Significant Reduction In Total Mortality Research Articles

Anatomy of health effects of Mediterranean diet: Greek EPIC prospective cohort study

Objective To investigate the relative importance of the individual components of the Mediterranean diet in generating the inverse association of increased adherence to this diet and overall mortality.Design Prospective cohort...

Impact of prehospital diagnosis in the management of ST elevation myocardial infarction in the era of primary percutaneous coronary intervention: reduction of treatment delay and mortality

The aim of the study is to assess, as primary endpoints, in-hospital mortality and percutaneous coronary intervention (PCI) mortality and to compare the outcome in ST elevation myocardial infarction (STEMI) patients with different pathways to a catheterization laboratory in the context of an area with 24 h availability of catheter facilities. Three hundred and ninety-nine STEMI patients, referred to an interventional centre for primary PCI, were divided into two groups according to the different pathways to the catheterization laboratory. Group A had 263 patients diagnosed following admission to First Aid. Group B had 136 patients diagnosed in a prehospital setting with telemedicine equipment and transferred directly to the interventional centre by advanced life support (ALS) ambulance. Significantly shorter treatment delay was observed in group B patients than in group A (262 +/- 112 vs. 148 +/- 81 min in group A vs. B, P < 0.001). A significant reduction in total mortality was observed in group B compared with group A (8.7 vs. 3% in group A vs. B, P < 0.05). After multivariate analysis, predictors of in-hospital mortality are age and Killip class (P < 0.01), different pathways to catheterization laboratory, pre-PCI TIMI flow and onset-to-balloon time (P < 0.05). The present study shows a reduction in treatment delay and in-hospital mortality by prehospital ECG and direct referral to catheterization laboratory.

The Women's Health Initiative: New evidence, new ideas and a better understanding

The Women's Health Initiative (WHI) trial was a major contribution to the understanding of the risks and benefits of hormone therapy (HT) in postmenopausal women. Further analyses of the results of the WHI trial and a seminal review by Kuhl and Stevenson have put a new perspective on the benefits and risks of HT.1 It is suggested that (A) Breast cancer (i) Body mass and prior HT are important factors in determining the risk of breast cancer associated with HT. (ii) The increased risk of breast cancer with CEE+MPA in the WHI trial is an artefact due to the low incidence of breast cancer in the placebo group of women. (iii) The, so far, unexplained reduction in risk of breast cancer with CEE only in women age 50-59 could be due to the estrogen-induced reduction in insulin levels in the women who were overweight or obese, the majority of whom probably had the “metabolic syndrome” and hyperinsulinaemia. (B) Coronary Heart Disease (CHD) (i) CEE only in younger healthy postmenopausal women decreases the incidence of CHD but CEE+MPA in older women increases the incidence of CHD. (ii) Addition of MPA to CEE in postmenopausal women increases the risk of CHD possibly due to an MPAinduced upregulation of thrombin receptors in the coronary arteries. (iii) The effect of HT on the incidence of CHD is determined by age and by time since menopause on initiating HT. It is hypothesised that “HT in younger postmenopausal women prevents atherosclerosis and reduces the risk of cardiovascular disease BUT in older postmenopausal women increases the risk of thrombosis and inflammation and of cardiovascular disease in women with atherosclerotic plaques”. (C)Stroke and Total Mortality (i) The increased incidence of stroke in women over age 60 with both the CEE+MPA and CEE only arms of theWHI trial is the main reason for caution in the use of HT in older postmenopausal women (ii) The reduction in total mortality in women under 60 with both CEE+MPA and CEE only is an important new finding and requires further investigation. (iii) The significant reduction in total mortality provides reassurance, if any is needed, of the safety and benefits of HT in younger postmenopausal womenO & G Forum Vol. 17 (4) 2007: pp. 105-110

Low-carbohydrate–high-protein diet and long-term survival in a general population cohort

