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Investigates the characteristics of published trials to establish the origin of the differing results obtained in trials of platelet inhibitors after peripheral arterial bypass procedures. Treatment benefit of platelet inhibitors on metal-analysis of the trials; Attribution of the improvement of graft patency by aspirin and related platelet inhibitors to an effect on patients with prosthetic grafts.

Objective: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure.Research Design and Methods: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression.Results: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025).Conclusions: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS -- PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS -- More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS -- Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure. [ABSTRACT FROM AUTHOR]

Objectives: This analysis from the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study assesses the effects of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes and a previous myocardial infarction (MI). Background: People with type 2 diabetes have an increased incidence of MI compared with the general population. Those with diabetes and MI have a worse prognosis than nondiabetic patients with cardiovascular disease. Methods: The PROactive study was a prospective, multicenter, double-blind, placebo-controlled trial of 5,238 patients with type 2 diabetes and macrovascular disease. Patients were randomized to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Treatment of diabetes, dyslipidemia, and hypertension was encouraged according to the International Diabetes Federation guidelines. Patients were followed for a mean of 2.85 years. The primary end point was the time to first occurrence of macrovascular events or death. Of the total cohort, the subgroup of patients who had a previous MI (n = 2,445 [46.7%]; n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group) was evaluated using prespecified and post-hoc analyses. Results: Pioglitazone had a statistically significant beneficial effect on the prespecified end point of fatal and nonfatal MI (28% risk reduction [RR]; p = 0.045) and acute coronary syndrome (ACS) (37% RR; p = 0.035). There was a 19% RR in the cardiac composite end point of nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death (p = 0.033). The difference in the primary end point defined in the main PROactive study did not reach significance in the MI population (12% RR; p = 0.135). The rates of heart failure requiring hospitalization were 7.5% (92 of 1,230) with pioglitazone and 5.2% (63 of 1,215) with placebo. Fatal heart failure rates were similar (1.4% [17 of the 92] with pioglitazone versus 0.9% [11 of the 63] with placebo). Conclusions: In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of fatal and nonfatal MI and ACS. (PROspective pioglitAzone Clinical Trial In macroVascular Events; http://www.clinicaltrials.gov/ct/show/NCT00174993?order = 1; ISRCTN NCT00174993). [Copyright &y& Elsevier]

Objectives: This study sought to evaluate what set of factors correlate with higher or lower C-reactive protein (CRP) levels in patients receiving standard and intensive statin therapy. Background: C-reactive protein levels in blood are becoming recognized as a potential means of monitoring cardiovascular risk. Although statin therapy is known to reduce CRP levels, many patients have a high CRP level despite statin therapy. Methods: This study was a cross-sectional study of 2,885 patients from the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, which assessed the relationship between uncontrolled cardiovascular risk factors and CRP level at four months after enrollment. Results: In a multivariate model, several risk factors were weakly but independently associated with higher CRP levels: age, gender (with or without hormone replacement therapy), body mass index >25 kg/m2, smoking, low-density lipoprotein ≥70 mg/dl, glucose >110 mg/dl, high-density lipoprotein <50 mg/dl, triglycerides >150 mg/dl, and the intensity of statin therapy. A direct relationship between the number of uncontrolled risk factors present and CRP levels (p < 0.0001) was observed for both statin regimens. Despite the presence of each uncontrolled risk factor, prior randomization to intensive statin therapy was associated with a lower CRP level (p < 0.0001). Across all strata, defined by the number of uncontrolled risk factors present, CRP levels were lower among those receiving intensive statin therapy. Conclusions: The use of intensive statin therapy lead to a lower CRP level independent of the presence of single or multiple cardiovascular risk factors. Even among patients receiving intensive statin therapy, a lower CRP level was observed in patients with the fewest coronary risk factors present, suggesting that control of multiple risk factors may be a means to further achieve lower CRP levels. [Copyright &y& Elsevier]

Summary Background Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor γ (PPAR γ) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. Methods We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. Findings Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34·5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0·90, 95% CI 0·80-1·02, p=0·095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0·84, 0·72-0·98, p=0·027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. Interpretation Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events. [ABSTRACT FROM AUTHOR]

Background: Chlamydia pneumoniae has been found within atherosclerotic plaques, and elevated titers of antibody to this organism have been linked to a higher risk of coronary events. Pilot studies have suggested that antibiotic treatment may reduce the risk of cardiovascular events. Methods: We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and evaluated the efficacy of long-term treatment with gatifloxacin, a bactericidal antibiotic known to be effective against C. pneumoniae, in a double-blind, randomized, placebo-controlled trial. Subjects received 400 mg of gatifloxacin daily during an initial 2-week course of therapy that began 2 weeks after randomization, followed by a 10-day course every month for the duration of the trial (mean duration, 2 years), or placebo. The primary end point was a composite of death from all causes, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. Results: A Kaplan–Meier analysis revealed that the rates of primary-end-point events at two years were 23.7 percent in the gatifloxacin group and 25.1 percent in the placebo group (hazard ratio, 0.95; 95 percent confidence interval, 0.84 to 1.08; P=0.41). No benefit was seen in any of the prespecified secondary end points or in any of the prespecified subgroups, including patients with elevated titers to C. pneumoniae or C-reactive protein. Conclusions: Despite long-term treatment with a bactericidal antibiotic effective against C. pneumoniae, no reduction in the rate of cardiovascular events was observed. N Engl J Med 2005;352:1646-54. [ABSTRACT FROM AUTHOR]

Background: A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. Methods: We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were scheduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an occluded infarct-related artery (defined by a Thrombolysis in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. Results: The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. Conclusions: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications. N Engl J Med 2005;352:1179-89. [ABSTRACT FROM AUTHOR]

Background: Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the optimal level of low-density lipoprotein (LDL) cholesterol is unclear. Methods: We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy) with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a composite of death from any cause, myocardial infarction, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke. The study was designed to establish the noninferiority of pravastatin as compared with atorvastatin with respect to the time to an end-point event. Follow-up lasted 18 to 36 months (mean, 24). Results: The median LDL cholesterol level achieved during treatment was 95 mg per deciliter (2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter (1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier estimates of the rates of the primary end point at two years were 26.3 percent in the pravastatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduction in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval, 5 to 26 percent). The study did not meet the prespecified criterion for equivalence but did identify the superiority of the more intensive regimen. Conclusions: Among patients who have recently had an acute coronary syndrome, an intensive lipid-lowering statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen. These findings indicate that such patients benefit from early and continued lowering of LDL cholesterol to levels substantially below current target levels. [ABSTRACT FROM AUTHOR]