PrimeCuts

Primecuts-This Week in the Journals

July 18, 2011

Benjamin Wu, MD

Faculty Peer Reviewed

The year started with a bang at NYU and brought with it new faces, opportunities, and challenges.  At the height of summer, we find the changes that are affecting the politics in the United States are similar to those affecting healthcare.  We have a looming debt crisis that may have lasting implications for our nation. While  the government is changing the mentality of ‘business as usual’ with regard to the debt ceiling, healthcare providers find themselves seeing that the evidence behind the standard of care may not be as strong as previously believed. As new research on familiar subjects starts to trickle into the medical literature, the subtle phenomenon of reversal is being recognized as newly published trials are challenging and even contradicting familiar medical truths.

In a research letter published by The Archives of Internal Medicine, Prasad, Gall, and Cifu discussed these recent reversals in current literature.  The authors defined reversals as new trials with increased power, improved design, and stricter controls that contradict current medical practice. [1] The authors analyzed publications during 2009 that appeared in the New England Journal of Medicine.  They found 212 original articles, and of those 16 (13%) were considered reversals.  Notable reversals that the research letter pointed to were the Quality of Life after Late Invasive Therapy for Occluded Arteries, Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma, and Intensive Versus Conventional Glucose Control in Critically Ill Patients. [1] The authors cited “Confidence that the pathophysiologic concepts underlying practices were rational” as one of the main reasons the  prior research was found to be contraindicated by newer studies.  They further conclude that reversals in medical literature are no longer so uncommon and at least 10% of new trials contraindicate, reverse, or at least challenge the commonly held standard of care.  Furthermore, results from the ACCORD trial raise more questions than provide answers in our treatment of patients with diabetes. [2] Unfortunately, the authors do not give a very thorough reason why there seems to be an increase in reversals in medical literature, but they assume that newer research based upon better-controlled and better-powered studies will give “stronger” truth claims. [1] The implications of the letter are serious.  Will reversals continue to challenge our standard of care? Have we as healthcare providers placed patients at increased risk for morbidity and mortality based upon trials, only to have our current thinking contraindicated by another study? Further clarification of the true impact of reversals will be needed, as more research may show us that our current standard of care and pathophysiological principles are misguided. 

In challenging old beliefs, the British Medical Journal published a meta-analysis of randomized controlled trials that demonstrated a mortality risk associated with tiotropium mist inhalers. [3] Prior research based upon the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial did not report a mortality risk in patients who used powdered tiotropium versus placebo. [4] However, physicians need to recognize that powdered tiotropium and mist-inhaled tiotropium are distinctly different medications.  Mist-inhaled tiotropium reached 35% higher blood concentration in the 5 ug dose and threefold higher in the 10 ug dose compared to the powered version. [3] The anticholingeric properties are used to explain both the physiological effects for symptomatic benefit in patients with chronic obstructive pulmonary disease (COPD) and the potential cause of major cardiovascular events in patients using the long-acting drug.  The primary end point the authors examined was mortality. The meta-analysis found that the relative risk for mortality was 1.52 (95%, CI 1.06 to 2.16; P = 0.02). [3] Cardiovascular risks also differed between doses of inhaled tiotropium.  The 5 ug dose of tiotropium was associated with a 46% increase in mortality (1.46, CI 1.01 to 2.10; P = 0.04), and the 10 ug dose doubled the relative risk (2.15, CI 1.03 to 4.51; P = 0.04).  [3] The authors also examined the number needed to cause one mortality and estimated that one mortality was caused by124 patients treated with the 5 ug dose. [3] The authors conclude that further examination of these results is needed to quantify the safety differences between mist inhalers and the powdered form of tiotropium.  The conclusions reached by the study were limited because at the time of the publication there is currently an on-going trial comparing mist inhalers and powered inhalers that will hopefully answer the mortality question definitively.

In patients with reactive airway disease,  a recent New England Journal of Medicine article addressed the role of albuterol, sham acupuncture, placebo or no intervention . The researchers sought to explore the powerful placebo effect in patients who suffered from mild-moderate asthma in a double-blind, crossover pilot study. [5] Not surprisingly, the patients who received albuterol had the only significant quantitative response. Patients who received albuterol had a 20.1% improvement in their FEV1 compared to placebo (7.5%), sham procedure (7.5%), and no-intervention (7.5%, P<0.001). [5] What was unexpected was that in all three groups, excluding the patients who had no intervention, patients reported significant subjective improvement.  The patients who received albuterol reported 50% subjective improvement with placebo (45%) and sham acupuncture (46%) reporting very similar improvements (P<0.001). The no-intervention group reported a 21% improvement. [5] Given that there were no pre-existing subjective measurements for acute asthma response, the authors created their own subjective assessment for the improvement in dyspnea. [5] The study was limited by small sample size, only 39 patients finished the study and seven (15%) dropped out by the time the study ended. [5] The impact of the dropouts may have a significant effect on the response to placebo in the study.  Did the patients who dropped out of the study do so because they found the sham procedure, placebo, or albuterol itself unhelpful?  Or did these patients actually have asthma with increased severity?  Furthermore, only patients in acute asthmatic exacerbations were studied while chronic asthmatics and other patients with reactive airway disease were not, yet may provide further insight into the placebo effect. Regardless, this study provides some insight into the subtle, yet powerful impact of the placebo in patients suffering from asthma. 

Straight from the Netherlands comes a new study for the use of steroids in patients who present with community acquired pneumonia (CAP).  In The Lancet, an article titled “Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial” showed that a small dose of dexamethasone decreased length of hospital stay in patients with CAP. [6] Researchers took 304 patients and randomized them into two arms. 151 patients received dexamethasone 5mg once a day for four days and the other 153 patients received a placebo.  All patients were given antibiotics at the start of the study. [6] The primary endpoint was length of hospital stay until  discharge or death.  Other secondary endpoints included admission to intensive care units, mortality, development of empyema, super-infection, readmission, level of C-reactive protein, interleukin-6, and interleukin-10, pulmonary function at day 30, and general quality of life by Rand-36 generic health survey. [6] The authors found that the length of hospital admission in those patients who received dexamethasone was 6.5 days (5.0-9.0) compared to patients who did not receive dexamethasone 7.5 days (5.3-11.5). The hazard ratio for discharge was 1.46 (95%, CI 1.13-1.89) favoring earlier discharge in patients who received dexamethasone therapy.  They conclude that the administration of steroids modulates the immune response and point to the rapid normalization of C-reactive protein and IL-6 as evidence for these changes in the systemic inflammatory response. The study was limited by a lack of patients with COPD (as patients with COPD exacerbations required steroids) and overrepresentation of Q fever as there was an outbreak in the spring of 2009. [6] Furthermore, the study is difficult to apply to US guidelines, as the antibiotic treatment is different given regional differences in flora. [6] The authors disclosed one particular adverse event with a patient developing a gastric perforation on dexamethasone. 

Finally, the Journal of the American Medical Association presents another reason why primary prevention can save lives in patients with prostate cancer. In an article titled “Smoking and Prostate Cancer Survival and Recurrence” authors conducted a prospective observational study of 5366 men diagnosed with prostate cancer between 1986 and 2006 with hazard ratios related to prostate cancer mortality, cardiovascular disease (CVD) mortality, and biochemical recurrence of cancer. [7] While the connection between smoking and increased mortality may be apparent from prior research, the current article explores the differences between never smokers, patients who stopped smoking 10 years prior to their diagnosis, patients who quit smoking less than 10 years prior to diagnosis, and those who currently were smoking at the time of their diagnosis and the impact on prostate and CVD mortality. [7] The patients who continued to smoke when compared to those who never smoked had a hazard ratio of 1.61 (95% CI 1.11-2.32) for prostate cancer mortality, 1.80 (95% CI 1.04-3.12) for prostate cancer with clinical stage T1 to T3, and 1.80 (95% CI 1.16-2.22) for biochemical recurrence. When examining patients for overall mortality the patients who were smoking at the time of their diagnosis had a hazard ratio of 2.28 (95% CI 1.87-2.80) for overall mortality and 2.13 (95% CI 1.39-3.26) for CVD mortality when compared to their never smoker cohorts. [7] Furthermore, the authors found that those smokers who quit for 10 or more years or quit less than 10 years, but smoked less than 20 pack-years had prostate cancer mortality risks similar to those who never smoked. [7] The authors suggest that smokers are at higher risk from carcinogen production in cigarette smoke (nitrosamines and cadmium) with gene variants in detoxification possibly promoting  more aggressive cancers. Aggressive prostate cancer in smokers may also be increased by testosterone or other androgens, and nicotine-induced angiogenesis. [7] Unfortunately, patients who quit less than 10 years prior to diagnosis (n = 297) and current smokers (n = 277) were underrepresented compared to never smokers (n = 2449) and 10-year quitters (n = 2063).  Researchers also found that smokers tend to have less PSA testing, and may explain why the smoking population was found with more advanced prostate cancer. [7] However, after adjusting for PSA screening the authors claim that associations between smoking and fatal prostate cancer were stronger, as opposed to there being an attenuation of the association.  This article further emphasizes the importance of smoking cessation and how it may be the best care that we can provide to our patients.

July in the hospital is filled with great potential and new encounters.  Recent evidence shows us that our understanding of the present medical literature can be challenged and possibly contradicted by new trials appearing on the horizon.  As our understanding of pathophysiology improves, better-controlled and better-powered research may flip our present understanding of medicine on its head.  As physicians we must be able to digest contradictory evidence and respond to an educated and informed patient population. If newer trials and studies represent true reversals of the standard of care, we can keep abreast of the changes and respond in kind. Like all science, medicine continues to be a vibrant and dynamic field, where truths are always ready to be found.

