High-Dose Rofecoxib Confirmed Prothrombotic, Study Shows
Pharmacology Watch

Debate over the cardiovascular effects of COX-2 inhibitors has raged for more than a year since a special communication was published in JAMA last August (JAMA. 2001;286: 954-959) suggesting an increase in cardiovascular events with rofecoxib (Vioxx). As the argument goes, unlike nonselective NSAIDs, COX-2 inhibitors have no effect on thromboxane thus they do not inhibit platelet aggregation. However they do inhibit vascular prostacyclin—an effect that may be prothrombotic. Nonselective NSAIDs inhibit both thromboxane and prostacyclin. Whether COX-2 inhibitors are prothrombotic or merely lack the antiplatelet action of nonselective NSAIDs is at the crux of the debate. Now a large retrospect, the cohort study from the Tennessee Medicaid program seems to confirm the prothrombotic effects of rofecoxib, at least in high dose. Researchers from Vanderbilt University reviewed the records of 202,916 patients who did not use anti-inflammatories, 151,728 patients who used "other" anti-inflammatories, and 24,132 patients on rofecoxib over the 18 months between January 1999 and June 2001. Participants were between 50 and 84 years of age and had no life-threatening noncardiovascular illnesses. Users of high-dose rofecoxib (50 mg/d) were 1.7 times more likely than nonusers to have serious CHD (95% CI, 0.98-2.95; P = 0.058). Among new users of high dose rofecoxib, the rate increased to 1.93 (1.09-3.42, P = 0.058). There was, however, no increase risk of CHD with lower doses of rofecoxib or with use of other NSAIDs (Lancet. 2002;360:1071-1073). This study supports the hypothesis that high-dose COX-2 inhibition may be prothrombotic. This evidence is supported by a study in genetically engineered mice. Mice that lack the prostacyclin receptor (a defect that is similar to the effects of COX-2 inhibitors) overproduce thromboxane A2—and are likely to form arterial clots (Science. 2002;296:539-541). A recent "Clinical Implications of Basic Research" elegantly depicts the eicosanoid balance and the effects of these drugs on clotting (N Engl J Med. 2002;347:1025-1026).

Losartan Better Than Atenolol for LVH Treatment

Losartan is a better option than atenolol for treating isolated systolic hypertension in patients with left ventricular hypertrophy according to a new study. More than 1300 men and women with systolic hypertension and ECG evidence of LVH were randomized to treatment with losartan or atenolol with hydrochlorothiazide added as a second agent as needed. The main outcome measure was a composite end point of cardiovascular death, stroke, or myocardial infarction. After a mean of 4.7 years of follow-up, the main outcome was reduced by 25% with losartan compared with atenolol. There were 25.1 events per 1000 patients years in the losartan group vs. 35.4 in the atenolol group (relative risk [RR] 0.75; 95% confidence interval, 0.56-1.01; P = 0.6). There was no difference in the rate of myocardial infarction; however, cardiovascular mortality was significantly decreased in the losartan group as was nonfatal and fatal stroke. Total mortality was also significantly lower than the losartan group (21.2 vs 30.2 events per thousand patient-years; RR, 0.72; 95% CI, 0.53-1.00; P = .046). New onset diabetes was also significantly reduced in the losartan group, a finding that has been seen in other studies of ARBs. Losartan was also better tolerated than atenolol (JAMA. 2002;288:1491-1498).

Lisinopril, Not Losartan, Improves Myocardial Perfusion

In a related study of patients with hypertension and LVH, long-term treatment with lisinopril but not losartan improved myocardial perfusion in maximal coronary blood flow. In this small study, 17 patients with hypertension and LVH (9 treated with lisinopril, 8 treated with losartan) were evaluated with positron emission tomography at baseline and after coronary vasodilation with dipyridamole. The same studies were done on 8 normotensive control patients. After treating with lisinopril, maximal coronary blood flow and myocardial perfusion reserve increased significantly compared with pretreatment values (P = 0.02, and P = 0.002 respectively). Post- treatment hyperemic flow in patients treated with lisinopril was not significantly different from corresponding measurements and control patients. No difference in either measure was noted with losartan. The authors postulate that angiotensin converting enzyme inhibitors potentiate endogenous bradykinins, which in turn improve myocardial perfusion reserve. Losartan, like other angiotensin receptor blockers, has no effect on bradykinins, which may explain the lack of improvement in this measure. The authors postulate that ACE inhibitors may be more effective in repairing the coronary microangiopathy associated with hypertension-induced LVH (J Am Coll Cardiol. 2002;40:703-709).

New Fluoroquinolone Study

It seems that every year there is a new study linking antibiotic use with a reduction in coronary disease. The most recent is a Dutch study of Type 2 diabetics. Using a national hospitalization database from 8 cities, researchers found a significantly reduced risk of CHD in patients who had used at least 14 days of a fluoroquinolone in the 3-year study period (odds ratio = .30; 95% CI, 0.12-0.75). No other antibiotic was associated with a reduction in CHD including tetracyclines, macrolides, cephalosporins, or penicillin derivatives (Eur Heart J. 2002;23:1575-1579). And while the explanation for such improvement is still elusive, ongoing research is looking into the CHD/inflammation/infection connection.

Warfarin After MI Better Than Aspirin Alone

Warfarin, with or without aspirin, is better than aspirin alone in preventing vascular events after myocardial infarction according to a new study. In a randomized, multicenter trial, 1216 patients received warfarin (target INR 2.8 to 4.2), 1206 received aspirin 160 mg per day, and 1208 received aspirin 75 mg per day combined with warfarin (target INR 2.0 to 2.6). The mean duration of the study was 4 years and the primary outcome was a composite of death, nonfatal reinfarction, or thromboembolic cerebral stroke. The results showed a recurrence rate of 20% in the aspirin group (241 of 1206), 16.7% in the warfarin group (203 of 1216), and 15% in the combined warfarin in aspirin group (181 of 1208). The difference between the warfarin and warfarin/aspirin group was not statistically significant. There was a statistically significant increase in major, nonfatal bleeding in both warfarin groups compared to the aspirin group (0.62% vs 0.17%, respectively [P < 0.001]). The authors conclude that warfarin given alone or in combination with aspirin is superior to aspirin alone in reducing the incidence of composite vascular end points after myocardial infarction; however warfarin therapy is associated with a higher risk of bleeding. No difference in mortality was noted between the 2 groups (N Engl J Med. 2002; 347:969-974).

FDA News

Valacyclovir (Valtrex-GlaxoSmithKline) has been approved for the treatment of cold sores (herpes labialis). The approval was based on to studies that showed that valacyclovir 2 g twice a day for 1 day shortens the duration of cold sore outbreaks by about 1 day.

The FDA is one step closer two approving tiotropium (Spiriva-Boehringer Ingelheim), a new long-acting anticholinergic agent for the treatment of COPD. The drug was reviewed by the FDA’s Pulmonary Allergy Drugs Advisory Committee and endorsed for the treatment of bronchospasm, however there was no support for the proposed indication of dyspnea.

The agency has strengthened its warnings on mefloquine (Larium-Roche) because of concerns of CNS side effects. Mefloquine is used in the treatment and prevention of malaria. The FDA specifically stated that mefloquine is contraindicated in patients with psychiatric disorders including active depression, recent history depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders, or with a history of convulsions. The FDA also warns that patients taking the drug for prophylaxis should discontinue it immediately if psychiatric symptoms should develop. Roche has recently issued a "Dear Dr. letter" regarding these warnings.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5517. E-mail: robin.mason@ahcpub.com. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.