010 Jan 28; 362:299-305.

9. Patel N, et al. Vaccine-Acquired Rotavirus in Infants with Severe Combined Immunodeficiency. NEJM. 2010 Jan 28; 362:314-319.

10. MacFarquhar N. Haiti Is Again a Canvas for Approaches to Aid. The New York Times. 2010 Jan 30.

 

PrimeCuts: This Week in the Journals

January 26, 2010

Jon-Emile Kenny MD

Faculty peer reviewed

As the leading cause of death in the United States (1), cardiovascular disease enjoys much basic and clinical research. This week’s PrimeCuts will focus on recent inquiry and review pertaining to this vital system.

JAMA reported that researchers have highlighted a putative link between omega-3 fatty acids and molecular aging in patients with baseline coronary heart disease (2). Telomeres are important lengths of DNA at the ends of chromosomes. Due to the mechanics of replication, small pieces of telomeres are lost with each successive copy. Indeed critical shortening of telomeres are thought to be an important cause of molecular aging and death. The authors found an inverse association between baseline omega-3 fatty acid levels and subsequent rate of telomere shortening over time. Mechanisms are many and unclear but may relate to decreased oxidative stress and increased telomerase activity.

Radiation from occupational, medical, and environmental exposures has been associated with risk of vascular disease. This was further studied among survivors of the Hiroshima atomic bomb, and presented in the BMJ (3). As reported, doses above 0.5 Gray are associated with an elevated risk of both stroke and heart disease and that this accounted for about one third as many radiation-associated excess deaths as did cancers among atomic bomb survivors. The mechanisms are unclear, but are potentially related to pro-inflammatory states and endothelial changes that result in microvascular disease.

Airflow obstruction and ventricular mechanics were studied and reported in this week’s New England Journal of Medicine (4). Their results showed that in a population-based study of subjects without very severe COPD, the degree of airflow obstruction was associated with significant decrements in left ventricular filling and cardiac output. Interestingly, in mild COPD the mechanism of impaired LV filling is likely not secondary to elevated juxtacardiac pressure or pulmonary venous compression but more due to loss of pulmonary artery cross-sectional area observed in early disease.

COPD also made news in Chest this month as investigators provided evidence that anticholinergic medicines such as ipratropium may increase cardiovascular morbidity (10). COPD patients within the Seattle VA Hospital system were analyzed and it was found that 44 percent were exposed to anticholinergics (mainly ipratropium) at some time during the study. Further, any exposure to anticholinergics within the past 6 months was associated with an increased risk of a cardiovascular event. These results are not new and have been previously discussed in Dr. Jani’s Clinical Correlations entry (11).

Also in the New England Journal of Medicine, a computer-based model was analyzed for the effect of salt reduction on cardiovascular health (5). This model found that reducing dietary salt by three grams per day (about 1200 mg of sodium) would result in 11 percent fewer cases of new heart disease, 13 percent fewer heart attacks, 8 percent fewer strokes, and 4 percent fewer deaths. The authors note that the effect of decreased adverse cardiovascular outcomes with lower salt intake may be greater in African Americans and therefore narrow health disparities. Regardless, this article may provide fuel to the fire in New York City over the proposed municipal salt restriction (6).

What about gender differences in cardiovascular risk? It has long been known that estrogen can stimulate vascular repair (e.g. in the uterus) but also in cardiac tissue. Little has been known about the effect of androgens on angiogenesis. However, researchers have published data in the Journal of Experimental Medicine showing the importance of androgens in neovascularization (7). Interestingly, castration of male mice impaired vessel growth and androgen replacement reversed this effect. This may have implications for androgen replacement in men.

Red wine may exert its beneficial effects via the estrogen receptor (8). Investigators published results in PloS One showing the effects of red wine polyphenols on vascular physiology. Importantly the beneficial effects of polyphenols act through the estrogen receptor in a nitric oxide dependent pathway. Not only does this provide a potential mechanism for the vascular effects of red wine, but may partially explain the epidemiological data that has showed lower cardiovascular risk in women than men; and why this protection progressively disappears after menopause.

In a similar, but seemingly paradoxical, vein investigators have replicated earlier findings that Bisphenol A (BPA) is associated with adverse cardiovascular outcomes (9). Oddly, BPA imparts some of its biochemical effects via the estrogen receptor, but also through the PPAR gamma receptor. The latter may also explain the association of elevated urinary BPA and insulin resistance. Regardless, the replication of these results in an independent population provides mounting evidence that environmental exposure to BPA may lead to adverse cardiovascular events.

Lastly, Tomlinson and Detsky from the University of Toronto, afforded a great commentary on composite end-points in randomized trials (12). These are frequently used in cardiovascular research and often frustrating when trying to interpret results. Frequently composite end-points are used for efficiency, but the trade-off is that less-severe surrogates of death and disease (e.g. hospitalization) may drive statistical significance. The authors recommend that readers and authors of randomized trials weight each of the outcomes by an importance factor (e.g. as quality of life is measured) and/or note that although a randomized trial was designed to detect a difference in a composite outcome, the trial may have mainly demonstrated an effect on surrogate outcomes and not definitive ones.

Dr. Kenny is a 3rd year resident in internal medicine at NYU Medical Center.

Primecuts-This Week in the Journals

January 18, 2010

martin-luther-kingMegha Shah, MD

Facutly Peer Reviewed

As you sit down to read this week’s Primecuts, just take a few moments to think about those affected by the tradegy in Haiti. The devastating earthquake that shook the small nation early last week not only affected the nine million inhabitants that call it home but people all over the world, including, as we do live in a global city, our colleagues, neighbors, and patients. As members of the medical community, it is, of course, our inclination to help and though not all of us may be able to make the journey and provide the physical support, there are several other things that we can do.  And, as always, thoughts and prayers are always free as Haiti makes its way towards recovery.