 Benjamin Wu is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Robert Gianotti, MD,  Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Prasad V, Gall V, Cifu A. “The Frequency of Medical Reversal.” Arch Intern Med. 2011 Jul 11. Published online. http://archinte.ama-assn.org/cgi/content/full/archinternmed.2011.299

 2. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. “Long-term effects of intensive glucose lowering on cardiovascular outcomes.” N Engl J Med. 2011 Mar 3;364(9):818-28.  http://www.nejm.org/doi/full/10.1056/NEJMoa1006524

3. Singh S, Loke YK, Enright PL, Furberg CD. “Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials.” BMJ. 2011 Jun 14;342:d3215. doi: 10.1136/bmj.d3215.  http://www.bmj.com/content/342/bmj.d3215.long

4. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. “A 4-year trial of tiotropium in chronic obstructive pulmonary disease.” N Engl J Med. 2008 Oct 9;359(15):1543-54. Epub 2008 Oct 5. http://www.nejm.org/doi/full/10.1056/NEJMoa0805800

 5. Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ. “Active albuterol or placebo, sham acupuncture, or no intervention in asthma.” N Engl J Med. 2011 Jul 14;365(2):119-26.  http://www.nejm.org/doi/full/10.1056/NEJMoa1103319

 6. Meijvis SC, Hardeman H, Remmelts HH, Heijligenberg R, Rijkers GT, van Velzen-Blad H, Voorn GP, van de Garde EM, Endeman H, Grutters JC, Bos WJ, Biesma DH. “Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.” Lancet. 2011 Jun 11;377(9782):2023-30. Epub 2011 Jun 1. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60607-7/fulltext

 7. Kenfield SA, Stampfer MJ, Chan JM, Giovannucci E. “Smoking and prostate cancer survival and recurrence.” JAMA. 2011 Jun 22;305(24):2548-55.  http://jama.ama-assn.org/content/305/24/2548.long

 

Primecuts – This Week In The Journals

July 11, 2011

By Rachel Bond, MD

Faculty Peer Reviewed

January 11, 2010: The New York City Department of Health and Mental Hygiene (DOHMH) announces proposed targets for the voluntary reduction of salt found in packaged and restaurant foods. The ultimate goal of this new policy is the reduction in cardiovascular events.[1]

Studies have shown that Americans consume roughly twice the recommended limit of salt each day which can lead to hypertension, a major risk factor for coronary artery disease (CAD) and cerebrovascular accidents (CVA). Much of the time, though, this is not a matter of choice. In fact, data from the DOHMH shows that nearly 80% of sodium is added to foods before they are sold or prepared. [1] Given these astonishing numbers, the National Salt Reduction Initiative (NSRI) was created. The NSRI is a coalition of local and state health authorities and health organizations that is working to help food manufacturers and restaurants voluntarily reduce the amount of salt in their products. The ultimate goal is to reduce Americans’ salt intake by 20% over a five year period. These actions are estimated to save tens of thousands of lives each year and billions of dollars in health care costs. These actions have already been implemented in a number of fast food chains.

With governments setting lower targets for salt intake and food manufacturers working diligently to remove high sodium content from their packaging, a number of large research trials are underway to get a broader understanding of the true benefits and risks of this salt reduction.

July 6, 2011.  A systematic Cochrane review by Taylor et al. published in the American Journal of Hypertension discussed how cutting salt consumption leads to slight reductions in systolic blood pressure; however, this does not equate to lower risk of heart disease or death.[2]

The authors found seven studies (three in normotensives, two in hypertensives, one in a mixed population of normo- and hypertensives, and one in heart failure patients) that together included 6,257 participants with follow-up of six months or longer. The studies compared dietary salt reduction to no intervention in order to elucidate cardiovascular morbidity and mortality data. Salt reduction was associated with reductions in urinary salt excretion (a marker of salt intake) between 27 and 39 mmol/24hr and reductions in systolic blood pressure between 1 and 4 mm Hg. Results showed no strong evidence that salt reduction reduced all-cause mortality or CVD morbidity in baseline normotensives or hypertensives (normotensives RR- 0.90, 95% confidence interval (CI): 0.58–1.40, and hypertensives RR-0.96, CI: 0.83–1.11).  A single randomized-controlled trial interestingly showed an increase in the risk of all-cause death in those with congestive heart failure receiving a low-sodium diet (RR-2.59, CI: 1.04–6.44).

Despite the fact that this meta-analysis as well as previous trials have found a benefit regarding BP, no one knows if this translates into better overall heart health in the population. A meta-analysis of 13 prospective studies with 177,000 participants reported that high salt intake was associated with a greater risk of stroke (RR-1.23, 95% CI: 1.06–1.43).[3] However, there was no association between salt intake and all CVD events, and total mortality was not reported. In fact, the relationship between salt reduction and BP control is the primary basis for the assumed belief that restriction in dietary sodium intake will prevent BP-related CVD events.[4]  Although the Taylor study did show that salt reduction was beneficial in normotensive and hypertensive patients in terms of lowering BP, it found little effect on morbidity or mortality of CVD except when evaluating patients with systolic heart failure.

A recent study published in JAMA in May went even further than the Taylor review and proposed that modest reductions in salt intake may be associated with an increased risk of CVD and death.[5] This is a shocking claim that contradicts everything we have been taught in medical school and from the media.

This was an observational study that followed 3,681 middle-aged Europeans without known hypertension or CVD for an average of 7.9 years. The researchers assessed the participants’ sodium consumption at the study’s start via a 24hr urinary sodium excretion.

The authors found that the less sodium consumed, the more likely the study participants were to die of heart disease. For the lowest third of salt consumption, the death proportion was 4.1% (95% CI: 3.5-4.7). For the middle third, the proportion was 1.9% (1.5-2.3), and for the highest third, 0.8% (0.5-1.1%). While those eating the most salt had, on average, a slight increase in systolic blood pressure–a 1.71mm Hg increase for each 2.5-gram increase in sodium per day–they were no more likely to develop hypertension than those in the other groups.

This certainly challenges the advice of a majority of healthcare workers and public health agencies (i.e. NSRI), who have been preaching to consumers to drastically cut back on their sodium consumption.  Can we take this one study and forget all we have been taught during the last 10 years? Before doing so, we need to take note of the key limitations of the study. First, this was an observational study.  Observational studies can only be suggestive, not conclusive. Second, although the study quotes a sample size of 3,681, the conclusions about CVD are based solely on the 84 participants who died during the study and not the total population followed. Third, the average age of inclusion was relatively young (~40 years old) leading to a potential underestimation of the risk of excessive sodium intake. Fourth, the study consisted only of white Europeans making it hard to extrapolate the conclusions in such an ethnically diverse population such as NYC where other races might be more salt sensitive. Fifth, sodium intake was only determined for one 24-hour urine collection at the start of the study, which may be insufficient to characterize an individual’s habitual salt intake, and no calorie or other nutritional data were collected. As such, the conclusions should be interpreted in the context of these potential limitations.

Regardless of the limitations, controversies, and unanswered questions from these studies, the authors certainly opened up a can of worms. So what is left to investigate?  Ultimately, should a low sodium diet, previously believed to reduce the risk of CVD, now be taken with a grain of salt?!  I feel that further research, including randomized controlled trials, is definitely needed that can effectively answer this question. Until then, I will continue to urge all my patients, and myself, to limit the amount of salt on my next order of French fries.

Rachel Bond is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Ishmeal Bradley, MD,  section editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1. Cutting Salt, Improving Health.  NYC Department of Health and Mental Hygiene.  Retrieved: July 7, 2011 from http://www.nyc.gov/html/doh/html/cardio/cardio-salt-initiative.shtml

2. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced Dietary Salt for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials (Cochrane Review). The American Journal of Hypertension, advance online publication July 6, 2011. http://http://www.nature.com/ajh/journal/vaop/ncurrent/pdf/ajh2011115a.pdf

3. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 2009; 339:b4567. http://www.bmj.com/content/339/bmj.b4567.full.pdf?sid=d6199964-f270-47e7-86da-73591c7120b2

4. Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, Marmot M. Intersalt revisited: further analyses of 24 hour sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group. BMJ 1996; 312:1249–1253. http://www.bmj.com/content/312/7041/1249.full

5. Stolarz-Skrzypek K, Kuznetsova T, Thijs L, Tikhonoff V, Seidlerova J, Richart T, Jin Y, Olszanecka A, Malyutina S, Casiglia E, Filipovsky J, Kawecka-Jaszcz K, Nikitin Y, Staessen J. Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion. JAMA. 2011;305(17):1777-1785. http://jama.ama-assn.org/content/305/17/1777.full.pdf+html

Primecuts – This Week In The Journals

July 5, 2011

Jeffrey Shyu, MD

Faculty Peer Reviewed

As the debt ceiling debate continues to rage stateside and as Greece’s financial bailout negotiations take up international headlines, this past week also proved to be a very active and exciting one for medical research.

This edition of Primecuts begins with controversy amongst experts in the spine field. A group of leading researchers submitted a scathing editorial to Spine Journal, blasting industry-sponsored research on recombinant bone morphogenetic protein-2 (rhBMP-2), a bone growth product popular in spinal fusion surgeries [1]. Medtronic, the maker of rhBMP-2 (trade name Infuse), has sponsored trials comparing the product to bone grafts, and according to its critics, the industry-sponsored studies frequently downplayed the risk of complications such as inflammation, osteolysis, cancer, infection, and male sterility. In a literature review published in the same issue, the authors found that the level of adverse events was downplayed 10 to 50-fold, with many of the prior authors having financial ties to the maker of the product [2]. For what it’s worth, Medtronic’s Chairman and CEO Omar Ishrak insists that the product is “safe” [3]. I for one applaud the editors and authors of this Spine Journal issue, and more disclosure and criticism of industry-sponsored research should be had in all fields of medicine.

The value of imaging for cancer screening was another major topic this past week, as two high-profile studies were published demonstrating a mortality benefit in the use of imaging to detect cancer. In Radiology, a three-decade long trial of over 133,000 women in Sweden who were randomized to mammography screening versus usual care found an absolute long-term benefit to mammography [4]. The study had previously reported a 30% reduction in breast cancer mortality among 40-74 year old women [5], and study participants were now followed for a longer period of time. In the current study, the number of women needed to screen for a period of 7 years to prevent one breast cancer death ranged from 414 to 519. Moreover, most of the deaths that were prevented would have occurred in the first 10 years of screening. This new study will surely create additional confusion about the benefit of mammography, especially regarding when a woman should start getting the exams, given that the US Preventive Services Task Force recommended in 2009 that mammography screening for most people should begin at age 50 instead of 40 [6]. Unfortunately, this study did not specifically look at the benefit of screening for people between 40 and 50.

Also, the New England Journal of Medicine published the final report came of a study whose results were first announced last year.  This study found a 20% relative mortality risk reduction for high-risk subjects when using chest CT compared to conventional x-ray (p 0.004) [7]. 53,454 people were enrolled in this prospective, multi-center study, and eligible subjects included people between 55 and 74 years of age who had at least 30 pack years of smoking history. Subjects were randomized to three low-dose CTs versus conventional chest x-rays. The survival benefit was attributed to detection of cancers at an earlier stage. However, as one might expect, the rate of positive screening results was substantially higher in the CT group compared to x-ray (24.2% versus 6.9%), and false positives were 96.4% and 94.5%, respectively. Given the increased number of positive results (the vast majority false positive), many subjects underwent further diagnostic workup including further imaging; some had invasive procedures, though adverse events from invasive procedures were rare in both groups. Although the mortality benefit to CT screening is real, many more people are likely to experience the anxiety that comes with a possible (though unlikely) cancer diagnosis if this screening test becomes widely adopted.

Also in the New England Journal, a randomized, multicenter trial with over 4600 patients looked at the timing of starting parenteral nutrition for critically ill patients who cannot obtain sufficient nutrition enterally [8]. Patients either had parenteral nutrition started within 48 hours after ICU admission (early group), or it was not initiated until after day 8 (late group). The researchers found that with late initiation, patients were 6.3% more likely to be discharged alive earlier from the ICU (p = 0.04) and from the hospital (p = 0.04). They also had fewer infections compared to the early group (22.8% versus 26.2%), although death rates in the hospital and at 90 days were similar. Previously, many had thought that early feeding (enteral or parenteral) was desirable. The authors also speculate that the increased risk of complications may be due to early parenteral nutrition causing delayed autophagy and inadequate clearance of microorganisms and cell damage.