We have evaluated the effects on mortality of habitual low carbohydrate-high-protein diets that are thought to contribute to weight control. Cohort investigation. Adult Greek population. SUBJECTS METHODS: Follow-up was performed from 1993 to 2003 in the context of the Greek component of the European Prospective Investigation into Cancer and nutrition. Participants were 22 944 healthy adults, whose diet was assessed through a validated questionnaire. Participants were distributed by increasing deciles according to protein intake or carbohydrate intake, as well as by an additive score generated by increasing decile intake of protein and decreasing decile intake of carbohydrates. Proportional hazards regression was used to assess the relation between high protein, high carbohydrate and the low carbohydrate-high protein score on the one hand and mortality on the other. During 113 230 persons years of follow-up, there were 455 deaths. In models with energy adjustment, higher intake of carbohydrates was associated with significant reduction of total mortality, whereas higher intake of protein was associated with nonsignificant increase of total mortality (per decile, mortality ratios 0.94 with 95% CI 0.89 -0.99, and 1.02 with 95% CI 0.98 -1.07 respectively). Even more predictive of higher mortality were high values of the additive low carbohydrate-high protein score (per 5 units, mortality ratio 1.22 with 95% CI 1.09 -to 1.36). Positive associations of this score were noted with respect to both cardiovascular and cancer mortality. Prolonged consumption of diets low in carbohydrates and high in protein is associated with an increase in total mortality.

Secondary Prevention of Coronary Artery Disease with Omega-3 Fatty Acids

Omega-3 fatty acid therapy is a promising intervention for the secondary prevention of coronary artery disease (CAD). Omega-3 fatty acids have properties that promote atherosclerotic plaque stability and decrease the incidence of ischemia-driven cardiac arrhythmias. A large number of clinical trials conducted in patients with CAD or prior myocardial infarction (MI) have examined hard cardiovascular end points, including total mortality, cardiovascular mortality, sudden death, and nonfatal MI. Several intermediate cardiovascular end-point studies have also examined whether ventricular arrhythmias can be suppressed in patients with implantable cardioverter defibrillators (ICDs). Significant reductions in total mortality and sudden death--20% to 50%--have been found in studies using doses of 0.85 to 4.0 g/day, with treatment durations from 12 to 42 months. Favorable trends toward reduction in the incidence of arrhythmic events have been demonstrated in some, but not all, ICD studies. Omega-3 fatty acid therapy shows a general positive trend toward benefit in reducing life-threatening events after MI and in patients with ICDs who have ischemic arrhythmias. Results of the recent Japan EPA Lipid Intervention Study (JELIS) in a large cohort (N = 18,645) of Japanese men and women suggest significant benefits in the reduction of unstable angina and nonfatal coronary events. The totality of evidence supports a strong role for omega-3 fatty acids derived from fish oil in secondary prevention through a presumptive role as an antiarrhythmic agent and through an ability to promote plaque stabilization.

Timing of arrhythmic death after myocardial infarction: does it affect timing of ICD implantation?The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

This editorial refers to ‘Temporal trends on the risk of arrhythmic vs. non-arrhythmic deaths in high-risk patients after myocardial infarction: a combined analysis from multicentre trials’ { by Y.G. Yap et al., on page 1385 In spite of significant reduction in total mortality observed in patients discharged after an acute myocardial infarction (MI), ventricular arrhythmias still account for 30–40% of deaths. This figure, which was initially provided by studies carried out in the pre-thrombolytic era, has been subsequently confirmed when most of the patients had been revascularized by thrombolysis or percutaneous coronary intervention (PCI). 1 Early revascularization and a more generalized use of beta blockers, angiotensin-converting enzyme-inhibitors, statins, and antiplatelet agents have largely contributed to the improvement in the prognosis of patients presenting with an ST-elevated acute MI. Nevertheless, identification of patients at risk remains an issue far from being adequately addressed. There is a general consensus that depressed ventricular function, as reflected by a left ventricular ejection fraction (LVEF) ,40%, represents the strongest negative prognostic factor in these patients. 1 Different cut-off values have proved effective in recent clinical trials and an LVEF ,30% has been used as a single inclusion criteria in studies aimed to evaluate, for example, the beneficial effect of implantable cardioverter defibrillator (ICD) after MI. After the publication of MADIT II results 2 that have clearly indicated a significant reduction of total and arrhythmic mortality in post-MI patients with ICD when compared with controls, ICD implantation has been recommended for almost all post-MI patients with an LVEF ,30%. This position has been only partially accepted by the most recent ACC/ AHA/NASPE and ESC guidelines. 3,4 The issue has become even more controversial after the publication of the results of the DINAMIT study. 5 More than 600 patients with a recent acute MI and reduced left ventricular function (LVEF , 35%) were randomized to ICD and control. Revascularization rate (either thrombolysis or PCI) was 62%. The so-called ‘best’ medical treatment was provided to most of the patients. The main result of the study was that prophylactic ICD therapy did not reduce overall mortality in this high-risk population. Moreover, by considering the type of death, it was evident that the reduction in the rate of death due to arrhythmia was offset by an increase in the rate of death from non-arrhythmic causes. A careful comparison of MADIT II with DINAMIT study characteristics provides a partial explanation for such a difference. In addition to the inevitable differences in study population and patient management, it is evident that in MADIT II, the mean time for enrolment was 81 months, whereas in DINAMIT it was 6–40 days. Thus, timing of implantation in relation to the index event was a critical factor not fully considered in the original report and only recently appreciated in the discussion of ICD indication in post-MI patients. Indeed, on reviewing a recent report by MADIT II study group, it is evident that no benefit from ICD could be observed in patients with a less remote MI (,18 months), whereas a tendency for a favourable effect or a significant benefit from ICD was detectable, respectively, at 18–59 months or longer (from 60 to .120 months) after the acute event. One could therefore extrapolate that, according to DINAMIT and MADIT II, ICD benefit cannot be detected in the first 2 years after an acute MI, thus casting additional doubts to the recommendation of an early ICD implantation in all patients with a depressed LVEF. The lack of benefit from ICD implantation in the first 2 years after an acute MI could be interpreted as an indirect evidence in which, in the reperfusion era, the risk of arrhythmic death becomes predominant only several months after the acute event. Is this opinion founded?