First in this week’s Primecuts- a SIGH of relief for those of us who shake at the idea of those darned multiple choice tests. The New York Times reports on a recent study published in the Journal of Applied Psychology that there may be a better way to predict a student’s success as a physician: personality testing. In the study, three psychologists from the United States and Europe analyzed whether extraversion, openness, conscientiousness, agreeableness, and neuroticism- traits which the researchers termed as the “Big Five”- had any significant correlations with medical school performance as judged by attrition rates and grade point averages. The study followed more than 600 students in Belgium where premedical and medical curriculums are combined into one seven year program. As is the case in the United States, the first part of the curriculum centers on acquiring basic science knowledge while the last years are devoted towards clinical practice. Students were asked to take a standardized personality test at the start of the study and analyzed based on their individual personality profiles. Overall, the study found that students who were extraverted, open, and, most of all, conscientious, academically performed better throughout the course of medical school.  In contrast, neuroticism was a constant predictor of poor performance and also of attrition. Of note, those who were extraverted struggled early on during the years of classroom work, but excelled when it came time to practice in the clinics. If nothing else, the study provides more evidence that success as a physician can be attributed to more than just test scores! WHEW! [1, 2]

Post-traumatic stress disorder (PTSD) is something commonly often encountered, particularly for those working in a VA setting. A study published in the New England Journal of Medicine reports that in civilians and military personnel with injuries suffered as a result of combat (excluding traumatic brain injury), the use of morphine during early resuscitation and trauma care was associated with a significantly lower risk of developing PTSD. The study included 696 U.S military personnel who were injured during a combat heavy period of 36 months during Operation Iraqi Freedom.  Of the 696, 243 received a diagnosis of PTSD within a 1-24 month period and of those, 61% received morphine. The other 453 did not develop PTSD and of those, 76% had received morphine (odds ratio 0.47, p<0.001). The study did have its limitations including a study design that was observational, missing medication data for some patients leading to their exclusion from the analysis, and an analysis that did not address a dose-response relationship between morphine and PTSD, but it did highlight not only the prevalence of PTSD but also of a potential strategy to keep it from occurring.

We all spend time in our clinics counseling patients on the risks of smoking, but what about the risk of smoking cessation? In this week’s Annals of Internal Medicine, researchers, as part of the Atherosclerosis Risk in Communities (ARIC) study, sought find whether smoking cessation, at least acutely, would lead to an increased risk of diabetes owing to cessation related weight gain. The study followed approximately 10,000 middle-aged adults who initially did not have diabetes from 1987 to 1989. In a nine-year followup period, 1254 of these patients developed type 2 diabetes. Those who smoked had an adjusted hazard ratio of incident diabetes of 1.42 (95% CI, 1.2- 1.67).  After adjusting for demographics and co-morbidities such as hypertension, hazard ratios of diabetes for those with a history of smoking as compared to those who never smoked were 1.22 for former smokers (those who quit within the first three years of followup), 1.31 for current smokers, and 1.73 for recent quitters (those who quit during years six to nine of followup) showing that, at least in the short term, smoking cessation had the highest risk of developing type 2 diabetes. The study stresses the importance of not only counseling patients on smoking cessation, but also on additionally advocating for other lifestyle modifications such as activity and diet for both the short and long term. [4]

In an early online publication of The Lancet,  researchers in the Platelet Inhibition and Patient Outcomes (PLATO) trial reported more findings to support the use of ticagrelor over clopidogrel in patients with acute coronary syndromes. The use of ticagrelor, a reversible platelet aggregation inhibitor manufactured by Astra Zeneca, was reported to have lower mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in an initial study published in the New England Journal of Medicine in September 2009. In this more recent study, ticagrelor and clopidogrel were compared in patients with ACS who were also planned for subsequent invasive management. Approximately 13,000 patients were randomized to either ticagrelor (180mg loading with 90mg twice a day maintenance) or clopidogrel (300-600mg loading with 75mg maintenance) with aspirin for 6-12 months. The primary composite endpoint (cardiovascular death, myocardial infarction, or stroke), occurred in fewer patients in the ticagrelor group with a total of 569 events versus that in the clopidogrel group with a total of 668 events (hazard ratio 0.84, p=0.0025), leading the researchers to conclude that ticagrelor may be a better option in patients with ACS undergoing invasive strategies. [5, 6]

Lastly, Lancet Neurology reports on the EARLY trial which compares outcomes in patients receiving dipyridamole with aspirin within 24 hours of presenting with symptoms of an acute ischemic stroke or transient ischemic attack versus those who receive dipyridamole after seven days of aspirin monotherapy. In this study, patients in 46 stroke centers in Germany were randomized to either aspirin plus dipyridamole within 24 hours or aspirin monotherapy for seven days with the subsequent addition of dipyridamole for 90 days. At 90 days, patients were contacted by phone and assessed for residual neurologic disability. A primary composite endpoint (non-fatal stroke, TIA, non-fatal myocardial infarction, and major bleeding complications) was also assessed. The study found no significant difference in either outcome. Mild or no disability was reported by 52%  of those who received dipyridamole with aspirin within 24 hours versus 56% who received dipyridamole after seven days of aspirin monotherapy (p= 0.45). A total of 28 patients in the former group and 38 patients in the latter reached the primary composite endpoint (hazard ratio 0.73, p=0.2). Thus, the study shows that the early use of dipyridamole is as effective and safe in minimizing neurologic disability as is dipyridamole used after seven days of aspirin monotherapy. [7]

That’s it for this week’s Primecuts- good luck to all the interns on the in-service exam and remember, personality counts!