Finally, in non-human medical news, for the second time in history a disease has been eradicated from the face of the earth [9, 10]. The first was smallpox, which most of our readers surely know about. This one is rinderpest, which is (was) a relative of measles and an ancient scourge of cattle and other cloven-hoofed animals, killing as much as 95% of afflicted creatures. Despite being noninfectious to humans, given our reliance on domesticated organisms, the virus has had a role in bringing down Rome and starting revolutions in France and Russia. But with vaccines, new diagnostic tests, and aggressive outreach to faraway lands, veterinarians have now conquered the “cattle plague”. This event should give us human doctors some optimism for eradicating our own ancient adversaries like polio or measles, although given the skepticism that some people hold towards vaccines these days, we may still have a long road ahead of us.

Dr. Jeffrey Shyu recently completed his preliminary year internal medicine residencyat NYU Langone Medical Center

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

Image courtesy of Wikimedia Commons

 References:

 1. Carragee EJ, Ghanayem AJ, Weiner BK, Rothman DJ, Bono CM. A challenge to integrity in spine publications: years of living dangerously with the promotion of bone growth factors. The Spine Journal 2011; 11: 463-468. http://www.spine.org/Pages/ConsumerHealth/NewsAndPublicRelations/NewsReleases/2011/pressrelease1_062811.aspx

 2. Carragee EJ, Hurwitz EL, Weiner BK. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. The Spine Journal 2011; 11: 471-491. http://www.spine.org/Pages/ConsumerHealth/NewsAndPublicRelations/NewsReleases/2011/pressrelease1_062811.aspx

 3. Medtronic CEO Omar Ishrak statement on rhBMP-2 articles in Spine Journal. July 28, 2011. http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1309287256363&lang=en_US

 4. Tabár L, Vitak B, Chen TH, Yen AM, Cohen A, Tot T, Chiu SY, Chen SL, Fann JC, Rosell J, Fohlin H, Smith RA, Duffy SW. Swedish Two-County Trial: impact of mammographic screening on breast cancer mortality during 3 decades. Radiology 2011. Published online before print June 28, 2011. http://radiology.rsna.org/content/early/2011/06/15/radiol.11110469.abstract

 5. Tabár L, Gad A, Holmberg LH, Ljungquist U, Kopparberg County Project Group, Fagerberg CJG, Baldetorp L, Gröntoft O, Lundström B, Mànson JC, Östergötland County Project Group, Eklund G, Day NE, Pettersson F. Reduction in mortality from breast cancer after mass screening with mammography: randomized trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. The Lancet 1985: 325 (8433). 829-832. http://www.sciencedirect.com/science/article/pii/S0140673685922044

 6. US Preventive Services Task Force: Screening for breast cancer. 2009 recommendations. http://www.uspreventiveservicestaskforce.org/uspstf/uspsbrca.htm

 7. The National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. New England Journal of Medicine 2011. Published online ahead of print June 29, 2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1102873?query=featured_homehttp://www.nejm.org/doi/full/10.1056/NEJMoa1104621

 8. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut SV, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. New England Journal of Medicine 2011. Published online ahead of print June 29, 2011. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1102662

 9. “Rinderpest, scourge of cattle, is vanquished”. Donald J. McNeil Jr. New York Times, June 27, 2011. http://http://www.nytimes.com/2011/06/28/health/28rinderpest.html

 10. Declaration of global freedom from rinderpest and implementation of follow-up measures to maintain world freedom from rinderpest. Draft resolution, Thirty-seventh session of the Food and Agriculture Organization of the United Nations. Rome, June 25 – July 2 2011. http://www.fao.org/docrep/meeting/022/mb363e.pdf

Primecuts-This Week in the Journals

June 27, 2011

By Saleem Ali, MD

Faculty Peer Reviewed

First up this week is a new study in NEJM about a new drug called bardoxalone methyl, currently being studied to treat CKD in patients with diabetes. [1] This drug is an antioxidation inflammation modulator. It activates the Keap1-Nrf pathways that are important in modulating oxidative stress on the kidney. Patients were given placebo vs. various dosages of bardoxalone. Their GFR were measured every 4 weeks for a total of 52 weeks.  The study showed a significant rise in GFR in those patients who received the drug as compared to placebo that was sustained over the duration of study. It remains to be seen how this drug will compare to ACE inhibitors in renal protection for our diabetic patients, but this is an interesting new drug that we should be on the lookout for in the near future.

 Blood pressure (BP) control and measurement is one of the most common things we do with our patients in the outpatient setting. Unfortunately we are usually left with these isolated measurements in the office to determine what to do with the patient’s medications.  This week in the Annals of Internal Medicine a study was published that compared BP measurements at home versus in the office. [2] This study utilized data from the HINTS trial, a randomized controlled trial.  These patients had their home BP monitored by machine, which relayed the information via telephone line. Typically, patients at home had a systolic BP of approximately 10 mmHg less than in the office. An increasing number of our patients are now able to measure their BP at home with their own device. This study found that a single clinic measurement may not be able to tell us whether a patient’s BP is in or out of control. By comparing it to the average home BP measurements we may have much higher certainty of a patient’s true blood pressure.

 Staying in the clinic, a meta-analysis was published this week to determine the risk of diabetes with intensive versus moderate dose statins. [3] In this study, data from 5 trials were analyzed. These trials were initially done to determine the cardiovascular risk reduction of intensive vs. moderate dose statin therapy. Of the 32,752 patients studied, there were 149 more cases of incident diabetes in the intensive dose therapy group. There translated into 2 additional cases of diabetes per 1000 patient-years in the intensive dose statin group and a number needed harm of 498 per year. However, there were 6.5 fewer cardiovascular evens per 1000 patient-years in the intensive dose group, equaling a number needed to treat of 155 to prevent one cardiovascular event per year.   The mechanism of this dose-dependent risk of statins on diabetes is unclear.  So, while small, the risk of new-onset diabetes appears to be present with higher dose statin therapy. However, it also appears that the risk of diabetes is outweighed by the cardiovascular benefits of statins. I would still continue aggressive lipid lowering therapy in my patients given such a small risk of diabetes.

 One of the most frequent topics of conversation with our patients regards weight loss. In a study released this week in NEJM, changes in diet and lifestyle were assessed in an attempt to quantify the weight gain or loss over a given time period. [4] This was a large prospective cohort study of people in the Nurses’ Health Study I and II (females only) and The Health Professionals study which was a group of male health professionals.  Participants were followed over a period of 20 years and had their lifestyle behaviors and weight assessed every 4 years.  Using a multivariate analysis each variable was related to an amount of weight change over each 4-year period.  Potato chips were associated with the highest amount of weight gain, 3.01 pounds over 4 years.  Yogurt was associated with the most weight loss, 1.16 pounds.  Sugar sweetened beverages, potatoes, fries, red meats, were all associated with a significant weight gain.  Nuts, vegetables, and fruits were associated with weight loss.  From this study, we now  have some quantitative evidence to show our patients and even help ourselves lose weight. 

 This week in Nature Medicine a review was published about biofilms and new ways to attack them. There is much work on developing a vaccine to prevent the formation of biofilms. [5] Biofilms typically form on foreign substances in the body, including prosthetic valves, pacemakers, orthopedic prostheses, and foley catheters. They are very difficult to treat with antibiotics alone (10-20% in some studies). This is due to the fact that circulating antibiotics are unable to penetrate the matrix surrounding the biofilms. Currently there are vaccines in development that will attack the proteins secreted by the bacteria that start the formation of biofilms. This has the potential to change how we manage infections in our patients with indwelling foreign material, possibly preventing us from having to remove patients’ indwelling material.

 There are numerous companies across the country that have been offering full body scans for patients. One such company, Heart Scan America, is now being sued by the Illinois attorney general for deceptive business practices. The company offers free heart scans to young otherwise healthy patients who would not likely need additional medical care. They are required to sit through a 2 hour-long presentation encouraging them to purchase their 10 year package of body scans at a cost of $7995 plus yearly fees. Some participants were reportedly bullied into taking out these packages. [6,7]  

 Finally, in the NY Times this week a new oral anticoagulant, Eliquis (Apixaban), was shown to be more effective than coumadin in preventing strokes with a lower bleeding risk. [8] The studies are scheduled to be released at the end of August, and we should all look out to hear much more about this new agent. This drug met the primary endpoint as being non-inferior and was also shown to be superior.  This year has been an exciting one in terms of oral anticoagulants as this would be the third agent to be released. All of them show promise to replace coumadin, the long-time anticoagulant of choice. They are, however, considerably more expensive at up to $6 per day for the newer agents versus pennies a day for coumadin.

Saleem Ali is a soon to be 3rd year resident at NYU Langone Medical Center

Peer reviewed by Danise Schiliro, MD,  contributing editor, Clinical Correlations

Image of wildfire courtesy of Wikimedia Commons.

References:

1. Pergola et al. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes. NEJM. 2011;10.1056. http://www.nejm.org/doi/full/10.1056/NEJMoa1105351?query=featured_home

2. Powers, B. et al. Measuring Blood Pressure for Decision Making and Quality Reporting: Where and How Many Measures? Annals of Internal Medicine 2011;154(12):781-788. http://www.annals.org/content/154/12/781.abstract?aimhp

3. Preiss D, et al. Risk of Incident Diabetes with Intensive-Dose Compared with Moderate-Dose Statin Therapy. JAMA 2011;305(24):2556-2564.  http://jama.ama-assn.org/content/305/24/2556.short

4. Mozaffarian, D  at al. Changes in Diet and Lifesyle and Long-term Weight Gain in Women and Men. NEJM 2011;365(25):2392-2404. http://www.nejm.org/doi/full/10.1056/NEJMoa1014296?query=featured_home

5. Pflumm M. Caught on Film. Nature Medicine. 2011;17(6):650-653. http://www.nature.com/nm/journal/v17/n6/abs/nm0611-650.html

 6. Allen, Marshall. Illinois Regulators Sue Heart Scan Company, Alleging Deceptive Practices. http://www.propublica.org/article/illinois-regulators-sue-heart-scan-company-alleging-deceptive-practices

7. Allen, Marshall. Body Imaging Business Pushes Scans Many Don’t Need — Including Me. http://www.propublica.org/article/heart-check-america-drawing-complaints-and-scrutiny

8. Duff, Wilson. Anticlotting Drug Shows Promise to Displace a Longtime Standard. New York Times. 2011, Jun 24 B7. http://www.nytimes.com/2011/06/24/health/24drugs.html?_r=4&ref=health

Primecuts – This Week In The Journals

June 20, 2011

By Megha Shah, MD

Faculty Peer Reviewed

Captain America has a shield, Thor has a hammer, the Green Lantern has a power ring, and we…well, we have our stethoscopes. While Dr. Superhero may not be the next big blockbuster to hit the movie theaters this summer, we as healthcare professionals certainly do our share in battling many of the villains- cardiac disease, dementia, cancer – that threaten us everyday. And while the X-Men might turn to Professor X for guidance and wisdom, you can always turn to Primecuts. So grab some popcorn and read on!

