Shelly Sapp

Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials

INTRODUCTION Oxidised LDL is thought to play an important part in the pathogenesis of atherosclerosis. Observational studies have associated alpha tocopherol (vitamin E), beta carotene, or both, with reductions in cardiovascular events, but not clinical trials. We did a meta-analysis to assess the effect of these compounds on long-term cardiovascular mortality and morbidity. METHODS We analysed seven randomised trials of vitamin E treatment and, separately, eight of beta carotene treatment; all trials included 1000 or more patients. The dose range for vitamin E was 50-800 IU, and for beta carotene was 15-50 mg. Follow-up ranged from 1.4 to 12.0 years. FINDINGS The vitamin E trials involved a total of 81788 patients and the beta carotene trials 138113 in the all-cause mortality analyses. Vitamin E did not provide benefit in mortality compared with control treatment (11.3 vs 11.1%, odds ratio 1.02 [95% CI 0.98-1.06] p=0.42) or significantly decrease risk of cardiovascular death (6.0 vs 6.0%, p=0.86) or cerebrovascular accident (3.6 vs 3.5%, p=0.31). Beta carotene led to a small but significant increase in all-cause mortality (7.4 vs 7.0%, 1.07 [1.02-1.11] p=0.003) and with a slight increase in cardiovascular death (3.4 vs 3.1%, 1.1 [1.03-1.17] p=0.003). No significant heterogeneity was noted for any analysis. INTERPRETATION The lack of a salutary effect was seen consistently for various doses of vitamins in diverse populations. Our results, combined with the lack of mechanistic data for efficacy of vitamin E, do not support the routine use of vitamin E.

Profile and prevalence of aspirin resistance in patients with cardiovascular disease

We determined the prevalence and clinical predictors of aspirin resistance by prospectively studying 325 patients with stable cardiovascular disease who were receiving aspirin (325 mg/day for > or =7 days) but no other antiplatelet agents. We also compared the detection of aspirin resistance with optical platelet aggregation, a widely accepted method, with a newer, more rapid method, the platelet function analyzer (PFA)-100, a whole blood test that measures platelet adhesion and aggregation ex vivo. Blood samples were analyzed in a blinded fashion for aspirin resistance by optical aggregation using adenosine diphosphate (ADP) and arachidonic acid, and by PFA-100 using collagen and/or epinephrine and collagen and/or ADP cartridges to measure aperture closure time. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and a mean aggregation of > or =20% with 0.5 mg/ml arachidonic acid. Aspirin semiresponders were defined as meeting one, but not both of the above criteria. Aspirin resistance by PFA-100 was defined as having a normal collagen and/or epinephrine closure time (< or =193 seconds). By optical aggregation, 5.5% of the patients were aspirin resistant and 23.8% were aspirin semiresponders. By PFA-100, 9.5% of patients were aspirin resistant. Of the 18 patients who were aspirin resistant by aggregation, 4 were also aspirin resistant by PFA-100. Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women (34.4% vs 17.3%, p = 0.001) and less likely to be smokers (0% vs 8.3%, p = 0.004) compared with aspirin-sensitive patients. There was a trend toward increased age in patients with aspirin resistance or aspirin semiresponders (65.7 vs 61.3 years, p = 0.06). There were no differences in aspirin sensitivity by race, diabetes, platelet count, renal disease, or liver disease.

Significance of Mild Transient Release of Creatine Kinase–MB Fraction After Percutaneous Coronary Interventions

BACKGROUND The clinical significance of minor elevations in creatine kinase-myocardial band isoenzyme (CK-MB) after coronary interventions has not been systematically evaluated. METHODS AND RESULTS We examined 4484 patients who underwent successful percutaneous transluminal coronary angioplasty or directional coronary atherectomy and whose peak CK levels did not exceed twice the upper limit of laboratory normal. Group 1 (3776 patients) had no CK or MB elevation after the procedure (ie, CK < or = 180 IU/L, with MB fraction < or = 4%). Group 2 (450 patients) had a peak CK level between 100 and 180 IU/L, with MB fraction > 4%, and group 3 (258 patients) had a peak CK level between 181 and 360 IU/L, with MB fraction > 4%. The strongest correlate of postprocedure CK-MB elevation was the performance of directional coronary atherectomy (odds ratio, 4.1; P < .0001), followed by the development of > or = 1 in-1ab minor procedural complication (odds ratio, 2.6; P < .0001). Clinical follow-up was available in 4461 patients (99.5%), with a mean duration of 36 +/- 22 months. Survival analysis, adjusted with Cox proportional hazards regression model, showed that the groups with elevated CK-MB had a significantly higher incidence of cardiac death (risk ratio, 1.3; P = .04) and myocardial infarction (risk ratio, 1.3; P = .03). Major ischemic complications (death, myocardial infarction, and coronary revascularization) occurred more frequently in the groups with increased CK-MB (groups 1 versus 2 versus 3, 37.3% versus 43.3% versus 48.9%; P = .01). CONCLUSIONS This study shows that minor elevations of CK-MB after successful coronary interventions identify a population with a worse long-term prognosis compared with patients with no enzyme elevations and appear to have an adverse effect on long-term prognosis. Future studies of percutaneous coronary revascularization should include routine measurements of biochemical cardiac markers as important predictors of long-term prognosis.

Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors

BACKGROUND Inhibition of the platelet glycoprotein IIb/IIIa receptor with the monoclonal-antibody fragment abciximab reduces the acute ischemic complications associated with percutaneous coronary revascularization, whereas coronary-stent implantation reduces restenosis. We conducted a trial to determine the efficacy of abciximab and stent implantation in improving long-term outcome. METHODS A total of 2399 patients were randomly assigned to stent implantation and placebo, stent implantation and abciximab, or balloon angioplasty and abciximab. The patients were followed for six months. RESULTS At six months, the incidence of the composite end point of death or myocardial infarction was 11.4 percent in the group that received a stent and placebo, as compared with 5.6 percent in the group that received a stent and abciximab (hazard ratio, 0.47; 95 percent confidence interval, 0.33 to 0.68; P<0.001) and 7.8 percent in the group assigned to balloon angioplasty and abciximab (hazard ratio, 0.67; 95 percent confidence interval, 0.49 to 0.92; P=0.01). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.70 (95 percent confidence interval, 0.48 to 1.04; P=0.07). The rate of repeated revascularization of the target vessel was 10.6 percent in the stent-plus-placebo group, as compared with 8.7 percent in the stent-plus-abciximab group (hazard ratio, 0.82; 95 percent confidence interval, 0.59 to 1.13; P=0.22) and 15.4 percent in the angioplasty-plus-abciximab group (hazard ratio, 1.49; 95 percent confidence interval, 1.13 to 1.97; P=0.005). The hazard ratio for stenting plus abciximab as compared with angioplasty plus abciximab was 0.55 (95 percent confidence interval, 0.41 to 0.74; P<0.001). Among patients with diabetes, the combination of abciximab and stenting was associated with a lower rate of repeated target-vessel revascularization (8.1 percent) than was stenting and placebo (16.6 percent, P=0.02) or angioplasty and abciximab (18.4 percent, P=0.008). CONCLUSIONS For coronary revascularization, abciximab and stent implantation confer complementary long-term clinical benefits.

Prognosis of patients with left ventricular dysfunction, with and without viable myocardium after myocardial infarction. Relative efficacy of medical therapy and revascularization.

BackgroundThe uptake of F-18 deoxyglucose into dysfunction segments after myocardial infarction identifies metabolically active (FDG+) or inactive (FDG−) myocardium. Although patients with FDG+ segments have been found to be at risk for adverse events, the prognostic significance of viable myocardium in relation to other influences on postinfarction prognosis, including revascularization, remain ill defined. The purpose of this study was to investigate the relative prognostic significance of FDG+ tissue and to establish whether myocardial revascularization in patients with viable tissue attenuates the risk of adverse outcome. Methods and ResultsOne hundred thirty-seven patients with left ventricular dysfunction and resting perfusion defects after myocardial infarction underwent positron emission tomography with both dipyridamole stress Rb-82 perfusion imaging and FDG imaging. After the exclusion of 4 patients proceeding to transplantation, 2 with uninterpretable scans and 2 lost to follow-up, 129 patients were followed clinically for 17 ± 9 months. Four groups were defined: patients with FDG+ dysfunctional myocardium who were revascularized (n = 49) or treated medically (n = 21) and those with FDG− segments who were revascularized (n = 19) or treated medically (n = 40). The groups of patients with FDG+ or FDG− findings, with and without revascularization, did not differ with respect to known determinants of postinfarction prognosis: age, left ventricular ejection fraction, or the prevalence of multivessel disease. Nonfatal ischemic events occurred in 48% of medically treated FDG+ patients compared with 8% of revascularized patients with FDG+ tissue (P < .001) and 5% of patients with FDG- myocardium (P < .001). Thirteen patients died from cardiac causes; 11 (85%) had a left ventricular ejection fraction of < 30%, and these patients were evenly distributed between FDG+ and FDG− groups. Using Coxs proportional hazards model, only the presence of FDG+ myocardium (odds ratio, 12.9; P < .001) and the absence of revascularization (odds ratio, 5.8; P = .002) independently predicted ischemic events, while only age (P = .02) and ejection fraction (P < .001) but not the presence of viable myocardium were predictive of death. ConclusionsResidual viable myocardium after myocardial infarction may act as an unstable substrate for further events unless it is revascularized. Despite this association, age and left ventricular dysfunction remained the strongest predictors of cardiac death after myocardial infarction in these patients with a spectrum of left ventricular dysfunction.

Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Increased Mortality With Oral Platelet Glycoprotein IIb/IIIa Antagonists A Meta-Analysis of Phase III Multicenter Randomized Trials

BackgroundNumerous clinical trials have established the benefits of intravenous glycoprotein IIb/IIIa inhibition in the management of coronary artery disease. In contrast, the recent large-scale, placebo-controlled, randomized trials of the oral glycoprotein IIb/IIIa antagonists have failed to provide commensurate reductions in late composite ischemic end points despite potent inhibition of platelet aggregation. Methods and ResultsThe ORs for death, myocardial infarction, urgent revascularization, and major bleeding from the 4 large-scale, placebo-controlled, randomized trials with oral glycoprotein IIb/IIIa inhibitors were calculated and combined. Stratification by low-dose or high-dose therapy and the use of concurrent aspirin was also undertaken. In 33 326 patients followed for >30 days, a consistent and statistically significant increase in mortality was observed with oral glycoprotein IIb/IIIa therapy (OR, 1.37; 95% CI, 1.13 to 1.66;P =0.001). This effect was evident regardless of aspirin coadministration and treatment with either low-dose or high-dose therapy. Although a reduction in urgent revascularization was observed with oral glycoprotein IIb/IIIa inhibition, pooled analysis favored an increase in myocardial infarction that did not demonstrate statistical significance. ConclusionsAlthough we found a highly significant excess in mortality consistent across 4 trials with 3 different oral glycoprotein IIb/IIIa inhibitor agents, this was associated with a reduction in the need for urgent revascularization and no increase in myocardial infarction. These findings suggest the potential for a direct toxic effect with these agents and argue against a prothrombotic mechanism. Further investigation to elucidate the cause of this increased fatality risk is warranted.

Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial

BACKGROUND We assessed in a randomised trial the long-term outcomes for potent adjunctive antiplatelet therapy given at the time of coronary stenting. METHODS In 63 hospitals in the USA and Canada, 2399 patients were randomly assigned stenting with abciximab, stenting with placebo, or balloon angioplasty with abciximab. Standard adjunctive therapy with aspirin, ticlopidine, and heparin was used. The major outcomes of death and myocardial infarction were assessed at 1-year follow-up by intention to treat. We also investigated the 1-year cost-effectiveness of combined stenting and abciximab therapy. FINDINGS At 1-year follow-up, eight (1.0%) of 794 patients in the stent plus abciximab group had died, compared with 19 (2.4%) of 809 in the stent plus placebo group (hazard ratio 0.43 [95% CI 0.19-0.97], p=0.037). The combined endpoint of death or large myocardial infarction occurred in 42 (5.3%) and 89 (11.0%), respectively (0.46 [0.32-0.67], p<0.001). By multivariate modelling, the factors independently associated with improved survival were assignment to stenting with abciximab (p=0.027) and greater preprocedural stenosis (p=0.002); those associated with worse survival were age greater than 70 years (p<0.001), previous heart failure (p=0.001), diabetes treated with insulin (p=0.02), and postprocedural occlusion (p<0.001). Relative to stenting plus placebo and balloon angioplasty plus abciximab, the incremental 1-year costs of stenting plus abciximab were US

Regional variation across the United States in the management of acute myocardial infarction. GUSTO-1 Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.

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Optimizing the Percutaneous Interventional Outcomes for Patients With Diabetes Mellitus Results of the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial) Diabetic Substudy

932. The corresponding cost-effectiveness ratios were US