Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis.

BACKGROUND: Pain management in patients with osteoarthritis or rheumatoid arthritis often requires long-term use of nonsteroidal antiinflammatory drugs (NSAIDs). However, the relative cardiovascular safety of these therapies remains uncertain. METHODS: The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial will evaluate the cardiovascular safety of celecoxib, ibuprofen, and naproxen. Approximately 20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for, or with, established cardiovascular disease will be randomized in this double-blind, triple dummy, multinational, multicenter study. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial will continue until 762 primary events occur with at least 18 months follow-up. Noninferiority of any of the regimens will require a 97.5% upper CI of the hazard ratio (HR) < or =1.33 and point estimate < or =1.12 for both intent-to-treat (ITT) and modified ITT populations. CONCLUSION: PRECISION, the first study of patients with high cardiovascular risk chronically treated with a cyclooxygenase-2 selective inhibitor or nonselective NSAID, will define the relative cardiovascular safety profile of celecoxib, ibuprofen, and naproxen and provide data to help guide NSAID use for pain management for this population.

Low levels of low-density lipoprotein cholesterol and blood pressure and progression of coronary atherosclerosis.

OBJECTIVES: We investigated coronary atheroma progression in patients with low levels of low-density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP). BACKGROUND: Low LDL-C and SBP beneficially impact coronary atherosclerosis. However, the association between intensive control of both risk factors and coronary plaque progression remains unclear. METHODS: Changes in atheroma burden monitored by intravascular ultrasound were studied in 3,437 patients with coronary artery disease (CAD) who were stratified according to on-treatment LDL-C and SBP. RESULTS: Patients with very low LDL-C (< or =70 mg/dl) and normal SBP (< or =120 mm Hg) had less progression in percent atheroma volume (PAV) (p < 0.001) and total atheroma volume (TAV) (p < 0.001), more frequent plaque regression (p = 0.01), and less frequent plaque progression (p < 0.001). In patients with SBP >120 mm Hg, very low LDL-C was associated with less progression of PAV (+0.30%, 95% confidence interval [CI]: -0.17% to 0.77% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.01) and TAV (-3.9 mm3, 95% CI: -7.24 to -0.63 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.001). In patients with LDL-C >70 mg/dl, normal SBP was not associated with less progression of PAV (+0.51%, 95% CI: 0.04% to 0.99% vs. +0.61%, 95% CI: 0.17% to 1.05%, p = 0.159) or TAV (-2.3 mm3, 95% CI: -5.59 to 1.05 mm3 vs. -1.2 mm3, 95% CI: -4.31 to 1.92 mm3, p = 0.617). CONCLUSIONS: Very low LDL-C and normal SBP are associated with the slowest progression of coronary atherosclerosis. Although a greater beneficial association is observed in patients with very low LDL-C, these findings suggest the need for intensive control of global risk in patients with CAD.

An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial.

AIMS: To examine the unanticipated, excess mortality observed in patients randomized to clopidogrel and aspirin vs. aspirin alone in the prespecified 'asymptomatic' subgroup of CHARISMA, we investigated whether dual-antiplatelet therapy may be associated with adverse cardiovascular (CV) events in a primary prevention population. METHODS AND RESULTS: Of 15 603 patients enrolled, 3284 were initially categorized as asymptomatic with CV risk factors, but 995 had a prior CV event, leaving 2289 patients to represent the primary prevention cohort. This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding. A multivariate analysis analysed predictors of CV death in this group. No post mortem data were available. Compared with aspirin alone, a significant increase in CV death (P = 0.01) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population. Within the primary prevention cohort, this excess CV death was not significant (P = 0.07). Multivariate analysis of the primary prevention group showed a trend towards excess CV death (P = 0.054; HR 1.72; CI 0.99-2.97) with dual-antiplatelet therapy (aspirin plus clopidogrel). Other independent predictors of CV death included increasing age, hypertension, atrial fibrillation, and a history of heart failure. There was a non-significant increase in moderate or severe bleeding (P = 0.218) with dual-antiplatelet therapy; thus, bleeding was an unlikely explanation for the excess event rate. CONCLUSION: These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population. In this subgroup analysis, CV death occurred more frequently than anticipated. The cause of this apparent harm is not elucidated, may represent play of chance, but requires further prospective evaluation.

Aspirin and clopidogrel resistance: an emerging clinical entity.

Antiplatelet therapy is a cornerstone of cardiovascular medicine. Aspirin and clopidogrel have emerged as critical therapies in the treatment of cardiovascular disease. Despite their efficacy, patients on these medications continue to suffer complications. Millions of patients are currently on low-dose antiplatelet therapy but it is unknown how many of these patients are under-treated or on the wrong medication. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as recurrent myocardial infarction, stroke, or death. The mechanism of resistance remains incompletely defined, but there are specific clinical, cellular, and genetic factors that influence therapeutic failure. These factors range from physicians who fail to prescribe these medications despite appropriate indications to polymorphisms of platelet membrane glycoproteins. Rapid and accurate diagnosis of antiplatelet resistance also remains an issue as new bedside tests are developed. By understanding the mechanism of therapeutic failure and by improving the diagnosis of this clinical entity, a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people.

Extensive fibromuscular dysplasia in a patient with Parkinson disease.

The cause of fibromuscular dysplasia is not known. Ergot derivatives have been reported as a potential causative agent. The anti-Parkinson medication pergolide is an ergot derivative, but an association between fibromuscular dysplasia and this drug has not been previously reported.