 The New York Times this week reports on clinical trials, published in the New England Journal of Medicine, for two drugs that may be effective against advanced melanoma. In one trial, 675 patients with untreated, metastatic melanoma with a specific mutation in the BRAF gene, were randomized to receive either vermurafenib, a BRAF kinase inhibitor, or dacarbazine, one of the mainstays of current melanoma management. At six months, overall survival was 84% with vermurafenib versus 64% with dacarbazine. Vemurafenib was also associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression when compared with dacarbazine (P<0.001 for both comparisons). In an interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. In the other trial, 502 patients were randomized to receive a combination of dacarbazine with ipilimumab, a monoclonal antibody, or placebo. After three years, 20.8% of those who received ipilimumab were alive compared to 12.2% who received placebo (P<0.001). Overall survival was 11.2 months versus 9.1 months respectively (P<0.001). While both drugs have significant side effect profiles, these initial trials are promising and provide new hope to thousands of patients diagnosed with melanoma every year. [1-3]

 The British Medical Journal published more findings from the Platelet Inhibition and Patient Outcomes (PLATO) trial which has been reporting evidence for the use of ticagrelor, a reversible platelet aggregation inhibitor, over clopidogrel in patients with acute coronary syndromes. In an initial study published in the New England Journal of Medicine in September 2009, ticagrelor was reported to have lower mortality rates than clopidogrel (9.8% vs. 11.7%, P<0.001). A second study, published in the Lancet in January 2010, showed that in patients with ACS undergoing invasive management, the use of ticagrelor led to fewer events (cardiovascular death, myocardial infarction, or stroke) than clopidogrel (P=0.0025). In the latest study, 5216 patients initially intended for non-invasive management were randomized to either ticagrelor or clopidogrel. The incidence of the primary end point (cardiovascular death, myocardial infarction, or stroke) was lower with ticagrelor than with clopidogrel (12% vs 14.3%, P= 0.04), leading investigators to conclude that ticagrelor was beneficial in all patients with ACS regardless of the management strategy. [4-6]

 In a randomized, double-blind, placebo-controlled study, researchers compared the use of clazosentan, an endothelin receptor antagonist, with placebo for reduction in vasospasm associated and all-cause morbidity in patients with aneurysmal subarchanoid hemorrhage (aSAH) after surgical clipping. Clazosentan had initially been shown to be beneficial in the reduction of vasospasm in patients with aSAH as part of the Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage, or CONSCIOUS-1, trial. In the more recent study, known as CONSCIOUS-2, approximately 21% of patients who received clazosentan met the primary composite endpoint (all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischemic neurological  deficit due to vasospasm, and rescue therapy for vasospasm) versus 25% in the placebo treated group (relative risk reduction 17%, P=0.1). While the findings, initially released in September 2010 and published now in the Lancet, disappointingly failed to show benefit with clazosentan with surgical clipping, researchers are now looking at clazosentan in patients with aSAH who have undergone coiling as part of the CONSCIOUS-3 trial. [7,8]

 The Food and Drug Administration (FDA) released a Drug Safety Communication warning that varenicline (Chantix) may be associated with an increased risk of certain cardiovascular events in patients with preexisting cardiac disease. The warning was prompted by a study that evaluated Chantix for smoking cessation in 700 patients aged 35-75 with stable, documented cardiovascular disease (other than or in addition to hypertension). In the trial, Chantix was effective in getting patients to quit smoking and also abstain from smoking for as long as a year but, while infrequent, also led to more adverse cardiovascular events including angina pectoris, nonfatal myocardial infarction, need for coronary revascularization, and new diagnosis of peripheral vascular disease or admission for a procedure for the treatment of peripheral vascular disease. The FDA has directed Pfizer, manufacturer of Chantix, to conduct a large meta-analysis of previous randomized, placebo controlled trials and for now has added the information to the Warnings and Precautions section and the patient Medication Guide. Chantix already carries a “black box” warning about the potential risk of psychiatric side effects including abnormal behavior, depression, and suicidality. While it has been shown to be efficacious in smoking cessation, these serious side effects must be considered prior to prescribing the medication. [9]

 From the lab: researchers in Europe identified enzymes that may play a big role in the development of idiopathic pulmonary fibrosis (IPF). By examining the fibrotic lungs from both patients with IPF and mice with bleomycin induced fibrosis, they were able to detect the increased expression of dimethylarginine dimethylaminohydrolases (DDAHs)- enzymes that play a role in collagen production and deposition. In mice models, the researchers were able to show that inhibition of the DDAHs reduced fibrosis and in some  cases normalized lung function. The findings, published this week in Science Translational Medicine, are certainly promising for patients with IPF, a disease process known to be refractory to most of the current pharmacological therapies and associated with high rates of morbidity and mortality. [10]

 That’s it for this week. Hoping you all got to spend some time this weekend with the greatest superhero of them all: Dad!

 Dr. Shah is a 2nd year resident at NYU Langone Medical Center

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

References:

1. Pollack, Andrew. Drugs Show Promise Slowing Advanced Melanoma. New York Times. Published online June 5, 2011 http://www.nytimes.com/2011/06/06/health/research/06melanoma.html

 2. Chapman PB, Hauschild A. et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. New England Journal of Medicine. Early online publication. June 5, 2011

 3. Robert C, Thomas L. et al. Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. Early online publication. June 5, 2011

 4. James SK, Roe MT. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial. British Medical Journal. June 2011; 342: 3547 http://www.bmj.com/content/342/bmj.d3527.full

5. 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

6. 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. January 2010; 375 (9711): 283-293 

7. MacDonald RL, Kassell NF et al. Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1). Stroke. April 2008; 39:3015  http://stroke.ahajournals.org/cgi/content/full/strokeaha;39/11/3015

8. MacDonald RL, Hagashida RT et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). The Lancet Neurology. July 2011; 10(7): 618-625

 9. The Food and Drug Administration. Chantix (varenicline): Label Change – Risk of Certain Cardiovascular Adverse Events. Posted online June 16, 2011. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm259469.htm

 10. Pullamsetti SS, Savai R. et al. The Role of Dimethylarginine Dimethylaminohydrolase in Idiopathic Pulmonary Fibrosis. Science Translational Medicine. June 2011; 3(87): 53  http://stm.sciencemag.org/content/3/87/87ra53.abstract

 

 

 

Primecuts – This Week In The Journals

June 13, 2011

By Christopher Schultz, MD

Faculty Peer Reviewed

News about the devastating tornado that flattened Joplin, MO had begun to fall from the headlines until reports of a relatively rare fungal infection in a surprisingly large number of people emerged this week.[1] Mucormycosis is generally spread via puncture wounds or through the air, not person-to-person. It mainly inflicts its woes on those with impaired immune systems. More troubling was the recent E. coli outbreak in Germany which caused 31 deaths and sickened thousands. [2] Health officials finally found the potential source, contaminated bean sprouts. Pictures of meals snapped with camera phones helped solved the mystery. Women appear to have developed much more severe disease than men when infected with this lethal strain of E. coli. [3]

With some nods to findings supportive of women’s health, let’s take a look at a few noteworthy medical news items this week. A multinational multicenter study published in the NEJM this week demonstrated benefits of the aromatase inhibitor, exemestane, compared with placebo in preventing the development of invasive breast cancer and pre-cancerous lesions. [4] The researchers studied women with increased risk as assessed by the Gail risk score and other criteria. [5] While earlier studies with tamoxifen and reloxifene, selective estrogen receptor modulators (SERMs), have shown reductions in cancer incidence, these trials failed to show a mortality benefit, and these drugs also exhibited toxic side effects. In this new study, there was a 65% reduction in incidence of invasive cancer at 3 years compared with placebo, with an even greater reduction at 5 years. Quality of life measures were similar between the two groups and there was a lack of significant adverse toxic events, such as fractures and myocardial infarction, as had been suggested before in head-to-head comparisons with tamoxifen. The downside is that the number needed to treat is much higher at 3 years than at 5 years, which proved difficult to achieve given the side effect profile.

A not-terribly-surprising, albeit strong, study came out of Boston this week which demonstrated that smoking was a significant risk factor for symptomatic peripheral artery disease in women. [6] Smoking is known to lead to cardiac disease and strokes, and it had been naturally assumed to lead to peripheral artery disease and intermittent claudication. This new study looked at participants in the Women’s Health Study and evaluated the relationship between smoking tobacco and claudication symptoms and surgical and catheter-based procedures to treat PAD. The researchers also examined inflammatory markers, including hsCRP and sICAM-1, and traditional markers for cardiovascular disease risk. Interestingly for clinicians is that smoking cessation reduces the risk of PAD, similar to that of cardiovascular disease. However, unlike in heart disease where risk levels fall to baseline after roughly 20 years of tobacco abstinence, risk for PAD does not. This underscores the importance of primary prevention, especially in younger, less educated, pre-menopausal participants. Education, whether at a university or in a clinician’s office, is an incredibly valuable tool to prevent disease.

Speaking of cardiac disease, our colleagues in England looked at the effects of simvastatin and ezetimibe in preventing major atherosclerotic events in patients with advanced kidney disease (serum creatinine greater than 1.7 in men and 1.3 in women, regardless of dialysis status) in the SHARP trial (Study of Heart And Renal Protection) [7]. The mechanism of cardiac disease seems to change from mostly atherosclerosis in patients with relatively good renal function to a multifactorial etiology (calcification, structural cardiac changes and sympathetic overactivity) in patients with poor renal function. The authors wanted to see if reducing LDL with lower statin doses would be beneficial to cardiovascular health, since patients with renal disease are more likely to develop myopathy at higher doses. And with the news this week that high dose simvastatin has an increased risk of muscle damage, this article is especially timely. [8]

Low-dose statin (simvastatin 20mg) was paired with a cholesterol-absorption inhibitor (ezetimibe 10mg). The reduction of 17% in atherosclerotic events was similar to results from other studies assessing risk in patients without advanced renal disease. Non-significant reductions in non-fatal myocardial infarction were seen, but the study was not powered effectively to look at finer components of cardiovascular risk. One standout is the 25% reduction in ischemic strokes. What will be interesting to learn is whether renal patients with known cardiovascular disease, who were excluded, would benefit as well.

Our colleagues uptown at Columbia published a study in the NEJM this week evaluating the non-inferiority of transcatheter aortic-valve replacement in high risk patients  as compared with surgical replacement. [9] Patients with severe aortic stenosis and NYHA Class II pump function or worse who were not too sick by their criteria to undergo surgical repair were randomized to either the transcatheter (transfemoral or transapical) or surgical arm.  More surgical patients fell out of the study than in the transcatheter arm, so both intention-to-treat and per-protocol analyses were presented for the primary outcome of death from any cause. There was a significant reduction in mortality at 30 days in the transfemoral approach in the intention-to-treat analysis, but there was no significance in any of the other analyses, either at 30 days or 1 year. The transcatheter approach performed equally well as the traditional method.