Megha Shah is a first year resident at NYU Medical Center

Peer Reviewed by Judith Brenner, MD Associate Editor, Clinical Correlations

Picture of Dr. Martin Luther King courtesy of Wikimedia Commons

References:

1. Chen, PW. Do You Have the “Right Stuff” to be a Doctor? New York Times. Jan 14, 2010

2. LieLiveLievens F, Ones DS, & Dilchert S. Personality Scale Validities Increase Throughout Medical School. Journal of Applied Psychology. Nov 2009; 94 (6): 1514-1535

3. Holbrook TL, Galarneau MR, Dye JL et al. Morphine Use After Combat Injury in Iraq and Post-Traumatic Stress Disorder. The New England Journal of Medicine. Jan 2010; 362 (2): 110-117

4. Yeh HC, Duncan BB, Schmidt MI et al. Smoking, Smoking Cessation, and Risk for Type 2 Diabetes Mellitus. Annals of Internal Medicine. Jan 2010; 152 (1): 10-17

5. Cannon CP, Harrington RA, James S et al. Comparison of Ticagrelor with Clopidogrel in Patients with a Planned Invasive Strategy for Acute Coronary Syndromes (PLATO): A Randomized Double-Blind Study. Lancet. Early online publication. January 14, 2010

6. Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. The New England Journal of Medicine. Sept 2009; 361 (11): 1045-1057

7. Dengler R, Diener HC, Schwartz A et al. Early Treatment with Aspirin Plus Extended Release Dipyridamole for Transient Ischemic Attack or Ischemic Stroke within 24H of Symptom Onset (EARLY trial): a Randomized, Open-Label, Blinded- Endpoint Trial. Lancet Neurology. Early online publication, January 8, 2010

PrimeCuts: This Week in the Journals

January 11, 2010

snow

Kathir Palanisamy MD

Faculty peer reviewed

With the recent Christmas day terrorist attack fresh in our memories, the New York Times published an article about some of the health risks of the proposed whole body airport scanners. The two major technologies used in these whole body scanners are backscatter and millimeter wave. Backscatter scanners use ionizing radiation, about 1% of the amount used in dental x-rays. To put this into perspective according to Robert Barish’s book, “The Invisible Passenger,” the dose delivered would be the same as a few minutes in a high altitude airplane. At high altitudes there is much less atmosphere to shield passengers from cosmic radiation. Even so, radiation experts are divided whether this small amount of radiation will collectively lead to more cancer deaths in a large population. Millimeter wave scanners utilize non ionizing radiation, however the image they create are not as clear. Ultimately, we have to decide as a society what inconveniences and possible health risks we are willing to accept in the name of safety. (1)

H1N1 influenza continued to be in the headlines this week with an article in the New England Journal of Medicine about the risks it poses in pregnant women. The study looked at data collected by the California Department of Health about reproductive age women who were hospitalized or deceased in the state of California from April 2009 to August 2009. The study had a couple of noteworthy findings. There was a high incidence of false negatives (38%) in the rapid antigen test as compared to the gold standard of RT-PCR. In addition, later treatment, defined as more than two days after symptom onset with antivirals, led to a relative risk of 4.3 for admission to the ICU or death as compared to early treatment. Thus, the study suggests that even with negative rapid antigen tests, treatment with antivirals should be considered. (2)

Also in this week’s New England Journal of Medicine were two articles focusing on the prevention of surgical infections. The first studied the efficacy of decreasing Staphylococcus aureus health care-associated infections in patients who are nasal carriers of this organism. A total of 917 patients who were expected to stay in the hospital for greater than four days and were identified by real-time polymerase-chain-reaction (PCR) assay as being nasal carriers of S.aureus were randomized to treatment with intranasal mupirocin and chlorhexidine soap versus placebo. All S. aureus strains identified on PCR assay in this study were susceptible to methicillin and mupirocin. The rate of post operative S. aureus infection in the mupirocin-chlorhexidine group was 3.4%, as compared with 7.7% in the placebo group (RR 0.42; 95% CI, 0.23 to 0.75). This relative risk of 0.21 was most pronounced for deep surgical-site infections. This article suggests that the number of surgical-site S. aureus infections acquired in the hospital can be reduced by rapid screening and decolonizing of nasal carriers of S. aureus on admission. (3)

The second study compared 849 patients undergoing clean-contaminated surgery who had received a single chlorhexidine-alcohol scrub versus a povidone-iodine scrub with the primary endpoint of surgical site infection within thirty days of surgery and secondary endpoint of the type of surgical site infection. Clean contaminated surgery is defined as surgery involving the respiratory, gastrointestinal, or genitourinary tracts without leakage or break in aseptic technique. The study found total surgical-site infections were reduced by 40% in the cohort who had received a single chlorhexidine alcohol scrub as compared to the povidone-iodine scrub group. (4)

These studies in this week’s Journal along with the majority of the literature suggests that chlorhexidine-alcohol should replace povidone-iodine as the standard for preoperative surgical scrubs. Interestingly in the chlorhexidine-alcohol versus a povidone-iodine study, the rate of S. aureus surgical-site infections was reduced by approximately 50% in the chlorhexidine-alcohol group despite none of the patients receiving intranasal mupirocin. From a prior study the chlorhexidine-alcohol solution as compared to povidone-iodine has also been found to reduce catheter-associated infections by approximately 50%. The use of intranasal mupirocin and chlorhexidine baths for carriers of S. aureus who have been identified preoperatively by means of a real-time polymerase-chain-reaction assay could be reserved primarily for patients who are undergoing cardiac surgery, all patients receiving an implant, and all immunosuppressed patients. The incremental value of preoperative baths with chlorhexidine alone for all surgical patients still requires further study, but the data reported in these two studies will likely change the approach to prevention of surgical infections. (5)

