By David Veal, MD
Faculty Peer Reviewed
Recent international intrigue–replete with secret identities and coded messages–reached a dénouement when ten Russian agents were exchanged for four Americans in Vienna and an Iranian scientist residing in the US repatriated. Despite our popular culture’s fascination with clandestine politics, these events unfolded without the panache that comes with ordering a martini shaken, not stirred, or the quixotic mojo of a certain Austin “Danger” Powers. Instead, with much speculation about what lies ahead for those involved, it is clear that this business, however vital to government, is fraught with liability and risk.
Speaking of risk, the FDA’s decision to leave the diabetes drug Avandia on the market made headlines, despite considerable concerns of increased cardiovascular events and mortality. This week’s Primecuts will reexamine a familiar theme in medicine: that important drugs used to treat disease sometimes have significant side effects that can render them double-edged swords.
Earlier 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 failure, stroke and death (2). While the occurrence of these adverse effects were elucidated from a meta-analysis published in 2007, an FDA advisory panel voted last week, in a 20-12 decision, to allow the drug to remain on the market, albeit with new restrictions (3). The advisory panel’s recommendation now awaits a response by the full FDA. However, the recommendation seems entirely baffling when the majority of the panel also concluded that the drug increased risk of heart attack and stroke.
In an interview with U.S. News, Arther Moss, a panelist who voted to keep Avandia on the market, expressed concern over the poor quality of studies being examined and the lack of randomized controlled studies, and pushed the industry to conduct future studies (4). One such study is the ongoing Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) trial, a randomized study comparing the adverse affects of Avandia, Actos and placebo. Unfortunately, the trial will not be complete until 2015 and some critics have already called the trial unethical given the current evidence regarding cardiovascular safety (5). The panel’s reluctance to pull the drug may also stem from the notion that in certain populations, the drug can be very effective and should, perhaps, be kept around as a second-line drug (6). Ultimately, the process of evaluating a medication, as well as the validity of such studies, is a difficult process, and any given drug may have a different benefit-to-risk profile depending on the patient population.
In other diabetes-related news, results of the Accord Eye Study Group published in NEJM concluded that intensive glycemic and lipid control in patients with type 2 diabetes who were at high risk for cardiovascular disease reduced the rate of progression of diabetic retinopathy (7). In the study patients were randomized to either standard or intensive treatment groups for glycemia (HgA1c <6.0% or 7.0-7.9%), dyslipidemia (statin or statin plus fenofibrate) and systolic blood pressure (<120 or <140 mm Hg). Reevaluated after four years, the primary outcome was either progression of diabetic retinopathy by at least three steps on the ETDRS Severity Scale or development of proliferative diabetic retinopathy requiring photocoagulation or vitrectomy. Differences in the rate of progression of retinopathy for standard and intensive treatments for glycemia (10.4% vs 7.3%) and dyslipidema (10.2% and 6.8%) were statistically significant while that for blood pressure was not. While the results of the study may come as no big surprise, they provide more evidence regarding the benefit of intensive glycemic control to slow diabetic retinopathy. Furthermore, this study included type 2 diabetics who were at high risk for cardiovascular disease, while previous studies focused on type 1 and relatively healthy type 2 diabetics.
Also published in NEJM, Jones et al. concluded in a randomized, controlled study that there were no significant differences in sustained-remission rates or severe side effects when comparing rituximab with cyclophosphamide as induction therapy in ANCA-associated renal vasculitis (8). ANCA-associated vasculitis, very frequently having renal involvement, is treated with high-dose glucocorticoids and cyclophosphamide. Although effective, cyclophosphamide is associated with leukopenia, severe infections, malignancy and ovarian failure (9). In this study, patients with newly diagnosed ANCA-associated vasculitis and renal involvement (either a positive renal biopsy, hematuria, or red blood cell casts) were randomized to a standard glucocorticoid regimen plus rituximab and cyclophosphamide, or a cyclophosphamide regimen followed by azathioprine. Primary endpoints were sustained-remission rates (Birmingham Vasculitis Activity Score of zero for 6 months) at 12 months, and the rate of severe side effects. There were no significant differences between the two groups. The authors suggested that rituximab’s effectiveness lends support for a B-cell role in the pathophysiology of ANCA-associated vasculitis, and that future studies could determine if the use of rituximab could avoid significant exposure to cyclophosphamide and the need for maintenance immunosuppression. With the administration of toxic medications that can frequently lead to fatal infections, the goal remains to seek safer and effective treatment regimens.