And there were some other benefits in the transcatheter arm, including shorter ICU and hospital stay and improved aortic gradient (albeit with an occasionally worse perivalvular regurgitation). Not surprisingly, the transcatheter procedure had a disturbingly higher rate of stroke but without increased mortality, regardless of approach. The authors report equipment design changes are likely needed. And the patients who were treated with the less invasive procedure were ambulatory more reliably at 30 days than those who went under the knife. But at one year, the surgical group appeared to fare just as well in pump function and exercise tolerance as their friends in the catheter group.

As if the glitazones didn’t have enough to bad press already. New reports have emerged regarding Actos and the increased risk of bladder cancer in the men who take this drug. [10] The German and French equivalents of the FDA have suspended sales in their respective countries. Stay tuned for the FDA’s official recommendation.

And now for the men. As if internists didn’t have enough of a challenge sorting out whether to recommend prostate cancer screening to begin with, the FDA has a sneaking suspicion that the 5-alpha-reductase inhibitors (think finasteride) may lead to high-grade (Gleason 8-10) prostate cancer, and recommend screening before starting these meds. [11]

And that’s a full lid. Remember, Father’s Day is this Sunday.

Dr. Christopher Schultz is a 3rd year resident at NYU Langone Medical Center

Peer reviewed by Ishmeal Bradley, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1.  Williams T. Rare Infection Strikes Victims of a Tornado in Missouri [Internet]. 10 June 2011.  http://www.nytimes.com/2011/06/11/us/11fungus.html?hp

 2.  Kupferschmidt K. Restaurant Photos Help Nail Sprouts in German Outbreak [Internet]. 10 June 2011. http://news.sciencemag.org/scienceinsider/2011/06/restaurant-photos-help-nail-bean.html?ref=hp

 3.  Neuman W. Sprouts, Poster Plant of Health Food, Can Pack Risks [Internet]. 10 June 2011. http://www.nytimes.com/2011/06/11/business/11sprouts.html?ref=science

 4.  Goss PE et al. Exemestane for Breast-Cancer Prevention in Postmenopausal Women [Internet]. NEJM 2011. E-pub ahead of print, 4 June 2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1103507

 5.  National Cancer Institute/U.S. National Institutes of Health. Breast Cancer Risk Assessment Tool [Internet]. Last updated: 16 May 2011. http://www.cancer.gov/bcrisktool/about-tool.aspx.

 6.  Conen D, et al. Smoking, Smoking Status, and Risk for Symptomatic Peripheral Artery Disease in Women: A Cohort Study [Internet]. Ann Int Med. 6 June 2011; 154 (11): 719-726. http://www.annals.org/content/154/11/719.abstract

 7.   Baigent C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial [Internet]. Lancet 2011. E-pub ahead of print, 9 June 2011. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60739-3/fulltext

 8.   Hensley S. FDA: High Dose of Popular Cholesterol Medicine May Damage Muscles [Internet]. 8 June 2011. http://www.npr.org/blogs/health/2011/06/08/137063562/fda-high-dose-of-popular-cholesterol-medicine-may-damage-muscles?sc=nl&cc=es-20110612

 9.   Smith CR, et al. Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients [Internet]. NEJM 9 June 2011; 364(23): 2187-2198.  http://www.nejm.org/doi/full/10.1056/NEJMoa1103510

 10.   Dow Jones for The Wall Street Journal. Update: France, Germany Suspend Takeda’s Actos On Bladder Cancer Risk [Internet]. 10 June 2011. http://online.wsj.com/article/BT-CO-20110610-700058.html

 11.    Stein R. FDA Issues Warning On Prostate Drugs [Internet]. 9 June 2011. http://www.washingtonpost.com/blogs/the-checkup/post/fda-issues-warning-on-prostate-drugs/2011/06/09/AG0IHfNH_blog.html

Primecuts – This Week In The Journals

June 6, 2011

By Aviva Regev

Faculty Peer Reviewed

Hello?  Can you hear me now?  Making big headlines this week is a topic that is likely to hit very close to home for many of our readers, as well as people from all walks of life, across the globe.  The World Health Organization (WHO)/International Agency for Research on Cancer (IARC) [1] published a press release classifying radiofrequency electromagnetic fields – those emitted by cellular phones – as “possibly carcinogenic to humans.”  The IARC found cell phone use to be associated with an increased risk of glioma, a malignant brain tumor.  For many people, who consider their cell phones almost an extension of their beings, this may be very distressing news.   While it may not be a bad idea to use that hands-free headset more, keep in mind that so far, cell phone waves only got a group 2B classification, which means there is limited evidence of carcinogenicity in humans and insufficient evidence in experimental animals.  This is in contrast to group 2A – the “probably carcinogenic” group – which shows limited evidence in humans but sufficient evidences in animals.  This may be due to the fact that though there are over 5 billion cell phone subscriptions among humans globally, animals seem to prefer other means of communication.  A more detailed report of the conclusions of the IARC will be published in The Lancet Oncology on July 1st, and earlier online. 

Also in the news this week is the German E. coli outbreak, which is causing unusually high morbidity and mortality in its victims.  As of June 5, more than 2,200 people were thought to be infected in 12 European countries, with 627 cases of hemolytic-uremic syndrome (HUS) in Germany alone and 22 deaths overall [10]. The Shiga toxin-producing E. coli (STEC), dubbed O104:H4, causes an illness very similar to that produced by the notorious EHEC 0157:H7 strain.  To date, four cases of HUS have been reported in travelers returning to the U.S. from Germany, all pending final laboratory confirmation [2].  ScienceInsider [3] reports that the culprit has been completely sequenced and identified as a new strain, which shares 93% of its DNA sequence with enteroaggregative (EAEC) 55989 E. coli, which was isolated in Africa and “known to cause serious diarrhea.”  On top of that, it has genes from other highly pathogenic bacteria including Salmonella and other distinct strains of E. coli.  According to the Chinese group that sequenced the genome, this combination makes the new STEC strain “supertoxic.”  Perhaps even more incredible is the fact that it took only 3 days to sequence all 5.2 million base pairs, considerably faster than the 15 years it took to sequence the first E. coli strain, which was completed in 1997. 

Speaking of diarrhea, some good news: this week, the FDA approved Dificid (fidaxomicin) for C. difficile diarrhea [4].  Dificid is a macrolide antibiotic, and was shown to be similar in efficacy to vancomycin in a trial published in NEJM [5].  Patients treated with Dificid had a significantly lower rate of recurrence of infection at 4 weeks compared to those treated with vancomycin. 

While it didn’t make headlines, the FEAST trial [6] published in NEJM last week is big news in the medical literature.  The trial assessed the role of fluid boluses in treating children with shock in resource-poor treatment settings.  In four hospitals in East Africa, 3141 children with a severe febrile illness and impaired perfusion, complicated by impaired consciousness, respiratory distress, or both, were randomized to receive no bolus or either albumin or saline bolus at 20-40 cc/kg.  Children with those criteria and severe hypotension were randomized to receive either albumin or saline bolus.   Those with malnutrition or gastroenteritis were excluded from the study. All children received maintenance fluid therapy at 2.5-4 cc/kg/hr as well as antibiotics, antimalarials, antipyretics, anticonvulsants, treatment for hypoglycemia, and transfusion, as indicated.  No ICU-level care was available.  The results were somewhat surprising: children in the bolus groups had increased mortality compared to those receiving no bolus, with a relative risk of 1.45 (p=0.01).  There was no significant difference between albumin and saline boluses.  Furthermore, these results were consistent across the subgroups analyzed, including the severity of shock, malaria status, and the presence of coma, sepsis, acidosis, or severe anemia.  The boluses were not found to be beneficial in any of these groups.  In fact, enrollment in the study was stopped short of the goal of 3600 when it became evident that the intervention was resulting in increased mortality.  Interestingly, there was no significant difference between groups in the rate of pulmonary edema or increased intracranial pressure, which were postulated to be adverse effects of fluid boluses.  Though fluid bolusing is a mainstay of shock therapy for children and adults in the developed world, “the results do not support the use of bolus resuscitation in severely ill febrile children with impaired perfusion in African hospitals and also raise questions about its use in other settings.” 

In the Lancet this week, a trial evaluated the use of dexamethasone as an adjunct to antibiotic treatment in patients with community-acquired pneumonia (CAP) [7].  The double-blind, placebo-controlled trial randomized 304 adults with confirmed CAP to receive IV dexamethasone (5mg/day) or placebo as well as standard of care according to national treatment guidelines.  Patients who were immunocompromised, on oral steroids, or required immediate admission to an ICU were excluded.  The demographics of the two groups were for the most part very similar, though there was a larger proportion of renal disease (13% vs. 7%) and of severe pneumonia, defined as Class 4 or 5 (52% vs. 42%) in the dexamethasone group.  The study found a decrease in the mean length of stay from 7.5 days in the placebo group to 6.5 days in the dexamethasone group (p=0.048).  The in-hospital and 30 day mortality rates as well as rate of readmission within 30 days were similar between the two groups.  There was a non-significant decrease in time to death (5.5 days vs. 8.8 days) as well as increase in length of ICU stay (21.5 days vs. 15.5 days) in the dexamethasone group.  Though the rate of hyperglycemia was higher in the dexamethasone group (p<0.0001), there was no significant difference in the number of patients requiring glucose-lowering therapy.  Though the study had a statistically significant result, clinicians must weight the benefit of a one-day earlier discharge against the potential adverse effects of systemic corticosteroid administration in each patient when decided whether to add dexamethasone to the treatment regimen of patients with CAP. 

If this issue of PrimeCuts had been written 30 years ago, it might have mentioned a strange group of cases from the CDC’s Morbidity and Mortality Weekly Report (MMWR) on June 5, 1981 [8].  Five men in Los Angeles had been diagnosed with Pneumocystis carinii pneumonia (PCP).  “The occurrence of pneumocystosis in these 5 previously healthy individuals without a clinically apparent underlying immunodeficiency is unusual,” the report stated.  These were the first reported cases of what would become recognized as AIDS.  In a nod to that historic report, this week’s MMWR [9] provides an update on HIV/AIDS in the United States: though AIDS diagnoses and deaths have steadily declined since the introduction of HAART in the 1990s, the number of people living with HIV has steadily increased, up to almost 1.2 million in the United States alone. While there have been great strides in the last three decades and HIV infection is no longer the death sentence it once was, this week’s MMWR reminds us that there is still a long way to go. 