Turning to general medicine practice related concerns, MDconsult reported on the ADA’s decision to add hemoglobin A1c to the diagnostic criteria for Type II diabetes. The four ways a patient can now be diagnosed with DMII are: the newly added HgbA1c with a cutoff of 6.5%, a fasting glucose greater than 126 mg/dl, a glucose level of greater than 200 mg/dl, 2 hours after 75g oral glucose tolerance test, or a random glucose greater than 200 mg/dl in a patient with symptoms of hyperglycemia. This new addition to the diagnostic criteria is a result of improvements in the standardization of the A1c assay across laboratories, greater convenience of a non-fasting test, the correlation between diagnostic cutoff levels of above mentioned tests and the known threshold risk for development of retinopathy. The downsides cited by the ADA were cost, limited availability in the developing world, and misleading results in patient populations with hemoglobinopathies or inherent alterations in their rate of glycosylation. (6)

Our last stop on this week’s tour of the medical literature is a meta analysis published in Chest which analyzed the cardiovascular safety of Tiotropium in patients with COPD. This meta analysis was done in light of recent findings published in the UPLIFT(Understanding Potential Longterm Impacts on Function with Tiotropium) trial. UPLIFT was a four year randomized, placebo controlled clinical trial which showed improvement in lung function, quality of life, survival, and decrease in COPD exacerbations in patients treated with tiotropium. Results from this trial were also noteable for a reduced risk of fatal CV events adding credence to the safety profile of tiotropium in COPD patients. In this setting a meta analysis of all randomized, double-blind, placebo controlled trials completed prior to 2008 of at least four weeks duration with inclusion criteria of spirometry confirmed COPD, greater than 10 pack year smoking history, and age greater than 40 was done. A review of these trials yielded a total of 19,545 patients randomized to one of two groups: 10,846 to Tiotropium and 8,699 to placebo.
The endpoints were incidence ratios of all cause mortality and composite endpoint of cv deaths, nonfatal myocardial infarction, nonfatal stroke, and sudden cardiac death. The RR in the Tiotropium group of all cause mortality was 0.88 and for CV events was 0.83. Thus, Tiotropium as compared to placebo lowered all cause mortality and composite CV events. (7)

Dr. Palanisamy is a 3rd year resident in internal medicine at NYU Medical Center.

Peer reviewed by Cara Litvin MD, Executive Editor, Clinical Correlations.

References:

1. Wald M. Cancer Risks Debated for Type of X-ray Scan. New York Times: 2010 Jan 8

2. Louie J, Acosta M, Jamieson D et al. Severe 2009 H1N1 influenza in Pregnant and Postpartum Women in California. NEJM. 2010 Jan 7; 362(1):27-35.

3. Bode L, Kluytmans J, Wertheim H et al. Preventing Surgical-Site Infections in Nasal Carriers of Staphylococcus aureus. NEJM. 2010 Jan 7; 362(1):9-17.

4. Darouiche R, Wall M, Itani K et al. Chlorhexidine-Alcohol versus Povidone-Iodine for Surgical-Site Antisepsis. NEJM. 2010 Jan 7; 362(1):18-26

5. Wenzel R. Minimizing Surgical-Site Infections. NEJM. 2010 Jan 7; 362(1):75-77

6. Tucker M. ADA officially endorses hemoglobin A1c criteria for diabetes diagnosis. MD Consult: 2009 Dec 30.

7. Celli B, Decramer M, Leimer I et al. Cardiovascular Safety of Tiotropium in Patients with COPD. CHEST. 2010 Jan; 137(1):20-30

PrimeCuts: This Week in the Journals

January 4, 2010

akglacierRamin Hastings MD

Faculty peer reviewed

While the journals and media continue to focus on the H1N1 virus, an article published in The Journal of the American Medical Association (JAMA) sparked a good deal of controversy. In fact, the New York Times referenced the study in an article entitled, “F.D.A to Seek New Standards on Human Tests (1).” Dhruva et al set out to study the premarket approval process for medical devices and the quality of the evidence used during that process (2). They performed a systematic review of 123 studies used in 78 premarket approvals for high-risk cardiovascular devices between January 2000 and December 2007. The approval process for these devices is the “most stringent type of device marketing application required by the FDA.” In their review they found the mean number of studies used to support an approval was 1.6 with 65% of approvals supported by only a single study. In the 123 studies, 27% were randomized, 14% were blinded, 96% were multi-centered, and study sizes ranged from 23-1548 with a mean of 308 subjects. The New York Times interviewed Dr. Jeffrey Shuren, the acting director of The Center for Devices and Radiological Health at the FDA. He stated that there will be changes in what the FDA will require for device approval, and the studies will require more sharply defined end points. In an unusual move, the FDA will release their own study which found that 40% of studies used to approve cardiovascular devices lacked “high-quality” data. Dr. Shuren went on to say that while changes have already been made since 2007, more are likely on the way.

Another controversial study, by a group from the National Institute of Health (NIH), was in the Archives of Internal Medicine this week (3). This study pointed out that the risk of radiation from Computed Tomographic (CT) scans might be worse than we originally thought. The researchers used health insurance data to estimate the number of CT scans performed each year. They estimated that 72 million CT scans were performed during 2007. They excluded CT scans performed during the last 5 years of life, leaving 57 million CT scans that would put patients at risk for the development of cancer. Using dosing from established protocols and cancer rates amongst patients with prior radiation exposure (much from the Japanese atomic bomb survivors), they estimated that these 2007 CT scans will cause 29,000 future cancers secondary to radiation exposure. While CT scans have become a mainstay in medicine and are often crucial in diagnosis, we must acknowledge that the scans are not completely benign and health professionals must become more prudent in patient selection for these scans.