Finally, in the Lancet, Chan et al. concluded that selective COX-2 inhibitors in patients with arthritis yielded lower significant clinical outcomes than a nonspecific COX inhibitor with omeprazole (10). While both treatment regimens are recommended for rheumatoid and osteoarthritis, the authors point out that these strategies are concerned exclusively with upper GI side effects of NSAIDs. Therefore, selective COX-2 inhibitors may have two advantage: first, in their avoidance of gastric mucosal COX-1 enzyme, and second, in their global effect across the entire GI tract. In a double blind study, 4484 patients were randomized to either 200mg celecoxib twice daily or 75mg diclofenac slow release twice daily with 20 mg omeprazole daily. All patients were H. pylori negative and were either over 18 years old with a history of gastroduodenal ulcers or hemorrhage or over 60 years old with or without a significant GI history . Patients on aspirin or anticoagulants were excluded. At six months, a composite endpoint of clinically significant GI symptoms was evaluated, which included bowel ulceration, bowel hemorrhage, and significant anemia. Rate of reaching primary endpoint for the celecoxib and diclofenac plus omeprazole groups (0.9% vs. 3.8%) was statistically significant. Thus, while the study does not apply to patients with cardiovascular risk factors, the authors suggest reexamining the guidelines for arthritis treatment in selected patients, which would ultimately reduce morbidity associated with long-term anti-inflammatory medications.
Dr. Veal is a first year resident at NYU Langone Medical Center
Peer reviewed by Ishmeal Bradley, MD, a 3rd year resident in internal medicine at NYU Medical Center.
References:
1. Hormozdi, David. Primecuts, July 6, 2010. https://www.clinicalcorrelations.org/?p=2821
2. 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
3. Avandia on Trial. http://online.wsj.com/article/SB10001424052748704682604575369232879016248.html?mod=googlenews_wsj
4. Kotz, Deborah. What Now for the Diabetes Drug Avandia? US News and Word Report, Online Edition. July 15, 2010. http://health.usnews.com/health-news/managing-your-healthcare/diabetes/articles/2010/07/15/what-now-for-the-diabetes-drug-avandia.html
5. Mike Mitka. Critics Press FDA to Act on Evidence of Rosiglitazone’s cardiac safety issues. JAMA. 2010;303(23):2341-2342 (doi:10.1001/jama.2010.788). http://jama.ama-assn.org/cgi/content/full/303/23/2341
6. Zajac, Andrew and Thomas H. Maugh II. FDA: Avandia Should Stay With Restrictions. The Los Angeles Times. July 15, 2010. http://www.latimes.com/news/health/sns-health-fda-avandia-restrictions,0,2350629.story
7. The ACCORD Study Group and ACCORD Eye Study Group. Effects of Medical Therapies on Retinopathy Progression in Type 2 Diabetes. N Engl J Med 2010;363:233-44. http://content.nejm.org/cgi/content/short/363/3/233
8. Jones et al. Rituximab versus Cyclophosphamide in ANCA-associated Renal Vasculitis. N Engl J Med 2010;363:211-20. http://content.nejm.org/cgi/content/short/363/3/211
9. Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 2008;67:1004-10. http://ard.bmj.com.ezproxy.med.nyu.edu/content/67/7/1004.full.pdf
10. Francis K L Chan, Angel Lanas, James Scheiman, Manuela F Berger, Ha Nguyen, Jay L Goldstein. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet 2010; 376: 173–9.
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