Aviva Regev is a 3rd year medical student at NYU School of Medicine and contributing editor, Clinical Correlations

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

Image courtesy of Google Images

References

1. World Health Organization/International Agency for Research on Cancer.  Press Release No 208: IARC Classifies Radiofrequency Electromagnetic Fields as Possibly Carcinogenic to Humans.  31 May 2011. http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf

2. Investigation Update: Outbreak of Shiga toxin-producing E. coli O104 (STEC O104:H4) Infections Associated With Travel to Germany.  Centers for Disease Control and Prevention (CDC).  June 3, 2011. http://www.cdc.gov/ecoli/2011/ecolio104/

3. Enserink M.  DNA Sequence Yields Clues to Germany’s “Super Toxic” E. coli Outbreak. ScienceInsider [Internet] 2 June 2011.  http://news.sciencemag.org/scienceinsider/2011/06/sequence-yields-clues-to-germany.html?ref=hp

4. FDA News Release: FDA approves treatment for Clostridium difficile infection.  May 27, 2011.  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257024.htm

5. Louie TJ, Miller MA, Mullane KM, et. al.  Fidaxomicin versus Vancomycin for Clostridium difficile Infection.  NEJM 2011: 364:433-31. http://www.nejm.org/doi/full/10.1056/NEJMoa0910812

6. Maitland K, Kiguli S, Opoka RO, et. al. Mortality after Fluid Bolus in African Children with Severe Infection.  NEJM 2011. E-pub ahead of print, May 26, 2011. http://www.nejm.org/doi/full/10.1056/NEJMoa1101549

7. Meijvis SC, Hardeman H, Remmelts HH, et. al.  Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomized, double-blind, placebo-controlled trial.  The Lancet 2011.  E-pub ahead of print, June 1, 2011. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60607-7/fulltext

8. Gottlieb MS, Schanker HM, Fan PT, Saxon A, Weisman JD.  Pneumocystis Pneumonia – Los Angeles. MMWR: Morbidity and Mortality Weekly Report. 5 June 1981; 30(21):1-3. Centers for Disease Control and Prevention.  http://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm

9. MMWR: Morbidity and Mortality Weekly Report. 3 June 2011; 60(21):1-40. Centers for Disease Control and Prevention.  http://cdc.gov/mmwr/PDF/wk/mm6021.pdf

10. CNN Wire Staff.  More deaths reported in historic German outbreak.  CNN [Internet].  June 5, 2011.  http://www.cnn.com/2011/WORLD/europe/06/05/europe.e.coli/index.html?hpt=hp_p1&iref=NS1

Primecuts – This Week In The Journals

May 31, 2011

By Varun Verma, MD

Faculty Peer Reviewed

Our thoughts and prayers this week are with the victims of Joplin, Missouri, who struggle to rebuild their lives after being struck with one of the deadliest tornadoes in US history. Although we can do little about unpredictable natural occurrences, this week’s medical journals reveal some promising interventions that may help us improve the health of our patients.

The New York Times highlighted the National Institutes of Health clinical trial AIM HIGH, [1] the results of which call into question the role of niacin in clinical practice and the importance of high-density lipoprotein (HDL) cholesterol as a risk factor for cardiovascular disease. The authors randomized 3,414 participants with low HDL and high triglycerides to either simvastatin and a placebo, or simvastatin and extended-release niacin (Niaspan) and followed them for 32 months. [2] The trial ended 18 months early because those in the Niaspan group were no less likely to suffer fatal or non-fatal myocardial infarctions, be hospitalized for acute coronary syndrome, or undergo revascularization procedures. More importantly, those in the Niaspan group were at increased risk of developing ischemic stroke: 28 strokes (1.6%) versus 12 strokes (0.7%) in the control group. [3] The fact that Niaspan did indeed increase HDL and lower triglycerides emphasizes that much remains to be discovered about cholesterol homeostasis. Although there will certainly be other studies to tackle the question of the effects of HDL and triglycerides on cardiovascular disease, given the increased risk of ischemic stroke with Niaspan, I will likely not recommend it to any of my patients with well-controlled low-density lipoprotein (LDL) cholesterol at this time.

Staying with cardiology for the moment, a prospective study in JAMA revealed that new-onset atrial fibrillation (AF) in middle aged women was independently associated with elevated all-cause, cardiovascular, and non-cardiovascular mortality. [4] The study included 34,722 women aged 45 or older (median follow-up of 15 years) with low overall cardiovascular risk factors, who were free of AF at baseline. In multivariate models, hazard ratios of new onset AF for all-cause, cardiovascular, and non-cardiovascular mortality were 2.14 (95% CI, 1.64-2.77), 4.18 (95% CI, 2.69-6.51), and 1.66 (95% CI, 1.19-2.30), respectively.  Interestingly, women with only paroxysmal AF, although not at increased risk for all-cause and non cardiovascular death, still remained at increased risk of cardiovascular death (HR, 2.94; 95% CI, 1.55-5.59; P=.001) after adjustment for cardiovascular risk factors. The authors conclude that not all of the mortality risk associated with AF could be accounted for by the development of cardiovascular disease, which underscores the need for more effective primary AF prevention strategies. When more closely analyzing the baseline characteristics of the incident AF group vs the non-AF group, the only statistically significant difference was prevalence of hypertension at the time of incident AF.

While digesting the next study, one wonders whether cardiac medications will one day run free like fluoride in our drinking water. The 400-participant 12-week randomized controlled trial in PLos ONE (an open-access peer-reviewed journal published by the Public Library of Science that I first discovered in the News section of BMJ) proclaims that a cardiovascular “polypill” halved the predicted risk of heart disease and stroke when compared to placebo in participants with no indications for any of these medications. The pill contains 75 mg aspirin, 10 mg lisinopril, 12.5 mg hydrochlorothiazide, and 20 mg simvastatin. [5] Although the participants were people with elevated cardiovascular risk (5-year Framingham risk of at least 7.5%), they had no indications for any of these medicines. The study was conducted in seven countries: Australia, Brazil, India, Netherlands, New Zealand, the United Kingdom, and the United States. Before we all reach for our prophylactic pill cabinets, the authors quite rightly point out the many limitations to their study, including the relatively short follow-up, the narrow patient population, and (perhaps most striking) the fact that the predicted reductions in cardiovascular risk are based on indirect estimates. Systolic blood pressure decreased by 9.9 mmHg (95% CI, 7.7-12.1) and LDL cholesterol by 0.8 mmol/L (95% CI, 0.6-0.9) compared with placebo. This is not the first study to consider a combination pill to address cardiovascular risk factors; a study from India was published in 2009 in Lancet with a drug consisting of three blood pressure-lowering drugs, a statin, aspirin, and folic acid. Given the prevalence, cost, morbidity, and mortality of cardiovascular disease, I assume it will not be the last.

Our last two studies hail from the Archives of Internal Medicine. To those of us who realize the importance of a multipronged approach to the practice of modern medicine, the findings of the next study should come as no surprise. This one-year randomized controlled trial examined the effect of involving a language-concordant layperson in the colorectal cancer screening process. [6] Patients assisted by a “healthcare navigator” were more likely to undergo fecal occult blood testing than control patients (33.6% vs 20.0%; P < .001) and also to be screened by colonoscopy (26.4% vs 13.0%; P < .001). Impressively, these patients were also more likely to have adenomas detected (8.1% vs 3.9%; P = .06). Whatever the reason for low screening rates among our patients–lack of trust in physicians, absence of symptoms, a fundamental disconnect experienced when communicating through an interpreter–the study outlines a simple and effective intervention. Hiring laypersons from the community to provide a health care intervention, emotional support, and empathy has been tested in the realm of global health. Partners In Health, based in Boston, trains and employs “accompagnateurs routinely in their HIV and TB compliance efforts throughout Haiti and Rwanda. Perhaps we will step away from our lone-ranger role as physicians, and treat medicine like the team sport it is.

A much overlooked problem in primary care practice is insomnia, particularly among the elderly. Since there are downsides to simply prescribing another drug (poly-pharmacy, cost, nonadherence), it is encouraging to see another study outline a simple intervention that delegates responsibility to another team member, in this case a nurse practitioner. The randomized trial in the Archives of Internal Medicine examined 79 older adults with chronic insomnia and found brief behavioral treatment more efficacious than handing out printed materials on insomnia. [7] The intervention arm consisted of a 45- to 60-minute individual session followed by a 30-minute follow-up session 2 weeks later and 20-minute telephone calls after 1 and 3 weeks.  Four main behavioral interventions were emphasized: “Reduce time in bed, get up at the same time every day regardless of sleep duration, do not go to bed unless sleepy, and do not stay in bed unless asleep.” Napping was discouraged. The study also displayed impressive potential for durability: at 6 months, 64% of patients in the treatment arm no longer met DSM-IV criteria for insomnia.

Dr. Verma is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Michael Tanner, MD, section editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. Harris, Gardener. Study Questions Treatment Used in Heart Disease New York Times. Published online May 28, 2011. http://www.nytimes.com/2011/05/27/health/policy/27heart.html?_r=1

2. AIM-HIGH Investigators.  The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol.  Rationale and study design.  The Atherosclerosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J. 2011;161(3):538-543. http://www.ahjonline.com/article/S0002-8703%2810%2901165-8/fulltext

3. NHLBI Communications Office. NIH stops clinical trial on combination cholesterol treatment. Lack of efficacy in reducing cardiovascular events prompts decision. http://www.nih.gov/news/health/may2011/nhlbi-26.htm

4. Conen D, Chae CU, Glynn RJ, et al. Risk of death and cardiovascular events in initially healthy women with new-onset atrial fibrillation.  JAMA. 2011;305(20):2080-2087. http://jama.ama-assn.org/content/305/20/2080.full.pdf+html

5. Rodgers A, PILL Collaborative Group, et al. An international randomised placebo-controlled trial of a four-component combination pill (“Polypill”) in people with raised cardiovascular risk. PLoS ONE. 6(5):e19857. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0019857

6. Lasser K, Murillo J, Lisboa S, et al. Colorectal cancer screening among ethnically diverse, low-income patients: a randomized controlled trial. Arch Intern Med. 2011;171(10):906-912. http://archinte.ama-assn.org/cgi/content/full/171/10/906

7. Buysse D, Germain A, Moul DE, et al. Efficacy of brief behavioral treatment for chronic insomnia in older adults. Arch Intern Med. 2011;171(10):887-895. http://archinte.ama-assn.org/cgi/content/full/archinternmed.2010.535

 

Primecuts – This Week In The Journals

May 23, 2011

By Vincent Santillo, MD

Faculty Peer Reviewed

The press and the public that devours it thrive on exciting headlines of misfortune and misdeeds. After a week filled with powerful men acting terribly, it was a relief to see the big new positive news stories — “Paralyzed now walk” and “Coffee Protects from Cancer”. Bring on the caffeine and science fiction as we take a look at some of the more interesting articles appearing this week. The New York Times excitedly announces that “a paralyzed man stands” as it discusses the results of a unique experiment presented in this week’s Lancet. The New York Times is also the source of our second article in which the name of the researchers’ institution figures prominently in the headline, one would suppose to lend weight to the promise that coffee prevents prostate cancer. Another topic always being magnified in all media is obesity, and we discuss a study from the Annals of Internal Medicine which shows that among the elderly the mortality risk may not be as great as one would assume and that it may be future disability that we may be preventing by encouraging weight loss. Lastly we have two studies on proton pump inhibitors – once which seems to give some hope to those wanting to avoid gastric surgery for GERD and another which hints at a new cardiac risk in PPIs via their impact on aspirin absorption.