In other journals, Circulation released more results from the BARI-2D study (4), further clarifying the optimal treatment for diabetics with coronary artery disease. The original BARI-2D study found that in diabetic (type 2) patients with stable ischemic coronary artery disease no decrease in all-cause death was noted when randomized to percutaneous coronary intervention (PCI) compared to optimal medical therapy. The study this week examined the secondary outcomes of BARI-2D, including cardiac death and myocardial infarction. The study design first had physicians decide if CABG or PCI would be the recommended revascularization procedure. The subjects were then randomized to that procedure plus intensive medical therapy or intensive medical therapy alone. The study also randomized subjects to insulin provision or insulin sensitization therapy in a 2×2 factorial design. Overall there was no difference between all-cause death, cardiac death, or MI between the revascularization group and medical therapy group. In subjects who physicians decided PCI would be the optimal procedure, the group randomized to PCI did not differ in overall death, cardiac death, or MI compared with the medical therapy group. In the group where physicians decided CABG would be the treatment of choice, there was no difference in death or cardiac death between the group receiving the CABG and the medical therapy alone group (8.0% cardiac death in CABG group vs. 9.0% in medical therapy group). However the CABG group had fewer MIs compared to the medical therapy group (10% 5-year rate of MI in the CABG group vs. 17% in medical therapy group; p-value 0.003). Additionally, there was no difference between the group randomized to insulin sensitization compared with the insulin provision group for any of the outcomes. This data supports that diabetic patients with stable coronary artery disease who would not undergo CABG receive no benefit from revascularization by PCI. However interpreting the CABG data is not as clear. The decrease in MIs did not relate to changes in mortality. The benefit may be obscured by the fact that the majority of MIs in the CABG group were procedural related, and those subjects who had MIs had a much higher risk of subsequent death during the follow up period.

Finally in this week’s New England Journal of Medicine there is a nice review of activated protein C use in severe sepsis, addressing several controversies surrounding its use (5). The review explains the pathophysiology behind activated protein C, including its anticoagulant activity and inhibition of the systemic inflammatory response during sepsis. The review goes on to explain the evidence behind the drug’s use in sepsis. The PROWESS trial (6) was the original study which showed a decrease in mortality from 30.8% in the placebo group to 24.7% in the activated protein C group. Analyses from that trial showed the majority of the effect occurred in subjects with severe sepsis (APACHE score > 25). Subsequent data has shown that there is no benefit in those with APACHE scores < 25 or only single organ dysfunction (ADDRESS trial (7)), as well as no benefit in children (8). Much controversy has surrounded the fact that the PROWESS trial was sponsored by Eli Lilly, (makers or recombinant human activated protein C (drotrecogin alfa); Xigris) and after just the single trial the Surviving Sepsis Campaign, also heavily supported by Eli Lilly stated in their position statement that they recommend using Xigris in subjects with severe sepsis. Critics charged that the Surviving Sepsis guidelines were really just an extension of Eli Lily’s marketing. In response to these charges the group changed the recommendation the following year to “we suggest.” Further in response, Eli Lilly has started another trial analyzing Xigris’ use in severe sepsis with APACHE scores > 25. Nevertheless, despite all the controversy, the authors of this review support Xigris’ use in subjects with severe sepsis (APACHE score > 25) and evidence of multi-organ dysfunction.

As we usher in a new year, we have time to look back at the biggest stories in medicine from 2009. Health care reform took center stage in politics, new recommendations for mammography sparked almost as much controversy, a mother gave birth to octuplets, and a strain of influenza terrified a nation. Nature’s year in review provided some interesting numbers to think about (9): The estimated death rate of the 1918 influenza pandemic was 2%, while H1N1 has a death rate of 0.007-0.045%. There are 6,250 deaths from H1N1 through November, while 250,000-500,000 people die every year from seasonal flu. Life expectancy has risen to 78 years in the US, while in Sierra Leone the life expectancy is 40 years. Death rate of uninsured emergency room patients is 5.7% while insured patients have a death rate of 3.3%. On a more uplifting note, the cost of sequencing a human genome dropped from $300 million in 2003 to $4,400 in 2009.

Dr. Hastings is a 2nd year resident in internal medicine at NYU Medical Center.

Peer reviewed by Neil Shapiro MD, Editor in Chief, Clinical Correlations.

REFERENCES:

1. Meier B. F.D.A to Seek New Standards on Human Tests. The New York Times. 2009 December 30, 2009;Sect. B1.

2. Dhruva SS, Bero LA, Redberg RF. Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices.

3. Berrington de Gonzalez A, Mahesh M, Kim KP, Bhargavan M, Lewis R, Mettler F, Land C. Projected cancer risks from computed tomographic scans performed in the United States in 2007. Arch Intern Med2009 Dec 14;169(22):2071-7.

4. Chaitman BR, Hardison RM, Adler D, Gebhart S, Grogan M, Ocampo S, Sopko G, Ramires JA, Schneider D, Frye RL. The bypass angioplasty revascularization investigation 2 diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction. Circulation2009 Dec 22;120(25):2529-40.

5. Toussaint S, Gerlach H. Activated protein C for sepsis. N Engl J Med2009 Dec 31;361(27):2646-52.

6. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Jr. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med2001 Mar 8;344(10):699-709.

7. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med2005 Sep 29;353(13):1332-41.

8. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet2007 Mar 10;369(9564):836-43.

9. 2009 by the numbers. Nature Medicine2009 12/2009;15(12):1351-2.

Primecuts-This Week in the Journals

December 28, 2009

champagneKevin Hsueh, MD

This week finally sees the passage of a belated, but significant milestone in healthcare reform in the United States.  On Christmas Eve ’09, the Senate passed its version of the healthcare reform bill,  potentially setting in motion a radical shift in the way health coverage is provided in the United States.  Of course, significant political wrangling still is yet to be done, as both the House and Senate versions need to be reconciled prior to the bill being signed into law.  Luckily for those of us tired of the endless partisan bickering, post-vote rancor has been somewhat muted, as lawmakers, lobbyists, and TV commentators have all taken off for the holiday recess.  It will have to wait till the new year to see how contentious the debate becomes now that reform is that much closer to realization.

Like the healthcare debate, healthcare news has also been largely subdued in the holiday lull.  One notable exception has been The New York Times’  December 23rd front-page report on the debate over the costs and benefits of aggressive medical treatment.  The article highlights a new study in the November 2009 issue of the journal Circulation, which was written largely as a response to the results of the Dartmouth Atlas of Health Care,  a study of Medicare recipients with chronic diseases in their last two years of life. Read more »

Primecuts-This Week in the Journals

December 22, 2009

trainIshmeal Bradley, MD

The year 2009 could aptly be named “The Year of the Swine Flu.” Indeed, the emergence of a new influenza pandemic was the biggest health story of the year. In a rather tongue-in-cheek approach, the journal Science named the new H1N1 strain “Virus of the Year.” (1) While the public health community had been focused on Asia as the source of the next great influenza pandemic, especially given the outbreak of H5N1 avian flu in 2003, H1N1 surfaced unexpectedly in North America. The virus, discovered in Mexico in March, quickly spread around the world. Then, on June 11, 2009, the World Health Organization declared a state of pandemic. As of last week, 28 countries had reported cases of H1N1 with an estimated death toll of 9,600 people worldwide.

Quickly after the appearance of this new virus, researchers began to the race to develop a vaccine. Since the virus appeared in the North American spring, drug manufacturers wanted to create a vaccine before the start of the autumn flu season. Both the New England Journal of Medicine and the Annals of Internal Medicine published articles on H1N1 vaccine trials at various sites worldwide. Some of the key questions in these three trials focused on the optimum dose of vaccine and whether multiple doses would be needed (especially for children and the elderly). Another article examined the cost effectiveness of a large scale vaccination program in a city the size of New York.

The first of these trials is a study out of England. (2) In this study by Clark et al., they tested an oil-in-water adjuvanted H1N1 vaccine at a single center in Leicester, England. This was a small, randomized, phase 1 study with only 176 patients. The researchers compared different doses of non-adjuvanted vaccine with different doses of adjuvanted vaccine, both given over the course of three weeks, to determine which dose would elicit the best immune response. One purpose of their study was to find out if an accelerated vaccination schedule (i.e. a single dose rather than two dose spread out over one to three weeks) would be sufficient to create immunity. They found that a single dose of adjuvanted H1N1 vaccine at 15µg would be sufficient. This study had several drawbacks, however, notably its inclusion only of adults aged 18-50 years old and its very small sample size. Since children and the elderly are the most vulnerable to influenza, data on these age groups would have been welcome.

These English results were echoed in a study out of Australia. (3) Greenberg et al. wanted to study which was the optimum dose of vaccine and if the elderly would benefit from multiple doses. Over the summer there was significant uncertainty in the medical community about the effect of age on the immune response. This larger, phase 2 study (240 patients) was randomized, observer-blind, and had four arms: subjects aged 18-49 with low-dose vaccine, 18-49 with high-dose vaccine, subjects aged 50-64 with low-dose vaccine, and 50-64 with high dose vaccine. Again, children and adolescents were excluded from this study. Each patient received a non-adjuvanted vaccine (either 15 or 30µg) 21 days apart. They observed that after a single low-dose vaccine, there was a 77% seroconversion rate for those aged 18-49, compared with a 71% conversion rate for those 50-64. After a single high-dose vaccine, there was an 85% conversion rate for those 18-49, compared with 77% for those 50-64. After a second dose, these seroconversion rates increased to 84% and 81% for the low-dose group and 88% and 91% for the high-dose vaccine group. Their results provided more information that a single dose of 15µg of H1N1 vaccine was adequate to protect most adults. Given the initial concerns that there would be a profound vaccine shortage, their study shows the vaccine supply could be stretched to cover more people if only one dose per person was used.

The last vaccine study comes from China. (4) This mammoth trial by Zhu et al. enrolled 2,200 patients in Taizhou, China, and it was more encompassing than the previous two studies. Their goal was to determine if certain age groups, namely the very young and very old, would mount an appropriate immune response after one dose of vaccine, or if a booster would be needed as data from other studies had suggested. In addition to the sheer size of this study, two other strengths are the remarkably high follow-up numbers (94% of subjects were included in the final analysis) and its focus on different age groups. These researchers stratified patients into four groups: children (3-11yo), adolescents (12-17yo), adults (18-60yo), and the elderly (+61yo). They also compared alum-adjuvanted vaccine with non-adjuvanted vaccine. Their data showed that the non-adjuvanted vaccine worked better than the adjuvanted one in creating immunity.