Implantable Defibrillators for the Prevention of Mortality in Patients With Nonischemic Cardiomyopathy

Implantable cardioverter defibrillator (ICD) therapy is effective in primary and secondary prevention of sudden cardiac death among patients with prior myocardial infarction and depressed ejection fraction. However, conclusive evidence of survival benefit in patients with nonischemic cardiomyopathy (NICM) is still lacking. To determine whether ICD therapy reduces all-cause mortality in patients with NICM. MEDLINE (1966-2004), EMBASE (1991-2004), the Cochrane Central Register of Controlled Trials (through first quarter, 2004), reports presented at scientific meetings (2003-2004), and bibliographic review of secondary sources. Search terms included defibrillator, randomized controlled trials, clinical trials, and sudden death. Eligible studies were prospective randomized controlled trials of ICD or combined cardiac resynchronization therapy and defibrillator (CRT-D) vs medical therapy enrolling at least some individuals with NICM and reporting all-cause mortality as an outcome. Of 675 potentially relevant articles screened initially, 8 reports of randomized trials enrolling a total of 2146 patients with NICM were included. Included studies were reviewed to determine the number of patients randomized, mean duration of follow-up, primary end point, mortality of ICD cohort, and mortality of control cohort. Five primary prevention trials enrolling 1854 patients with NICM were identified; pooled analysis suggested a significant reduction in total mortality among patients randomized to ICD or CRT-D vs medical therapy (risk ratio [RR], 0.69; 95% confidence interval [CI], 0.55-0.87; P = .002). Mortality reduction remained significant even after elimination of CRT-D trials. Two of the 3 secondary prevention trials presented subgroup estimates for ICD efficacy in NICM. Pooled analysis of these secondary prevention trials (n = 256 patients with NICM) indicated an equivalent but nonsignificant mortality reduction with ICD therapy (RR, 0.69; 95% CI, 0.39-1.24; P = .22). Analysis of all 7 trials combined demonstrated a statistically significant 31% overall reduction in mortality with ICD therapy (RR, 0.69; 95% CI, 0.56-0.86; P = .002). ICD therapy appears to significantly reduce mortality in selected patients with NICM.