The health section of the New York Times captivated readers with news that an “Electrode experiment shows promise as a paralyzed man stands”. The authors were relating the results of a case report published this week in The Lancet [1] that presented the case of a 23-year-old man who, having been made paraplegic from a motor vehicle accident in 2006 was able to achieve weight-bearing status. The authors hypothesized that tonic epidural spinal cord stimulation could modulate spinal circuitry that would enable sensory input from standing and stepping movements to serve as a source of neural control to undertake these tasks. The patient had no contraction of trunk of leg muscles after his accident and at the time of implantation of the study’s electrodes, 3.4 years after he was struck by a motor vehicle, the patient was “unable to stand or walk independently or to voluntarily move his legs despite standard-of-care rehabilitation and additional intensive locomotor training.” The 16-electrode array was implanted at T11-L1. After epidural stimulation of the caudal segments (L5-S1) of the spinal cord was combined with sensory information related to bilateral extension and loading the patient was able to generate standing without any assistance on his first attempt with 65% bodyweight support, which was progressively reduced to full weight bearing. In addition to the ability to bear weight, the patient has also seen functional gains in bladder and sexual function as well as temperature regulation. The key problem with the study is that it is an experimental situation with one subject and may not be generalizable. However, it provides valuable information and researchers will be able to use their methods and findings to provide hope where there has been only hopelessness.

Under the very impressive headline “Prevention: Coffee Lowers Risk of Prostate Cancer, Harvard Study Says”, The New York Times presented the results of a study published online in The Journal of the National Cancer Institute that described a “strong inverse association between coffee consumption and risk of lethal prostate cancer.” [2]  The data was taken from baseline food frequency questionnaires filled out by 47,911 men in the Health Professionals Follow-up Study. Participants were asked to recall their consumption of various food items over the prior year. This kind of data collection is rife with recall bias. The recall bias may be tempered in this case by the habitual and ritualized use of coffee by most users. In this study, heavy coffee drinkers (>=6 cups/d) had less than half the risk for lethal and advanced prostate cancers as nondrinkers. Confounding provides little explanation as heavy coffee users were also smokers and sedentary, both of which may increase the risk for advanced prostate cancer. The authors present several hypothetical ways in which coffee may modify the course of prostate cancer, however data is limited. While the study is intriguing and may provide worthy avenues for further investigation, it would be premature to encourage increased coffee consumption as a prostate cancer preventative measure.

In this week’s Annals of Internal Medicine [3] a cohort study was published that showed that obesity is not necessarily associated with a higher risk for premature death. In fact, as the article points out, there have been safety concerns surrounding weight control in elderly persons. The authors relied on the secondary analysis of data from the Medicare Current Beneficiary Survey collected from 1994 to 2000 and linked to Medicare enrollment files through 2008. Their analysis showed that “compared with respondents with a BMI of 22.0 to 24.9 kg/m^2, those with a higher BMI did not have a higher hazard for death, except for those with a BMI of 35 kg/m^2 or greater.” There was some racial disparity in the data as a higher BMI did not confer an increased mortality risk for African American men. Outside of mortality, the study also attempted to quantify the impact of obesity on functional decline. The authors evaluated participants at baseline and annually for two years and “asked whether they had any difficulty performing 6 activities of daily living (ADLs) (bathing or showering, dressing, eating, getting in and out of chairs, walking, and toileting) and 6 instrumental activities of daily living (IADLs) (using the telephone, doing light housework, doing heavy housework, making meals, shopping, and managing money).” The authors found that increasing BMI was “significantly associated with the presence of both ADL and IADL disability at baseline.” While the impact on mortality may be minimal, BMI, even just slightly above normal, was “associated with new or progressive ADL and IADL disability in a dose dependent manner in both men and women.” While the mortality benefit of weight control may be tempered in older populations, there appears to be a mortality benefit of having a BMI <35. As well, a reduced BMI may help to reduce the risk of further functional decline.

This week JAMA published the results of the LOTUS (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) randomized clinical trial to evaluate the role of continued optimized PPI therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD.[4]  In order to participate in the study, a 3 month run-in period was required to confirm clinical response to esomeprazole 40mg/d. After that, participants were randomized to either undergo LARS or to receive esomeprazole (initially at 20mg/d). At 5 years, most participants in both groups were in remission; in the LARS group 85% remained in remission (sufficient control without PPI therapy) as compared to 92% in the esomeprazole group (sufficient control without esomeprazole greater than 20mg po bid). The authors state that “this study is not designed as a superiority or equivalence trial”. However, on multiple occasions they refer to remission being achieved using either LARS or esomeprazole as if they are equivalent therapies. It is important to keep in mind that while there was no surgical mortality associated with LARS in this study, there were 33 treatment failures in that group (29 patients required other treatment to control reflux symptoms, 1 needed more than 1 dilatation, a 3 had postfundoplication adverse events including 1 gastric perforation and 2 with severe flatulence, bloating, and diarrhea). It is important to remember that all of these surgical issues are being experienced by patients whose symptoms were controlled on esomeprazole alone after their 3 month run-in. In fact, most of the treatment failures in the LARS group found their symptoms controlled with the addition of acid suppressive drugs. While chronic PPI usage has been associated with cardiac events and bone fractures, this study does not make a strong enough case to give a clinician certain guidance on LARS vs long-term PPI therapy. While awaiting further data, the prudent path may be to continue medical management until the patient is refractory before considering LARS.

The issue of chronic PPI therapy has received a lot of press and research attention vis-à-vis the interactions between PPIs and clopidogrel. However, as an article published online by BMJ this week showed, PPIs may also impact the effectiveness of aspirin. [5]  In a manner similar to its effect on clopidogrel, the use of PPIs may increase the gastric pH above the pKa of acetylsalicylic acid which leads to reduced lipophilicity and reduced absorption of the drug. In this retrospective study, 19,925 Danish patients treated with aspirin-only after a first myocardial infarction were followed for one year. During the study period 17% of the aspirin treated patients had a recurrent MI, stroke or CV death (the study’s combined endpoint). The hazard ratio for the combined end point in patients receiving proton pump inhibitors was 1.46 (p<0.001). The authors raise the intriguing question as to whether the “putative interaction between clopidogrel and proton pump inhibitors may be explained, at least in part, by an interaction between aspirin and proton pump inhibitors, as virtually all patients treated with clopidogrel also receive aspirin.” While PPIs are widely used for the prevention of peptic ulcer disease in patients on chronic aspirin therapy, data being gathered on their impact on the efficacy of clopidogrel and, per this new study, aspirin may lead to reconsidering such broad use. Randomized prospective studies are needed to improve clinical decision making.

Dr. Santillo is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Michael Poles, section editor, Clinical Correlations

Image Courtesy of Wikimedia Commons

References:

[1]    Harkema, Susan et al. Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study. Lancet. Published online May 20, 2011. http://http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60547-3/fulltext

[2]   Wilson, Kathryn et al. Coffee consumption and prostate cancer risk and progression in the Health Professionals Follow-up Study. J Natl Cancer Inst. 2011;103:1-9. http://jnci.oxfordjournals.org/content/early/2011/05/17/jnci.djr151.abstract

[3]    Wee, Christina et al. Obesity, race, and risk of death or functional decline among Medicare beneficiaries. Ann Intern Med. 2011;154:645-55. http://www.annals.org/content/154/10/645.abstract?aimhp

[4]   Galmiche, Jean-Paul et al. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD. JAMA. 2011;305:1969-77. http://jama.ama-assn.org/content/305/19/1969.short

[5]    Charlot, Mette et al. Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study. BMJ. Published online May 2011. http://www.bmj.com/content/342/bmj.d2690.abstract

 

 

Primecuts – This Week In The Journals

May 16, 2011

By Matthew Ingham, MD

Faculty Peer Review

Change to the established order, in politics as in medicine, is a slow and painstaking process. Across the Middle East and particularly in Syria and Libya, the initial excitement and intensity of popular uprisings has faded as opposition groups dig in to continue their threat to existing regimes. A series of articles in the major medical journals this week present evidence that similarly threatens to overturn our current way of doing things, but, as in politics, change is likely to be slow.  Highlights include yet more evidence that beta blockers may be beneficial, not harmful, in patients with chronic obstructive pulmonary disease, as well as a dramatic study suggesting HIV transmission can be cut impressively by early initiation of HAART. And one study in this week’s JAMA highlights just how slow change to clinical practice can be, showing that despite the COURAGE trial and the strong evidence for optimal medical therapy as compared PCI in patients with stable coronary disease, few of our patients are taking the right medications.

Evidence continues to mount against the traditional view that beta blockers should be withheld in patients with underlying COPD. A retrospective cohort study in this week’s British Medical Journal used an NHS database of patients with COPD in Scotland to examine the effects of beta blocker use on all cause mortality, mortality from myocardial infarction and COPD alone and on hospital admissions for COPD exacerbations. [1] Beta blocker use was associated with a statistically significant 22% reduction in all cause mortality, and the mortality benefit persisted when controlling for known underlying coronary disease. Additionally, the mortality effect and a significant reduction in hospital admissions persisted when beta blockers were added stepwise to existing COPD treatment regimens, such as inhaled corticosteroids, and inhaled corticosteroids combined with long-acting beta agonists. No significant difference in effect was found for cardioselective versus non-cardioselective beta blockers. The proposed mechanism involves up-regulation of beta-2 receptors by chronic beta blockade, which may then improve the efficacy of beta-2 agonists. The benefit on mortality and hospital admission seems all the more impressive as beta blockers are probably a marker for sicker patients. As with other recent studies showing a mortality benefit for beta blockers in the COPD population, it remains unclear whether the observed benefits are derived from the treatment of undiagnosed silent coronary disease versus a physiologic effect on COPD itself. This study also failed to address non-fatal adverse effects in the beta blocker treated group such as bronchospasm.

A forthcoming study from the National Institutes of Health, reported this week in the New York Times, may change clinical practice in the treatment of HIV/AIDS patients. [2] The study – HPTN 052 – enrolled 1763 sero-disconcordant couples at 13 sites across Asia, Africa and America. The HIV positive partner – who was required to have a CD4 count of 350-550 at enrollment – was randomized to immediate initiation of HAART, or initiation of therapy only when the CD4 count fell below 250. Across five years of follow-up, the study found 27 episodes of HIV transmission (confirmed by testing to be the positive partner’s genotype) in the delayed treatment group as compared only one in the early therapy group. The delayed therapy group was given placebo HAART. These results seem to confirm that inducing a low level of viremia significantly reduces transmission risk. The study’s authors conceded that over 90% of the couples in the study were heterosexual. Given the significantly magnified risk of HIV transmission in a homosexual medium, it remains questionable whether the protective benefit would be as pronounced in this group, which still accounts for the majority of infections in the United States. The information released thus far also did not comment on the incidence of adverse effects from HAART or the potential for development of resistance by initiating treatment earlier, although assessing the latter would, of course, require a much longer period of follow-up.

