Prognostic value of plasma von willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation

extension study with 6950 patient-years of exposure to celecoxib was 0.98/100 patient years. Conclusions: In a comparative analysis with placebo or NSAIDs, there is no evidence of increased risk of CV thrombotic events. Perspective: While still not conclusive, this is good news for the population with arthritis. The initial concern regarding an increased risk attributable to COX-2 inhibitors was based on a comparison with naproxen, which was apparently cardioprotective. The experimental evidence for an increased risk is relatively weak and should not preclude use in patients with or without CHD if salt/water retention can be tolerated. In fact, there is some emerging data of a possible role for COX-2 inhibitors in preventing plaque instability. MR

of cardiovascular events in those with elevated plasma levels of vWF. RM

Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease Topol EJ, Easton D, Harrington RA, et al., on Behalf of the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) Trial Investigators. Circulation 2003;108: 399 – 406. Study Question: What is the efficacy and safety of lotrafiban, an orally administered IIb/IIIa receptor antagonist in patients with vascular disease (cardiac, peripheral and cerebrovascular)? Methods: Based on their age and predicted creatinine clearance, patients with vascular disease were randomized to lotrafiban 30 –50 mg BID or placebo. Those aged ⱖ65 years and creatinine clearance of ⱕ60 mL/min were given 30 mg BID of the study drug. In addition, all patients received aspirin in dose ranging from 75–325 mg/day. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization and urgent revascularization. Results: Of the patients enrolled from 23 countries and 690 hospitals (n⫽9190), 41% had cerebrovascular disease at the time of entry and 59% had coronary artery disease. Mortality was higher in the lotrifiban group than in placebo treated patients (3.0% vs. 2.3%, hazard ratio 1.33, 95% CI 1.03–1.72, p⫽0.026). The cause of excess death was vascular related. The primary end point occurred in similar proportion of patients (16.4% vs. 17.5%, respectively; hazard ratio 0.94, 95% CI 0.85–1.03, p⫽0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; p⬍0.001) and in those receiving higher doses of aspirin (⬎162 mg) with or without lotrafiban. Conclusions: In patients with vascular disease, the use of Lotrafiban is associated with a 33% increase in death rate, which was vascular in origin. This risk was independent of the type of atherosclerotic involvement at entry to the trial. Additionally, this trial showed that the risk of bleeding is higher with doses higher than 162 mg/day. Perspective: The 33% excess mortality with lotrifiban in vascular patients is similar to the 37% increased risk of death seen in the previous four trials of oral IIb/IIIa inhibitors including Orbofiban, Xemilofiban and Sibrafiban. The subthreshold inhibition of the IIb/IIIa receptor may promote the shedding of CD40 platelet receptors, or these agents may potentiate P-selectin expression. Both of these mechanisms increase thrombosis and may explain some of the increased risk of vascular events seen with these agents. RM

Prognostic Value of Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 994 Patients With Nonvalvular Atrial Fibrillation Conway DSG, Pearce LA, Chin BSP, Hart RG, Lip GYH. Circulation 2003;107:3141–5. Study Question: Do markers of prothrombotic states such as elevated plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) predict future stroke or cardiovascular outcome in patients with nonvalvular atrial fibrillation (AF)? Methods: Participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial (n⫽994) had vWf and sP-sel levels measured by ELISA at study entry or after 3 months. The relationship of these indices to the subsequent incidence of stroke and vascular events was evaluated. Results: Plasma vWf levels were a significant predictor of both stroke (p⫽0.03) and vascular events (p⬍0.001), with the greatest risk for those with the highest levels of vWf. While the relationship between vWf and stroke became nonsignificant after adjustment baseline clinical variables, vWf remained an independent predictor of vascular events (relative risk, 1.2 [95% CI, 1.0 –1.4] per 20 IU/dL increase in vWf; p⫽0.02). In contrast, no significant relationships were found between sP-sel levels and outcome. Conclusion: In patients with AF receiving aspirin, raised levels of vWf (endothelial damage/dysfunction) were associated with increased risk of stroke and vascular events. In contrast, raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. These data suggest that endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF. Perspective: It remains to be seen if coumadin therapy (as opposed to aspirin) would help attenuate the increased risk

ACC CURRENT JOURNAL REVIEW Nov/Dec 2003

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