Vascular viewpoint

Question: Does adherence to a Mediterranean diet improve total mortality, as well as mortality due to coronary heart disease (CHD) and cancer? Population: Men and women aged 20 86 years from all geographic areas within Greece. Subjects having CHD, cancer, and diabetes mellitus at the time of enrollment were excluded. Design and methods: A cohort of 28 572 participants was recruited as part of the European Prospective Investigation into Cancer and Nutrition (EPIC) and 22 043 were followed prospectively for a median duration of 44 months. Baseline measurements of diet were obtained using a validated semi-quantitative food-frequency questionnaire, and adherence was determined using an aggregate 10-point scale (from zero to nine, indicating greater adherence with increasing score) devised a priori to incorporate nine prominent components of the traditional Mediterranean diet. A binary value was assigned based on the relative consumption of presumed beneficial or detrimental components. Participants whose consumption of beneficial components (vegetables, legumes, fruits and nuts, cereal, fish, ratio of monounsaturated to saturated fats) was above sex-specific medians were assigned a score of one. Participants whose consumption was below-median were assigned a score of zero. Detrimental components (meat and poultry, dairy) were scored in the opposite fashion -participants whose consumption was above-median were assigned a score of zero, and participants whose consumption was below-median were assigned a score of one. Scoring of alcohol intake was based on whether consumption was within beneficial sex-specific consumption ranges (males, 10 50 g per day; females, 5 25 g per day). Cause of death was obtained from death certificates and official records, and was classified by physicians blinded to diet score. Cox proportional hazards regression models were used to measure the association between studied food groups, adherence to the Mediterranean diet and mortality after adjustment for age, sex, energy expenditure, smoking status, anthropomorphic measures, and other confounding factors. Results: Over the follow-up period, 81 139 person-years were accrued and 275 deaths were recorded. Adherence to the Mediterranean diet was inversely related to mortality. A two-point increase in the aggregate score resulted in an adjusted hazard ratio for death of 0.75 (95% confidence interval [CI], 0.64 to 0.87). Mortality due to CHD (adjusted hazard ratio, 0.67 [95% CI, 0.47 to 0.94]) and mortality due to cancer (adjusted hazard ratio, 0.76 [95% CI, 0.59 to 0.98]) were also inversely associated with a two-point increase in the aggregate score. Consumption of individual food components in the Mediterranean diet was generally not associated with total mortality. Consumption of fruit and nuts (adjusted hazard ratio 0.82 [95% CI, 0.70 to 0.96]) and the ratio of monounsaturated fats to saturated fats (adjusted hazard ratio 0.86 [95% CI, 0.76 to 0.98]), however, were associated with reduced mortality. Conclusion: Adherence to the Mediterranean diet is associated with a significant reduction in total mortality, CHD, and cancer mortality. Individual components of the diet are not generally predictive of total mortality, suggesting that multiple dietary components are necessary to yield the most protective effect.

Use of beta blockers in cardiovascular diseases and bronchial asthma/COPD

Numerous extensive, randomized clinical trials of beta-blockers have shown significant reduction of total mortality in patients with myocardial infarction and chronic heart failure. The life-saving therapy of myocardial infarction or chronic heart failure with beta-blockers, however, is often withheld from patients with COPD/asthma. Several studies demonstrate that especially patients with COPD would benefit from such a therapy due to their high cardiovascular risk profile. Recent meta-analyses show that cardioselective beta-blockers are well tolerated by these patients without causing relevant limitations in lung function. Present findings suggest that the mortality reduction of beta-blocker therapy may outweigh the risks in patients with COPD and possibly even in patients with mild asthma. Contraindications for beta-blockers include acute exacerbations and severe forms of COPD as well as moderate to severe asthma and the regular use of beta(2)-sympathomimetics. beta-Blocker therapy should be given with low initial doses on an individual basis after careful consideration of the benefit to risk ratio, preferably using cardioselective substances with proven mortality benefits for myocardial infarction and chronic heart failure.

Angiotensin receptor blockers as anti-hypertensive treatment for patients with diabetes mellitus: meta-analysis of controlled double-blind randomized trials.

To assess the evidence for possible reduction of all-cause mortality, cardiovascular morbidity and mortality, and end-stage renal disease in diabetic patients treated with angiotensin II type 1 receptor blockers (ARBs) as an anti-hypertensive treatment. Systematic review and meta-analysis of randomized, double-blind controlled trials of at least 1 year's duration. ARBs were used in the intervention group vs. placebo or standard anti-hypertensive treatment in the control group. The main outcome measures were all-cause mortality, cardiovascular morbidity and mortality, and end-stage renal disease. Three studies fulfilled the inclusion criteria. Separate analyses were conducted for comparisons of ARBs with groups given placebo and those given standard anti-hypertensive treatment. There was no significant difference in mortality between the ARBs and placebo groups, with an estimated odds ratio (OR) of 0.99 [95% confidence interval (CI) 0.81, 1.20]. There was a non-significant difference in patients treated with ARBs compared with standard anti-hypertensive treatment, with an OR of 0.78 (95% CI 0.45, 1.36). No statistically significant difference in cardiovascular morbidity and mortality between the intervention and placebo groups was found, with an OR of 0.91 (95% CI 0.77, 1.08). When ARBs were compared with standard treatment, the OR was estimated at 0.85 (0.54, 1.33). Data on end-stage renal disease were available for two studies comparing ARBs vs. placebo and showed a statistically significant advantage of ARBs, with an OR of 0.73 (95% CI 0.6, 0.89). As only one study compared end-stage renal disease outcome for ARBs vs. standard treatment, a meta-analysis was not possible. This study reported a considerable benefit of ARBs [OR = 0.73 (0.54, 1.01)] compared with the calcium channel blocker amlodipine. ARBs failed to show significant reduction in total mortality and cardiovascular morbidity and mortality in diabetic patients. The only statistical benefit was the reduction of end-stage renal disease compared with placebo. Therefore, at this time ARBs have not proved to be superior to standard anti-hypertensive treatment in diabetic patients.

