Primecuts – This Week in the Journals

July 6, 2010

By David Hormozdi, MD

Faculty Peer Reviewed

Ah July! A time filled with backyard barbeques, family vacations, and fireworks.  But for new attendings, fellows, and housestaff across the country, July 1 marks the start of added responsibility, trepidation, and autonomy.  With the added responsibility comes the age-old phrase – do no harm – and in this weeks Primecuts we explore controversial medications that may be doing little good for our patients.  This week we will take another look at statin therapy for primary prevention of cardiovascular events, the controversial oral diabetes medication rosiglitazone, and review the role of vitamin supplementation in lowering the risk of vascular events.    

 The debate regarding statin therapy for primary prevention in healthy individuals rages on as the results of the controversial JUPITER trial are again making headlines. Published in November 2008, the JUPITER trial showed significant reductions in nonfatal MI, risk of nonfatal stroke, and composite endpoint (nonfatal MI, stroke, hospitalization for unstable angina, revascularization, and death from cardiovascular cause) in healthy people with elevated C-reactive protein (CRP) taking rosuvastatin compared to  placebo (1). This week the Archives of Internal Medicine published 4 articles critical of the JUPITER trial results, questioning not only the conflict-of-interest issue (the majority of authors had financial ties to sponsor and the principle investigator has a monetary stake in the CRP test) and premature study termination, but methodological and clinical inconsistencies present in the report.

 In a critical appraisal by Lorgeril, et al. the authors note the study was prematurely terminated after two years due to “unequivocal reduction in cardiovascular mortality.” Interestingly, the original articles fail to clearly report cardiovascular mortality data, and when extrapolated from the published report, death attributed to cardiovascular cause was identical or not significantly different between the two groups (2-3).  Moreover, the authors argue the lack of effect on cardiovascular death but significant reduction in cardiovascular events and low mortality rate in the placebo group implies the data may be subject to bias.  Specifically, the authors note the extremely low ratio of fatal to nonfatal myocardial infarction (9/22 for rosuvastatin, 6/62 for placebo) and myocardial infarction-related death rate (29% and 8.8%) contradict prior epidemiological reports that approximately half of people die within 3-4 weeks of myocardial infarction. The authors conclude that that in light of these inconsistencies the results of the JUPITER trial are flawed and should not change practice guidelines.  The authors encourage lifestyle modification as a proven means of prevention of cardiovascular complications and mortality.

 Published in the same issue, a meta-analysis of 11 randomized trials of 65,000 patients failed to show a significant relative risk reduction of all-cause mortality with statins in patients with intermediate or high-risk of cardiovascular disease.  With enormous monetary and health implications at stake, the debate surrounding statin therapy for primary prevention will likely continue.  While the results of the JUPITER trial are hard to ignore, questions surrounding the methods and  inconsistencies in data will likely keep physicians from dramatically changing their prescribing habits until more definitive data  is published. 

 Beginning with  the publication of a meta-analysis in 2007,  much controversy has swirled around the Type 2 Diabetes medication rosiglitazone. This study showed a significantly higher risk of myocardial infarction and cardiovascular death in patients taking rosiglitazone compared to other diabetes treatments. (4).  While subsequent studies have offered mixed results, safety concerns have prompted a review by the FDA with a formal FDA hearing scheduled for next month. Published last week in JAMA, a new observational cohort study by Graham, et al. compares rosiglitazone and pioglitazone (Actos) and the risk of cardiovascular events and death (5). The cohort study reviewed 222,571 Medicare patients 65 or older being treated with either drug.  The data showed a 1.25-fold (95% CI, 1.16-1.34) increase in risk of heart failure, 1.27-fold (95% CI, 1.12-1.45) stroke, and a 1.14-fold (95% CI, 1.05-1.24) death in patient’s taking rosiglitazone compared with pioglitazone.  While observational studies have intrinsic limitations, this large study supports the notion that safer alternatives to Rosiglitazone exist for the  treatment of Type 2 Diabetes. 

