Risk of cardiovascular events associated with selective COX-2 inhibitors

treated with ACE inhibitors (median 0.44 ␮g/L, interquartile range [IQR] 0.19 –2.65 ␮g/L vs. median 4.18 ␮g/L; IQR 0.91–12.41 ␮g/L; p⫽0.01). Pretreatment with aspirin (57.3% of patients) did not significantly reduce the odds of troponin-I release, but was associated with 60% lower peak troponin I concentration compared with patients not pretreated with aspirin (median 2.33 ␮g/L; IQR 0.72– 8.02 vs. median 5.85 ␮g/L; IQR 1.19 –12.79; p⫽0.05). There was no association between ACE genotype and troponin-I release. Conclusion: In non-ST elevation ACS, ACE inhibition is associated with reduction in the troponin release, most likely mediated through the beneficial treatment effects on vascular reactivity and coagulation. Perspective: Since the level of troponin in non-ST elevation ACS has been shown to correlate with the risk of adverse events, the reduction in the positivity as well as the peak levels of troponin-I by ACE inhibitors suggests another potential mechanism of the beneficial effect of ACE inhibition in secondary prevention. RM

rates for COX-2 inhibitors in both these trials were significantly higher than that in the placebo group of a recent meta-analysis of 23,407 patients in primary prevention trials (0.52%): 0.74% with rofecoxib (p⫽0.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (p⫽0.02 compared with the placebo group of the meta-analysis). Conclusion: This study raises a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors that needs to be confirmed and the magnitude of risk elucidated in prospective trials. Perspective: Given the large number of patients in the US on COX-2 inhibitors, the findings of this study call for a large prospective randomized trial soon to evaluate the cardiovascular safety of these agents. Until then, such agents should be used cautiously in patients at risk for cardiovascular morbidity. RM

Peripheral Arterial Disease Detection, Awareness, and Treatment in Primary Care. The Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (Partners) Program Investigators

Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors Mukherjee D, Nissen SE, Topol EJ. JAMA 2001;286:954 –9.

Hirsh AT, Criqui MH, Treat-Jacobson D, et al. JAMA 2001;286: 1317–24.

Study Question: Do selective cyclooxygenase 2 (COX-2) inhibitors have any detrimental cardiovascular effects when used for arthritis and musculoskeletal pain in patients without coronary artery disease? Methods: A MEDLINE search was performed to identify all English-language articles on use of COX-2 inhibitors published between 1998 and February 2001. Additionally, relevant submissions to the US Food and Drug Administration by pharmaceutical companies were also reviewed. Results: Two major randomized trials, the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; n⫽8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; n⫽8059 patients), as well as two smaller trials with approximately 1000 patients each were identified as a result of this search. The VIGOR trial was a double-blind, randomized, stratified, parallel group trial comparing the occurrence of gastrointestinal toxicity with rofecoxib or naproxen during long-term treatment for patients with rheumatoid arthritis. The Class trial similarly evaluated the gastrointestinal toxicity of celecoxib compared to ibuprofen or diclofenac. VIGOR showed that the risk of developing a thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke and transient ischemic attacks) was increased with rofecoxib treatment compared with naproxen (Relative risk 2.38, 95% confidence interval 1.39 – 4.00; p⫽0.002). Cardiovascular events (myocardial infarction, stroke and death) were similar for celecoxib and nonsteroidal anti-inflammatory agents in CLASS. The annualized myocardial infarction

Study Questions: 1) What is the feasibility of detecting peripheral arterial disease (PAD) in primary care clinics? 2) What is the awareness of PAD by physicians in a primary care practice setting? 3) What are the intensity of risk-factor treatment and the use of antiplatelet therapies for patients with PAD? Methods: Patients 70 years and older or 50 through 69 years with a history of cigarette smoking or diabetes (n⫽6979 across 27 sites in 25 cities and 350 primary care practices throughout US) were evaluated for PAD by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was ⱕ0.90, if it was documented in the medical record or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral or abdominal aortic aneurysmal disease. Results: PAD was detected in 1865 patients (29%); 13% had PAD only, 16% had PAD and CVD, 24% had CVD only and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Classic symptoms of PAD, i.e., claudication, was present in only 11% of patients with PAD, while atherosclerosis risk factor profiles was similar in patients with PAD and CVD. Smoking behavior was more frequently treated in patients with PAD compared to those with CVD, whereas treatment of diabetes and

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