Perspectives from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial - Lipid Lowering Trial and the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm

The design, process and outcomes are compared between two large clinical trials of LDL cholesterol reduction with statin treatment in patients with known high blood pressure. This new information is placed in the context of previous clinical trials of cholesterol reduction, which have provided analyses of sub-groups with high blood pressure. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial failed to find a significant reduction of total mortality (primary endpoint), cardiovascular mortality or major cardiovascular events. This differed sharply from the Anglo-Scandinavian Cardiac Outcomes Trial, Lipid Lowering Arm, which was stopped before the planned termination due to a marked reduction (36%) in coronary death or myocardial infarction (primary endpoint). This trial also found significant reductions in stroke (27%) and separately, all major vascular events (21%). The two studies were similar in that they each contained over 10 000 participants with documented high blood pressure requiring drug therapy and they both used a fixed dose of a single statin. Pravastatin (40 mg/day) was used in the former and atorvastatin 10 mg/day in the latter. The major difference was that the control group in the Anglo-Scandinavian trial was treated with placebo with a double blind design whereas antihypertensive and lipid-lowering trial was open label with controls receiving usual care. The benefit of achieving and maintaining significant LDL cholesterol reduction in patients with high blood pressure was convincingly demonstrated in the Anglo-Scandinavian trial. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial failed to achieve similar success due to use of a less effective drug and loss of the differential effect with increasing statin treatment in the usual care control group.

Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension

Background: We describe the effect of controlled-release/extended-release (CR/XL) metoprolol succinate once daily on mortality and hospitalizations among patients with a history of hypertension complicated by chronic systolic heart failure. Methods and Results: We enrolled 3,991 patients with chronic heart failure of New York Heart Association functional class II–IV with an ejection fraction of ≤0.40, stabilized with optimum standard therapy, in a double-blind randomized placebo-controlled study. A total of 1,747 patients (44%) had a history of hypertension; 871 were randomized to receive metoprolol CR/XL and 876 to receive placebo. Treatment with metoprolol CR/XL compared with placebo resulted in a significant reduction in total mortality (relative risk [RR], 0.61; 95% confidence interval [CI], 0.44–0.84; P =.0022), mainly because of reductions in sudden death (RR, 0.51; 95% CI, 0.33–0.79; P =.0022) and mortality from worsening heart failure (RR, 0.49; 95% CI, 0.25–0.99; P =.042). Total number of hospitalizations for worsening heart failure was reduced by 30% in the metoprolol CR/XL group compared with placebo (P =.015). Metoprolol CR/XL was well tolerated: 12% fewer patients withdrew from study medication (all-cause) compared with placebo (P =.048). Conclusions: A subgroup analysis of MERIT-HF shows that patients with heart failure and a history of hypertension received a similar benefit from metoprolol CR/XL treatment as all patients included in the total study.

Prevention of sudden cardiac death in heart failure: which beta blocker is best suited?

Three large studies of patients who have survived a myocardial infarction have clearly demonstrated that the beta blockers timolol, propranolol and metoprolol could reduce long-term mortality and the effect was especially marked on sudden cardiac death. More recently, very large trials have been conducted in patients with congestive heart failure of various etiologies, also with a significant reduction of total mortality and, even more pronounced, of sudden cardiac death. Bisoprolol and metoprolol were used in these studies. The beta blockers which have reduced mortality and sudden cardiac death in all these studies have two properties in common, beta-1-blockade and a higher degree of lipophilicity. The two beta blockers with the best documentation on sudden cardiac death in patients with heart failure are metoprolol and bisoprolol, both being beta-1-selective with a higher degree of lipophilicity.

