End Point Of Nonfatal Myocardial Infarction Research Articles

The Effect of Pioglitazone on Recurrent Myocardial Infarction in 2,445 Patients With Type 2 Diabetes and Previous Myocardial Infarction: Results From the PROactive (PROactive 05) Study

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). 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. 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. 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). 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).

Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial

A prespecified objective of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was to assess whether any synergistic effects were apparent between the lipid-lowering and blood-pressure-lowering regimens in preventing cardiovascular events. A total of 19 257 hypertensive subjects were randomized to an amlodipine-based regimen or an atenolol-based regimen. Of these, 10 305 subjects with total cholesterol < or =6.5 mmol/L were further randomized to atorvastatin 10 mg daily or placebo. In this analysis, the effects of atorvastatin were compared with placebo on coronary heart disease (CHD), cardiovascular and stroke events in those assigned amlodipine-based and atenolol-based regimens. In the ASCOT lipid-lowering arm (LLA), overall, atorvastatin reduced the relative risk of the primary endpoint of non-fatal myocardial infarction and fatal CHD events by 36% (HR 0.64, CI 0.50-0.83, P=0.0005), total cardiovascular events by 21% (HR 0.79, CI 0.69-0.90, P=0.0005), and stroke by 27% (HR 0.73, CI 0.56-0.96, P=0.024). However, atorvastatin reduced the relative risk of CHD events by 53% (HR 0.47, CI 0.32-0.69, P<0.0001) among those allocated the amlodipine-based regimen, and by 16% (HR 0.84, CI 0.60-1.17, p: n.s.) among those allocated the atenolol-based regimen (P=0.025 for heterogeneity). There were no significant differences between the effects of atorvastatin on total cardiovascular events or strokes among those assigned amlodipine (HR 0.73, CI 0.60-0.88, P<0.005 and HR 0.69, CI 0.45-1.06, P: n.s., respectively) or atenolol (HR 0.85, CI 0.71-1.02, P: n.s and HR 0.76, CI 0.53-1.08, P: n.s, respectively). Differences in blood pressure and lipid parameters (placebo corrected) between the two antihypertensive treatment limbs could not account for the differences observed in CHD outcome. These findings of an apparent interaction between atorvastatin and an amlodipine-based regimen in the prevention of CHD events are of borderline significance, and hence generate an hypothesis that merits independent evaluation in other trials.

Lowering of Central Aortic Blood Pressure-Not All Antihypertensive Agents Are Created Equal: Differential Impact of Blood Pressure-Lowering Drugs on Central Aortic Pressure and Clinical Outcomes: Principal Results of the Conduit Artery Function Evaluation (CAFE) Study. Circulation 113: 1213-1225, 2006.

Lowering of Central Aortic Blood Pressure-Not All Antihypertensive Agents Are Created Equal: Differential Impact of Blood Pressure-Lowering Drugs on Central Aortic Pressure and Clinical Outcomes: Principal Results of the Conduit Artery Function Evaluation (CAFE) Study. Circulation 113: 1213-1225, 2006.

Lipid-lowering therapy and the patient with multiple risk factors: what have we learned from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)?

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was the first trial of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to assess the benefits of lipid lowering in the primary prevention of coronary heart disease (CHD) in patients with hypertension who were not deemed to have dyslipidemia by conventional measures. A total of 19,342 patients with hypertension and > or =3 cardiovascular risk factors, but without CHD, were enrolled in ASCOT. Of these, 10,305 patients with a serum cholesterol level of < or =250 mg/dL (< or =6.5 mmol/L) were randomized to either atorvastatin (10 mg/day) or placebo in the ASCOT lipid-lowering arm (ASCOT-LLA). Follow-up was planned for an average of 5 years. The ASCOT-LLA was stopped after 3.3 years owing to the superiority of atorvastatin 10 mg over placebo in reducing the primary end point of nonfatal myocardial infarction (MI) and fatal CHD. Patients receiving atorvastatin experienced a significant reduction in total cholesterol (50 mg/dL [1.3 mmol/L]) and low-density lipoprotein cholesterol (46 mg/dL [1.2 mmol/L]) levels after 1 year compared with those who received placebo. Cholesterol lowering with atorvastatin was associated with a highly significant reduction in the primary end point of nonfatal MI and fatal CHD (36%, P = 0.0005). The observed benefit was consistent across the secondary end points and the 18 prespecified subgroups. The ASCOT-LLA findings have influenced lipid-lowering guidelines and support the concept that treatment strategies to reduce cardiovascular disease should be based on the assessment of all cardiovascular risk factors, rather than on numerical thresholds of individual risk factors, to determine treatment strategies.