Briefly, they found that in the children group, 83% seroconverted after a single high-dose vaccine (30µg), compared with 75% in the low-dose group (7.5µg). After the second dose, both those in the high- and low-dose groups had a >95% conversion rate. For the adolescents in both the high- and low-dose groups, after a single shot, there was a 97% conversion rate, which increased to 100% after the second dose. In the adult group, there was >93% seroconversion after a single administration of either high- or low-dose vaccine. After the second dose, the conversion rate increased to >97%. And finally, in the elderly group, 79% converted after a single low-dose vaccine and 84% with the high-dose. After a second administration, these rates increased to 93% in the low-dose group and 96% in the high-dose group.

Age was an important factor in the immune response generated. Children and the elderly did not have as robust a response as adolescents or adults. However, after the second dose, they did reach >90% conversion. It also showed that since adolescents and adults mounted a significant response after one dose, a second dose did not substantially offer more benefit. This could affect public health policy by requiring the elderly and children to receive two doses, and offering only one does to adolescents and adults, thus saving much-needed vaccines for those in more need.

The benefit of these studies is that they give us valuable information about who should be vaccinated first and who would need repeat vaccinations. During a pandemic, it is crucial to know which citizens will need repeat vaccinations and at what dosing intervals to prevent catastrophic spread of a contagious disease. One more study from the Annals looks at the effectiveness and cost-effectiveness of a widespread vaccination campaign in the city the size of New York. (5) In their complicated statistical model, this team of public health researchers concluded that an early, widespread campaign would be cost-saving. If the pandemic peaked in October, then a vaccination campaign would save the city about $469 million if they assumed moderate infectivity, and $302 million if the pandemic peaked in November. Also, vaccinating the population in October would prevent 2,051 deaths compared with 1,468 deaths if the campaign started in November. A key finding of their model was that not everyone needed to be vaccinated in a pandemic. They found that only 40% of the population needed to be vaccinated to create herd immunity and limit viral transmission. This finding is important given the early limited supply of vaccines.

These four studies all assumed a relative paucity of available vaccine, which is not a trivial matter in a global pandemic. But thanks to the accelerated efforts by drug manufacturers, the American public will have many more vaccines than originally anticipated, about 100 million doses, the New York Times reported. (6) No longer is the vaccine restricted to high-risk patients (pregnant women, seniors, and those with chronic illnesses). Despite the high numbers of people who have already been vaccinated, the CDC is still recommending that more people get the shot to prevent a third wave of illness, especially now that more doses are available.

So, what should we be doing? It’s not too late to offer the vaccine to everyone, regardless of age, that comes into our office. There may have been a lot of hype earlier this year about the threat of pandemic, but thanks to the swift action of public health authorities, with quarantines and the rapid development of vaccines, it appears that much of that threat has remained unrealized. H1N1 may not have turned out to be great pandemic, but we did get valuable first-hand experience in preparing for the next big one.

References:

1. Enserink, Martin and Jon Cohen. Virus of the Year: the Novel H1N1 Influenza. Science. 2009;326:1607. http://www.sciencemag.org/cgi/reprint/326/5960/1607.pdf

2. Clark, T.W. et al. Trial of 2009 Influenza A (H1N1) Monovalent MF59-Adjuvanted Vaccine. NEJM. 2009;361:2424-35. http://content.nejm.org/cgi/reprint/361/25/2424.pdf

3. Greenberg, M.E. et al. Response to a Monovalent 2009 Influenza A (H1N1) Vaccine. NEJM. 2009; 361:2405-13. http://content.nejm.org/cgi/reprint/361/25/2405.pdf

4. Zhu, F.-C. A Novel Influenza A (H1N1) Vaccine in Various Age Groups. NEJM. 2009;361:2414-23. http://content.nejm.org/cgi/reprint/361/25/2414.pdf

5. Khazeni, N. et al. Effectiveness and Cost-Effectiveness of Vaccination Against Pandemic Influenza (H1N1) 2009. Annals of Internal Medicine. 2009;151:829-839. http://www.annals.org/content/151/12/829.full.pdf+html

6. Associated Press. More Vaccine Has US Urging Swine Flu Shots for All. New York Times [internet]. 2009 Dec 17. http://www.nytimes.com/aponline/2009/12/17/health/AP-US-MED-Swine-Flu.html?scp=15&sq=December+17+2009&st=nyt

Primecuts-This Week in the Journals

December 14, 2009

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Sarah Lee, MD

As the national healthcare debate rages on and while winter decides to give us a premature hello,  Primecuts turns its view towards the overuse of antibiotics in the Petri dish we call the intensive care unit, more discussion on the HIV vaccine we discussed last week, the plight of the uninsured and an in depth analysis of the Tiger Woods story… ok now that we have your attention…

Throughout the world today, infection continues to be one of the main contributors to morbidity and mortality in intensive care units (ICU’s).  There have been few studies addressing our ability to control and understand the patterns of infection that occur in ICU’s internationally. This week in  JAMA, Vincent and colleagues look at the global struggle to combat infection and infection-related deaths in the critical care setting.  Their study (known as EPIC II) was a point prevalence investigation that looked at 13,796 patients in over 1200 ICU’s in 75 different countries on  a single day.  This study served as a follow-up to the 1995 EPIC (European Prevalence of Infection in the ICU) conducted 15 years earlier which similarly surveyed ICU’s in western Europe. (1)  Their results revealed a dismal report of news from the battlefront: of the ICU patients surveyed on the given day, 51% were considered infected and 71% of patients were being administered antibiotics (including prophylactically), with the majority receiving multiple antibiotics. This is in stark contrast to the original EPIC study which showed an infection rate of 44.8% with 62.3% of ICU patients receiving antibiotics. Of the infections, gram-negative infections accounted for 63% of infections compared to 39.1 % in the 1995 EPIC study.  There was likewise a marked increase in multi-drug resistant gram-negative organisms such as acinetobacter and pseudomonas. (2) In North America, most of the S. aureus infections were found to be methicillin-resistant and prevalence of fungal infections increased from 17-19%.  Infections among the most critically ill are certainly not declining.  And so, as Opal and Calandra write in an accompanying editorial we should use antimicrobials wisely-limit their use to clear infection over colonization and discontinue antibiotics as early as possible. These are principles we know, but must recall and put into practice.