Statins in the prevention of coronary heart disease.

Although epidemiologic studies proved that a causal relationship exists between elevated serum cholesterol levels and coronary heart disease, it is only recently that cholesterol-lowering strategies have shown significant reductions in total mortality. In the last few years, three landmark coronary artery disease-reduction trials with HMG-coenzyme A reductase inhibitors (statins) showed significant reductions in coronary heart disease and mortality. Statins have beneficial effects on coronary heart disease and overall mortality in primary and secondary prevention, including in women and the elderly. Angiographic studies reveal the potential mechanisms through which statins exert their clinical benefits.

Review of Recent Clinical Trials of Lipid Lowering in Coronary Artery Disease

Early trials with lipid-lowering therapy in patients with established coronary artery disease revealed favorable trends in cardiovascular events but did not yield significant reductions in total mortality. Recent clinical trials using hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (“statin”) therapy have shown significant decreases in total mortality, cardiovascular events, hospitalizations, and the need for revascularization procedures, with its usage (1) to lower low-density lipoprotein (LDL) cholesterol after myocardial infarction (secondary prevention); and (2) in high-risk patients without evidence for coronary artery disease (primary prevention). Secondary prevention benefits have been seen for both men and women, in the young and elderly, and among diabetic and nondiabetic patients. The beneficial effects of LDL-cholesterol reduction occur early and are additive to other risk-reduction therapies. Lipid-lowering therapy should be part of the comprehensive treatment of all patients with atherosclerotic vascular disease and patients at high risk.

Effect of Propranolol Versus No Propranolol on Total Mortality Plus Nonfatal Myocardial Infarction in Older Patients with Prior Myocardial Infarction, Congestive Heart Failure, and Left Ventricular Ejection Fraction ≥40% Treated With Diuretics Plus Angiotensin-Converting Enzyme Inhibitors

At 32-month follow-up of older patients with prior myocardial infarction, congestive heart failure, and a left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors, and also with digoxin if atrial fibrillation was present, propranolol caused a 35% significant reduction in total mortality and a 37% significant decrease in total mortality plus nonfatal myocardial infarction compared with no propranolol. At 1-year follow-up, propranolol caused a significantly greater increase in left ventricular ejection fraction (6%) and a significantly greater reduction in left ventricular mass (34 g) than did no propranolol (2% and 20 g, respectively).

Overview of Randomized Trials of Angiotensin-Converting Enzyme Inhibitors on Mortality and Morbidity in Patients With Heart Failure

Objective. —To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure. Data Sources and Study Selection. —Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat, regardless of sample size. Trials were identified based on literature review and correspondence with investigators and pharmaceutical firms. Data Extraction. —Using standard tables, data were extracted by one author and confirmed where necessary by the other author or the principal investigator of the trial. Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm. Data Synthesis. —The data for each outcome were combined using the Yusuf-Peto adaptation of the Mantel-Haenszel method. Overall, there was a statistically significant reduction in total mortality (odds ratio [OR], 0.77; 95% confidence interval [CI], 0.67 to 0.88;P Conclusions. —Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients. (JAMA. 1995;273:1450-1456)

Cumulative meta-analysis of therapeutic trials for myocardial infarction.

The large volume of published randomized, controlled trials has led to a need for meta-analyses to track therapeutic advances. Performing a new meta-analysis whenever the results of a new trial of a particular therapy are published permits the study of trends in efficacy and makes it possible to determine when a new treatment appears to be significantly effective or deleterious. We describe the use of such a procedure, cumulative meta-analysis, to assess therapeutic trials among patients with myocardial infarction. We performed cumulative meta-analyses of clinical trials that evaluated 15 treatments and preventive measures for acute myocardial infarction. An example of this method is its application to the use of intravenous streptokinase as thrombolytic therapy for acute infarction. Thirty-three trials evaluating this therapy were performed between 1959 and 1988. We found that a consistent, statistically significant reduction in total mortality (odds ratios, 0.74; 95 percent confidence interval, 0.59 to 0.92) was achieved in 1973, after only eight trials involving 2432 patients had been completed. The results of the 25 subsequent trials, which enrolled an additional 34,542 patients through 1988, had little or no effect on the odds ratio establishing efficacy, but simply narrowed the 95 percent confidence interval. In particular, two very large trials, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico trial in 1986 (11,712 patients) and the Second International Study of Infarct Survival trial in 1988 (17,187 patients) did not modify the already established evidence of efficacy. We used a similar approach to study the accumulating evidence of efficacy (or lack of efficacy) of 14 other therapies and preventive measures for myocardial infarction. Cumulative meta-analysis of therapeutic trials facilitates the determination of clinical efficacy and harm and may be helpful in tracking trials, planning future trials, and making clinical recommendations for therapy.