Residents everywhere rejoice when the elective post-catheterization patient lands on their service overnight, as these patients typically demand little more than checking for distal pulses and ruling out a bruit. But a new study shows that these patients may benefit from closer attention while highlighting the barriers to translating published research into clinical practice. The paper, published in this week’s JAMA, finds that 4 years after the COURAGE trial – which showed that PCI offers no benefit in preventing MI or death in patients with stable CAD as compared optimal medical therapy (OMT) – fewer than half of patients with stable CAD are on such therapy (aspirin, a beta blocker and a statin) before PCI. [3] Before COURAGE, 43.5% of patients were taking OMT prior to PCI, and after the publication, a paltry 44.7% were optimized. Although this difference was statistically significant, both the overall rate of OMT and the minimal increment after the study’s release are notable. Patients discharged from the hospital after PCI fared somewhat better, with 63.5% receiving OMT on discharge prior to COURAGE, and 66.0% after. Compliance with aspirin therapy was highest. The authors were able to exclude patients with a contraindication to any of the OMT medications. The JAMA study raises important concerns about why the results of such a highly publicized and generally well regarded $33.5 million dollar study are not better reflected in clinical practice. The results also suggest room for improvement in systems and communication amongst healthcare teams. Read more »

Primecuts – This Week In The Journals

May 9, 2011

By Megha Shah, MD

Faculty Peer Reviewed

This week we were witness to the courage, perseverance, and ultimately, the triumph of the American military in the ongoing efforts against terrorism. In a similar, albeit physically less threatening manner, scientists, researchers, and physicians work everyday to prevent and eradicate disease. In this week’s Primecuts, we celebrate those who fight to eliminate threats to our well-being and bring you the latest in the scientific headlines.

The New York Times reported on a study published in the New England Journal of Medicine comparing the efficacy of Lucentis (ranibizumab) with Avastin (bevacizumab) in the treatment of macular degeneration.[1] Avastin, typically a cancer drug, is much cheaper than Lucentis and, given its similar mechanism of action, has been used off-label for several years. The trial, sponsored by the National Eye Institute, included 1200 patients and showed that patients receiving Avastin could read an average of 8 letters more on an eye chart after a year of treatment, similar to the 8.5 letter improvement seen in those using Lucentis. Though larger and longer studies are pending, the findings show a potential way of saving hundreds of millions of dollars in Medicare costs and making the treatment for macular degeneration more accessible.

In a retrospective cohort study, researchers in Toronto compared survival in older patients with COPD who received either long-acting β-agonists or anticholinergics for treatment. The study, funded by the Government of Ontario and published in the Annals of Internal Medicine, included a total of 46,403 patients and showed that mortality was higher in patients initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled β-agonist (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]).[2] Rates of hospitalizations and emergency room visits were also higher in the former group. Though controlled randomized trials need to be conducted, the study does give some perspective on what treatment options may be more efficacious when initiating COPD management.

 This week’s New England Journal of Medicine published a study that compared watchful waiting with radical prostatectomy in patients with early prostate cancer.[3] A total of 695 men were recruited over a ten year period and randomly assigned to either management arm. At fifteen year follow-up, the cumulative incidence of death from prostate cancer was 14.6% with radical prostatectomy and 20.7% with watchful waiting (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (P=0.01). In addition, those with extracapsular tumor growth after surgery had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (95% CI, 2.6 to 18.4). The study highlights that while watchful waiting is often the preferred route of management in early prostate cancer, more aggressive measures with surgery, including adjuvant chemotherapy for those with extracapsular growth, should be more seriously considered.

In an early online publication, a study in The Lancet Infectious Diseases looked at the efficacy of chloroquine in the prevention of influenza.[4] Approximately 1500 healthy young adults were randomly assigned to receive either chloroquine or placebo. Eight of 738 participants had laboratory confirmed clinical influenza in the placebo group versus 12 of 724 in the chloroquine group (P=0.376). A total of 29 in the placebo group versus 38 in the chloroquine group had laboratory confirmed (with or without symptoms) influenza (P=0.261). Approximately 45% of participants in the chloroquine group reported side effects versus 33% in the placebo group (P=0.0001). The study concluded that chloroquine was not an effective drug for the prevention of influenza and that further research and drug development is needed.

Lastly, the Lancet Oncology published a study comparing intravenous and subcutaneous administration of bortezomib (Velcade) in patients with relapsed multiple myeloma.[5] This non-inferiority study included 222 patients who were randomized to either group and received an average of eight cycles of the drug. Overall response rate was 42% in both groups (P=0.002). In addition, there were no significant differences in time to progression (P= 0.387) or one year overall survival (P=0.504). By showing that subcutaneous administration is non-inferior, the results of the study may allow patients to spend less time in the hospital or clinical setting and provide a viable option for patients with difficult vascular access.

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

Peer reviewed by Danise Schiliro, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1.  Pollack, Andrew. Cheaper Drug to Treat Macular Degeneraton. New York Times. Published online April 28, 2011. http://www.nytimes.com/2011/04/29/business/29eye.html?_r=3&ref=research

2.  Gershon A., Croxford R. et al. Comparison of Inhaled Long-acting Beta Agonist and Anticholinergic Effectiveness in Older Patients with Chronic Obstructive Pulmonary Disease. Annals of Internal Medicine. 2011; 154 (9): 583-592. http://www.annals.org/content/154/9/583.abstract

3.  Bill-Axelson A., Holmberg L. et al. Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer. New England Journal of Medicine. 2011; 364: 1708-1717. http://www.nejm.org/doi/full/10.1056/NEJMoa1011967

4.  Paton NI, Lee L et al. Chloroquine for influenza prevention: a randomized, double-blind, placebo controlled trial. The Lancet Infectious Diseases. Early online publication. May 6,2011. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(11)70065-2/fulltext

5.  Moreau P., Pylypenko H. et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. 2011; 12(5): 431-440. http://www.thelancet.com/journals/lanonc/article/PIIS147020451170081X/fulltext

Primecuts – This Week In The Journals

May 2, 2011

By Ian Fagan, MD 

Faculty Peer Reviewed

Is springtime the season for love? Take a look outside—the birds are chirping, the bees are buzzing, the flowers are blooming. There are strangers mingling in the parks, couples out and about holding hands. The energy is palpable and signs of blossoming love are abundant. Even this week’s journals couldn’t avoid matters of the heart.

For instance, the New England Journal of Medicine published an article looking at coronary-artery bypass grafting (CABG) in patients with left ventricular dysfunction. Between 2002 and 2007, roughly 1,200 patients with an ejection fraction less than 35% and known CAD were randomized to medical therapy alone or medical therapy plus CABG. The primary outcome was death from any cause. The researchers found that the primary outcome occurred in 41% of patients in the medical therapy group versus 36% in the CABG group, a non-significant difference. The secondary endpoint was death due to a proven cardiovascular cause. This occurred in 33% of patients in the medical therapy group compared to 28% of patients in the CABG group, a significant difference (p = 0.05). Although the evidence is far from conclusive, this study supports the idea that ischemic heart failure patients may do just as well without that trip to the operating room.

Picking up on the heart failure theme, JAMA published an article this week looking at health literacy and its affects on outcomes in patients with heart failure. In a retrospective cohort study conducted in Colorado, outpatients with heart failure were surveyed by mail. Their health literacy was assessed using established screening questions and was then categorized as low or adequate.  Of the 1,494 responders, 262 (17.5%) had low health literacy. These patients, on average, were older, of lower socioeconomic status, less likely to have a high school education, and had higher rates of comorbid illness. Low health literacy was independently associated with higher mortality (crude  mortality rate of 17.6% versus 6.3% for those with adequate health literacy, with an adjusted hazard ratio of 1.97 (1.3 – 2.97)). This suggests that in a disease like heart failure, which requires significant self-management and self-titration of medications, understanding your patients’ limitations and tailoring your education correspondingly may make all the difference.

This week, the Archives of Internal Medicine examined whether the HIV virus is an independent risk factor for heart failure. In this retrospective cohort study, 8,486 HIV-infected and HIV-uninfected veterans were studied. During the 7.3 years of follow up, 286 incident heart failure events occurred. After adjusting for age and race, the heart failure rate for HIV-infected patients and HIV-uninfected patients were 7.12 and 4.82 per 1000 person-years, respectively. This corresponded to a hazard ratio of 1.81 (1.39 – 2.36). This association remained even after adjusting for more confounders such as prior heart failure and history of alcohol abuse. Furthermore, those HIV-infected patients with an HIV-1 RNA level greater than 500 copies/mL had a greater risk of heart failure than those with less than 500 copies/mL (adjusted hazard ratio of 2.28 (1.57 – 3.32)). Although the mechanism of disease is unclear, it seems as though HIV may truly be a risk factor for the development of heart failure.

Even the gastroenterologists were concerned with the heart this week. A group of researchers from the University of Miami published an article in the American Journal of Gastroenterology looking at whether inflammatory bowel disease (IBD) is associated with an increased incidence of cardiovascular events.  In this longitudinal cohort study, 356 IBD patients and 712 matched controls were monitored for the development of CAD. They found an unadjusted hazard ratio of 2.85 (1.82 – 4.46). Of note, IBD patients had significantly lower rates of traditional CAD risk factors such as hypertension, diabetes, dyslipidemia, and obesity. After adjusting for these factors, the hazard ratio increased to 4.08 (2.49 – 6.70). Researchers believe that the chronic systemic inflammation seen in IBD may be an independent risk factor in the pathogenesis of CAD. Furthermore, some believe that the inflammation may affect the coagulation cascade, which then induces endothelial dysfunction. Their exciting results highlight the need for more basic science research into this area.

On a similar note, the American Journal of Cardiology published an article this week regarding the impact of caffeine ingestion on endothelial function in patients with coronary artery disease. Researchers compared 40 patients with CAD to 40 controls on the basis of brachial artery flow-mediated dilation (FMD). After overnight fasting, discontinuation of all meds for 12 hours, and the absence of caffeine for 48 hours, patients received 200mg caffeine capsules or placebo.  FMD was then measured one hour after ingestion. At baseline, FMD was significantly lower in patients with CAD compared to controls (5.6% versus 8.4%), and acute caffeine ingestion significantly increased FMD in both CAD patients (14.6%) and controls (18.6%). Although the jury is still out, this study shows that caffeine ingestion actually improves endothelial function. Interestingly, caffeine did not significantly impact the resting heart rate in either group. While new love this spring might give you a hummingbird heartbeat, it seems that caffeine officially does not.

Ian Fagan is a first year resident at NYU Langone Medical Center

Peer reviewed by Ishmeal Bradley, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

1. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011; 364: 1607 – 1616 http://www.nejm.org/doi/full/10.1056/NEJMoa1100356

2. Peterson PN, Shetterly SM, Clarke CL, et al. Health literacy and outcomes among patients with heart failure. JAMA. 2011;305(16):1695-1701 http://jama.ama-assn.org/content/305/16/1695

 3. Butt AA, Chang CC, Kuller L, et al. Risk of heart failure with human immunodeficiency virus in the absence of prior diagnosis of coronary heart disease. Arch Intern Med. 2011;171(8):737-743 http://archinte.ama-assn.org/cgi/content/short/171/8/737

 4. Yarur AJ, Deshpande AR, Pechman DM, et al. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. Am J Gastroenterol 2011; 106:741–747. http://www.nature.com/ajg/journal/v106/n4/full/ajg201163a.html

 5. Shechter M, Shalmon G, Scheinowitz M, et al. Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease. Am J Cardiol 2011;107:1255–1261) http://www.ajconline.org/article/S0002-9149%2811%2900125-1