 Finally,  in JAMA, the results of the SEARCH trial showed no benefit in vascular outcomes in patient’s taking folic acid and vitamin B12 supplementation to lower blood homocysteine levels (6).  Several observational studies have shown elevated homocysteine levels are an independent risk factor for occlusive vascular disease. Since folic acid and vitamin B12 supplementation is known to lower blood levels homocysteine by up to 35%, the authors postulated that daily supplementation with folic acid and B12 could have beneficial effect on vascular outcomes.  12,064 post myocardial infarction patients were randomly assigned to daily 2 mg folic acid plus 1 mg vitamin B12 or placebo and followed for 7 years.  While blood homocysteine levels were lowered by an average of 28% in the treatment group there was no significant difference between the treatment and placebo group in major coronary events (20.4% vs. 19.6%), stroke (4.5% v. 4.4%) or deaths attributed to vascular cause (9.6% vs. 9.3%).  Also, there was no significant increase in the incidence of cancer or adverse effects on cancer at any particular site in the supplementation group.  Previous studies with folic acid supplementation had suggested a possible role in tumor growth (7) and increased risk of prostate and lung cancer (8,9).  This study found no such link.  Unfortunately this study did not show any cardiovascular benefit to a relatively inexpensive therapy. 

 So as the summer heat swelters around us and we retreat to the cool confines of our overly air conditioned hospitals, we remind ourselves that every decision we make in the name of preventing a bad outcome must always be balanced with a thoughtful review of the potential risks and thus always strive to Do No Harm.  Stay cool…

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

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

 References:

1. Ridker PM, Danielson E, Fonseca FA, et al.  Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.  url: http://content.nejm.org/cgi/content/short/359/21/2195

 2. de Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy. A critical reappraisal. Arch Intern Med. 2010; 170:1032-1036.  url: http://archinte.ama-assn.org/cgi/content/short/170/12/1032

 3. Chan PS, Nallamothu BK, Hayward RA. Rosuvastatin in patients with elevated C-reactive protein [letter]. N Engl J Med. 2009;360(10):1039.   

4.  Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471  url: http://content.nejm.org/cgi/content/full/NEJMoa072761

 5. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Scholley C, Worrall C, Kelman JA. Risk of myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone [published online ahead of print June 28, 2010]. JAMA. doi:10.1001/jam  url: http://jama.ama-assn.org/cgi/content/full/jama.2010.920

 6.  Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effects of Homocysteine-Lowering With Folic Acid Plus Vitamin B12 vs Placebo on Mortality and Major Morbidity in Myocardial Infarction Survivors: A Randomized Trial. JAMA, 2010; 303 (24): 2486-2494.  url: http://jama.ama-assn.org/cgi/content/short/303/24/2486

 7. Cole BF, Baron JA, Sandler RS, et al. Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351-2359.  url: http://jama.ama-assn.org/cgi/content/full/297/21/2351

 8. Figueiredo JC, Grau MV, Haile RW, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009;101(6):432-435.  url: http://jnci.oxfordjournals.org/cgi/content/short/101/6/432

9. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009;302(19):2119-2126.  url: http://jama.ama-assn.org/cgi/content/short/302/19/2119

3 Responses to Primecuts – This Week in the Journals

  1. Literary Database. | Dump DB on July 6, 2010 at 9:31 am

    [...] Primecuts – This Week in the Journals | Clinical Correlations [...]

  2. [...] this month, Primecuts featured an observational study in JAMA comparing Avandia to Actos (1). The study concluded that Avandia was associated with a significantly higher rate of heart [...]

  3. [...] about cancer. Let’s talk about another top-ten cause of mortality: heart disease. In a July Primecuts, our own Dr. Hormozdi commented on the use of statins for primary prevention, citing the JUPITER [...]

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