Clinical trials including an update on the Helsinki heart study

The incidence of myocardial infarction (MI), sudden death and other clinical manifestations of coronary heart disease can be reduced by lowering the blood cholesterol level. This is now well established by multiple clinical trials using a variety of interventions including diet and lipid-lowering drugs. Dietary studies in Los Angeles and in Oslo, Norway, have induced a reduction in blood cholesterol of between 10 and 15% with correlated reductions in coronary disease of 20 to 50%. Both niacin and clofibrate in separate cohorts demonstrated a significant reduction in new MI during 5 years of treatment in the Coronary Drug Project. Similar reductions in new MI occurred in the World Health Organization Study with clofibrate. However, in this trial and different from all other trials, mortality in the drug-treatment group actually increased. This finding remains unexplained. In the more recent Lipid Research Clinics Coronary Primary Prevention Trial using the bile acidbinding resin cholestyramine, only a 9% reduction in total cholesterol resulted in a highly significant reduction in the major end points—MI and sudden death—as well as in other secondary end points, including the need for coronary artery bypass graft surgery, ischemic changes on exercise electrocardiography and new-onset angina. Recently, another primary prevention trial using gemfibrozil produced a similar reduction in total cholesterol but a much more significant increase in high-density lipoprotein cholesterol. The reduction in coronary heart disease was in excess of 34% and was strongly related to both low-density lipoprotein cholesterol reduction and high-density lipoprotein elevation. Combination drug studies have produced larger reductions in total cholesterol. In the Stockholm Heart Study, niacin and clofibrate produced a statistically significant reduction in total mortality in patients who had had recent Ml. Similarly, in men who had undergone coronary artery bypass graft surgery, the combination of niacin, colestipol and diet produced strong evidence of a reduced rate of progression of arteriosclerotic lesions as demonstrated by coronary angiography. This study, conducted at the University of Southern California, was the Cholesterol-Lowering Atherosclerosis Study. It also produced evidence of lesion regression in some patients. Although these studies have been carried out primarily in middle-aged men, the older segments of these populations have appeared to do as well with regard to disease prevention as the younger members of the cohorts. We can now treat patients with high blood cholesterol levels both before and after manifestation of coronary disease with significant assurance that beneficial effects will accrue. Additional studies with newer and more powerful lipid-lowering agents are needed, as are studies in women and the elderly.

Long-Term Treatment After Acute Myocardial Infarction

Even if the prognostic significance of ventricular arrhythmias (VA) has been documented in post-AMI CAD, which post-AMI patient showing VA should be treated is still controversial, because no beneficial effects of antiarrhythmic treatment has ever been proved in clinical trials using phenytoin, aprindine, tocainide, mexiletine, and the drugs recently utilized in the CAPS for EVBs. Probably, the rationale for antiarrhythmic therapy is more conclusive in patients with ventricular arrhythmias other than EVBs, and the need for antiarrhythmic drugs should be evaluated in each case, considering other clinical variables of prognostic importance (EF%, extent of coronary lesions, etc.). The type of antiarrhythmic drugs to be used is discussed, considering that, while many traditional antiarrhythmic agents are undoubtedly effective in the treatment of an acute arrhythmia, in the chronic setting, most of the time, a significant reduction in ventricular arrhythmias on Holter monitoring can be proved, without a significant reduction in total mortality. Conversely, we comment on the positive results of some empirical studies showing beneficial effects of antiarrhythmic therapy in high-risk patients reported by Lown's group. Furthermore, it can be stated that patients showing efficacy of antiarrhythmic therapy by both noninvasive and invasive evaluation of antiarrhythmic therapy efficacy had better long-term outcomes. To confirm these data, we report the results of a clinical study of the treatment of complex and frequent EVBs in cardiac patients. A different mortality on follow-up was observed in responders and nonresponders vs. patients not receiving drugs (2.2, 28, and 24%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)