How Should Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction Be Managed? A Meta-analysis of Randomized Trials

Abstract Purpose Patients with unstable angina or non-ST-segment elevation myocardial infarction (MI) may be managed with either an or conservative strategy. It is unclear which of these strategies is superior. Methods We identified studies with MEDLINE and EMBASE searches (1966-September 2003) and by reviewing reference lists. Studies were included if they were randomized controlled trials comparing management strategies for patients in the early post-unstable angina/non-ST-segment elevation MI period and had follow-up data for at least 3 months. Results Seven trials that randomized a total of 9212 patients were included. The pooled odds ratio (OR) for all-cause mortality was 0.96 (95% confidence interval [CI]: 0.72 to 1.27). The occurrence of fatal or nonfatal re-infarction was reduced with an invasive strategy (OR 0.73; 95% CI: 0.61 to 0.88) as was readmission to hospital (OR 0.67; 95% CI: 0.48 to 0.94). The endpoints of nonfatal MI and the composite of death or nonfatal MI showed nonsignificant trends favoring an invasive strategy. Trials that included a higher proportion of patients with ST-segment depression on admission and trials in which a larger proportion of patients underwent revascularization showed a greater magnitude of benefit for an invasive strategy. Conclusion For patients with unstable angina/non-ST-segment elevation MI, an invasive strategy reduces rates of fatal or nonfatal re-infarction and hospital readmission, but not all-cause mortality, when compared with a noninvasive strategy. These results suggest that an invasive management strategy should be considered for all patients with unstable angina/non-ST-segment elevation MI and perhaps in particular those with ST-segment depression.

Implications of recent end-point trials on future management of hypertension and dyslipidaemia

A significant proportion of patients with hypertension are likely to have additional cardiovascular (CV) risk factors, such as hypercholesterolaemia. Several trials have demonstrated that lipid lowering can provide significant benefits in terms of reduced risk of CV mortality and morbidity. Trials such as the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) trial have shown regression of atherosclerosis after aggressive lipid-lowering treatment with statins. The Heart Protection Study (HPS) also demonstrated a significant reduction in the incidence of major vascular events in high-risk patients, irrespective of baseline cholesterol levels, after treatment with a statin. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is of particular significance because it investigated the impact of combining the effects of antihypertensive therapy with a statin. ASCOT was a multi-centre, 2×2 factorial design, randomized trial comparing two blood pressure (BP)-lowering regimens in the antihypertensive arm, and double-blind atorvastatin (10 mg) versus placebo in a separate lipid-lowering arm (LLA). The objective of the LLA was to compare the effects of low-dose atorvastatin versus placebo for the combined end-point of nonfatal myocardial infarction and fatal coronary heart disease (CHD) in hypertensive patients with normal to mildly elevated cholesterol levels (total cholesterol ≤6.5 mmoll−1; ≤250 mgdl−1). The ASCOT–LLA represents the first study to assess the benefits of lipid lowering in the primary prevention of CHD in well-controlled hypertensive patients who are not conventionally deemed dyslipidaemic. Secondary end-points included all-cause mortality, fatal and nonfatal stroke and total coronary events. The ASCOT–LLA, which had a 5-year planned follow-up, was terminated prematurely by the Data Safety Monitoring Board, after a median follow-up of 3.3 years due to a highly significant reduction in the primary end-point of 36% compared with placebo (P=0.0005). ASCOT and other end-point studies suggest that controlling both BP and dyslipidaemia may have a synergistic benefit on CV mortality and morbidity. Future treatment strategies should therefore be aimed at addressing global CV risk in each patient and not just individual risk factors.

The ALLHAT-LLT and ASCOT-LLA trials: are the discrepancies more apparent than real?

During the past decade, numerous landmark trials of statins in secondary and primary prevention and their meta-analyses have demonstrated statistically significant and clinically important reductions in myocardial infarction, stroke, and vascular death (by about one third), as well as total mortality (by about one fifth). In the past year, two trials of statins have been reported among hypertensive subjects enrolled in blood pressure-lowering trials, one in the United States and the other in Europe. The US trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial--Lipid Lowering Trial (ALLHAT-LLT), was reported as showing no significant benefit. In contrast, the European trial, the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA), was terminated early based on the unanimous recommendation of the Data and Safety Monitoring Board, due principally to the emergence of a statistically extreme 36% reduction in the primary endpoint of nonfatal myocardial infarction and death from coronary heart disease (P<0.0005). These trial results have been viewed as discrepant, but methodologic issues of inadequate power of ALLHAT due to lower than projected sample size and poor compliance due to an open design render these discrepancies more apparent than real. The ALLHAT-LLT trial should be viewed not as null, but as uninformative, as the 95% confidence limits around the point estimate include the most plausible small to moderate benefit of statins. The totality of evidence on statins continues to strongly support their benefits in a wide range of patients on a large number of cardiovascular disease endpoints.

The relation of the type a behaviour pattern, factors of the structured interview, and anger to survival after myocardial infarction

The Type A behaviour pattern remains poorly defined and difficult to measure. The Structured Interview (SI) is generally regarded as the best measure of Type A, with predictive validity for Coronary Heart Disease (CHD). The present study reports the findings of factor analyses of the SI in a large clinical sample aimed at investigating its stability across employment status, the contribution of speech style to Type A classification, and its relationship to CHD endpoints of nonfatal myocardial infarction (MI) and death. Furthermore, it examines the role of trait anger in relation to Type A classification and CHD. Factor analysis of item content revealed three clear factors, namely (a) hard-driving, hurried behaviour, (b) impatience, and (c) anger. Inclusion of speech characteristics yielded a fourth factor. The factor structure remained essentially unchanged across employment status. Speech style, in particular “potential for hostility” and “speed”, has a strong influence on Type A ratings. Neither the SI factors nor trait anger were related to death or reinfarction in me 12 months following an acute MI.