Research in the field of infectious disease continues to make headway with studies on the development of a safe and effective vaccination against HIV-1.  Last week’s Primecuts touched on the search for the elusive HIV vaccine and here we dig a little deeper into the article found in last week’s New England Journal of Medicine.   Thailand is a country which has seen a dramatic increase in HIV infection prevalence due to its commercial sex-trade and high rates of IV drug use.  It is here that Rerks-Ngarm and colleagues evaluated the efficacy of a potential vaccination in a randomized, multicenter, double-blind, placebo-controlled efficacy trial centered in 2 Thai provinces. Subjects were 16,402 non-HIV infected men and women, primarily heterosexual, volunteer subjects between the age of 18 and 30. (3) Vaccination protocol consisted of four priming injections with a recombinant vector vaccine (ALVAC-HIV vCP1521) followed by 2 booster injections of a recombinant glycoprotein vaccine (AIDSVAX B/E).  This prime-boost concept had been previously established to induce both cellular and humoral responses. (4)  In this intention-to-treat analysis 132 subjects, were diagnosed with HIV during 52,985 person-years of follow-up 56 of whom were vaccinated and 76 of who received placebo. Overall, results of the study demonstrated a modest vaccination efficacy of 31.2%.  Moreover, immunogenicity, determined by the presence of gamma-interferon produced by T cells, measured by ELISASPOT testing was positive in 19.1% of vaccinated subjects 6 months after the completion of the vaccination series. Unfortunately, the vaccination was not shown to demonstrate any reduction in viral load or in CD4+ T-cell count in subsequently infected subjects. The study thus shows that there is indeed potential for possible protection against infection with the virus through vaccination although efficacy and maintenance of efficacy over time in high risk populations have yet to be more convincingly demonstrated. Given the widespread effect of the global epidemic incurred by the HIV-1 virus, the realization of this potential someday would indeed be profound.

Many agree that the most realistic solution to the lack of universal health coverage in the United States may be through steadily increasing the inclusiveness of existing governmental programs such as Medicare and Medicaid. The obvious issue is the cost incurred by increasing the number of uninsured Americans who would be covered by these programs. Is it possible that we could offset some of these costs  by covering uninsured adults so that they are healthier once they reach the age of 65 ?  This week in the Annals of Internal Medicine, McWilliams and colleagues examine the economics of increasing the inclusiveness of Medicare.  They compared Medicare expenditure for previously uninsured adults to that of previously insured adults, all of whom were then enrolled in Medicare at the age of 65. (5)  In particular, they looked at differential costs incurred in clinical subgroups of patients who had cardiovascular disease (hypertension, heart disease, stroke), diabetes, or required joint replacement. Moreover the study categorized annual spending for claims in four general services: hospital stays, outpatient institutional visits, physician office visits, and days in skilled nursing facilities. After controlling for confounding factors such as deteriorating health causing uninsurance (vs. the converse) and geographical variation in spending, the study showed that adjusted annual total Medicare spending was significantly higher for previously uninsured than previously insured adults ($5796 vs. $4773; difference, $1023 [95% CI, $29 to $2016].  Furthermore, it showed that differences in costs were most notable amongst patients in the highest quartile of spending distributions with $26,787 for previously uninsured compared to $21,813 for previously insured patients in the 95th percentile of Medicare spending. For hospitalizations, 66.7% of the adjusted difference in inpatient spending between previously uninsured and insured adults was accounted for by complications due to cardiovascular disease, diabetes, and joint replacement.

Given the current economic climate, and the increasing numbers of uninsured, the policy implications for the study are significant. It has been calculated that providing healthcare coverage to the uninsured between ages of 51-64 for a continuous period of 4 years would increase spending by $197 billion. However, this study suggests that increasing this coverage would ultimately decrease Medicare spending after the age of 65 by at least $98 billions. Thus it appears that the cost of increasing the inclusiveness of Medicare would be significantly offset by the decrease in Medicare spending after the age of 65.  Clearly this concept needs to be factored into the analyses and arguments on both sides of the aisle.

And as for Tiger Woods…well maybe another time…

Sarah Lee is a first year internal medicine resident at New York University Medical Center

Peer Reviewed by: Neil Shapiro, MD Editor-in-Chief, Clinical Correlations

1. Vincent J. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA. 2009;302(21):2323-2329.  http://jama.ama-assn.org/cgi/content/abstract/302/21/2323

2. Opal S, Calandra T. Antibiotic Usage and Resistance: Gaining or Losing Ground on Infections in Critically Ill Patients? JAMA. 2009;302(21):2367-2368.  http://jama.ama-assn.org/cgi/content/extract/302/21/2367

3. Rerks-Ngarm S. Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand. NEJM. 2009;361(23):2209-2220.  http://content.nejm.org/cgi/content/full/361/23/2209

4. Belshe R.  Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. JAMA 1994;272:475-480.  http://jama.ama-assn.org/cgi/reprint/272/6/475

5. McWilliams J. Medicare Spending for Previously Uninsured Adults. Ann Intern Med. 2009;151:757-766.  http://www.annals.org/gca?submit=Get+All+Checked+Abstracts&gca=annintmed%3B151%2F11%2F757