Calcium antagonists in coronary artery disease and hypertension. Time for reevaluation?
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Calcium Channel Blockers↗
Biomedical subjects
S Yusuf
Publications and source records attributed to S Yusuf.
Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials.
OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme (ACE) inhibitors on mortality and morbidity in patients with symptomatic congestive heart failure. DATA SOURCE AND STUDY SELECTION: Data were obtained for all completed, published or unpublished, randomized, placebo-controlled trials of ACE inhibitors that were at least 8 weeks in duration and had determined total mortality by intention to treat,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 Unpublished data were obtained by direct correspondence with the principal investigator of each study or pharmaceutical firm.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 < .001) and in the combined endpoint of mortality or hospitalization for congestive heart failure (OR, 0.65; 95% CI, 0.57 to 0.74; P < .001). Similar benefits were observed with several different ACE inhibitors, although the data were largely based on enalapril maleate, captopril, ramipril, quinapril hydrochloride, and lisinopril. Reductions for total mortality and the combined endpoint were similar for various subgroups examined (age, sex, etiology, and New York Heart Association class). However, patients with the lowest ejection fraction appeared to have the greatest benefit. The greatest effect was seen during the first 3 months, but additional benefit was observed during further treatment. The reduction in mortality was primarily due to fewer deaths from progressive heart failure (OR, 0.69; 95% CI, 0.58 to 0.83); point estimates for effects on sudden or presumed arrhythmic deaths (OR, 0.91; 95% CI, 0.73 to 1.12) and fatal myocardial infarction (OR, 0.82; 95% CI, 0.60 to 1.11) were less than 1 but were not significant. CONCLUSIONS: Total mortality and hospitalization for congestive heart failure are significantly reduced by ACE inhibitors with consistent effects in a broad range of patients.
Aged↗
Magnesium in acute myocardial infarction.
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Animals↗
Effects of exercise training in patients with congestive heart failure: a critical review.
Congestive heart failure is a potentially debilitating disorder that affects a significant number of patients. The age-adjusted death rate has doubled over the past decade. Patients live an average of 4 to 5 years, and nearly all suffer from fatigue and breathlessness, which limits exercise capacity and produces a poor quality of life. Patients have usually been advised to avoid exercise because of concerns that they would experience a further decline in cardiac function. However, it has been demonstrated that exercise capacity is not related to the degree of left ventricular systolic dysfunction. This has led to the suggestion that peripheral changes in skeletal muscle and blood supply may play a major role in determining the exercise capacity of patients with congestive heart failure. Studies have demonstrated abnormalities of skeletal muscle blood flow, metabolism and structure, all of which are consistent with the impaired performance observed in these patients. Although the effects of exercise training have been examined in only a relatively few number of patients, the results have been promising. Exercise training has been found to improve exercise capacity and reduce symptoms. However, to our knowledge no data exist as to the impact of exercise training on left ventricular function, hospital stay or mortality in this population. Even though the early results are promising, they require confirmation of feasibility, clinical benefit and safety in larger, long-term randomized trials. It should be determined whether training has a long-term beneficial impact on measures more closely related to daily activities and quality of life. Ultimately, it would be important to determine whether training has an impact on mortality and morbidity.
Clinical Trials as Topic↗
Neurohumoral variability in left ventricular dysfunction. SOLVD Investigators. Studies of Left Ventricular Dysfunction.
The immediate and longer term variability of selected vasoactive- and volume-regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction < or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short-term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Does PTCA in acute myocardial infarction affect mortality and reinfarction rates? A quantitative overview (meta-analysis) of the randomized clinical trials.
BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results. METHODS AND RESULTS: A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patient. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87). CONCLUSIONS: Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.
Angioplasty, Balloon, Coronary↗
Issues Regarding the Use of Heparin Following Streptokinase Therapy.
The success of thrombolytic therapy is dependent upon the balance of fibrinolytic activity and procoagulant activity. Streptokinase produces fibrin degradation products that have anticoagulant effects and may potentially protect against reocclusion. However, streptokinase also activates platelets and thrombin, and the prothrombotic effects may be more marked than after administration of recombinant tissue plasminogen activator (rt-PA). Administration of high-dose, delayed subcutaneous heparin after streptokinase and aspirin has been shown to have some benefits and some risks. The benefits and risks of adding intravenous heparin to aspirin and streptokinase have not been clearly defined.
Journal Article↗
Advances in antithrombotic drug therapy for coronary artery disease.
Compounds which inhibit the coagulation cascade and antagonize platelet function are fundamental to the successful treatment of acute coronary syndromes. In a high proportion of patients with acute myocardial infarction, unstable angina, or sudden cardiac death, the acute ischaemic event is precipitated by intracoronary thrombus. Occlusive or non-occlusive thrombi have been found in the majority of cases, either in vivo or at autopsy. Aspirin and unfractionated heparin have been the cornerstones of antithrombotic therapy in such patients for the past decade, but while their benefits have been convincingly demonstrated, there are significant pharmacokinetic, pharmacodynamic, and clinical limitations. These limitations have provided the impetus for the development of newer antithrombotic agents with several theoretical advantages over aspirin and heparin. This paper has four aims. First it reviews the pathogenesis of intracoronary thrombi in acute coronary artery syndromes. Second, it outlines the limitations of current antithrombotic therapies. Third, it explores the potential advantages of new antithrombin and antiplatelet compounds, which may be understood and classified by their mechanism of action (Table 1); how the theoretical advantages may translate into clinical practice will be examined. Fourth, the initial clinical experience with these new agents will be reviewed briefly.
Animals↗
Patterns of medication use in patients with heart failure: a report from the Registry of Studies of Left Ventricular Dysfunction (SOLVD).
To determine patterns of medication use based on clinical variables in patients with heart failure, we analyzed data from 5,999 patients participating in the Registry of Studies of Left Ventricular Dysfunction (SOLVD). The Registry comprised a broad spectrum of patients with heart failure, including some with predominantly diastolic dysfunction. Drug use was determined in a population cross-sectional manner at the time of identification (74% hospitalized). The median number of drugs per patient was four, with diuretics taken by 62%, digitalis by 45%, angiotensin-converting enzyme inhibitors (ACE-I) by 32%, calcium channel blockers by 36%, antiarrhythmics by 22%, and beta-blockers by 18%. Only 18% were on the combination of ACE-I, diuretic, and digitalis. Stratification for diagnosis, heart failure symptoms, and ejection fractions demonstrated that triple-drug therapy (digitalis, diuretic, and ACE-I) was common only in those with ejection fractions less than .20 and several signs or symptoms of heart failure. Older patients were taking diuretics frequently (73% of patients older than 70 years of age), and our European center used fewer drugs overall, while prescribing digitalis about half as frequently as North American clinics. These data serve as the baseline for analysis of evolving therapeutic practice in patients with heart failure.
Aged↗
Effects of ACE inhibitors on mortality when started in the early phase of myocardial infarction: evidence from the larger randomized controlled trials.
This review summarizes the evidence from five of the larger randomized controlled trials evaluating the effects of angiotensin converting enzyme inhibitors started in the early phase of myocardial infarction on subsequent mortality and major morbidity. Altogether, information on about 98,000 patients is available from these trials. In four studies, trial treatment was started within 24 h, and in one study within 36 h, of the onset of symptoms of acute myocardial infarction, and mortality was assessed after a few weeks or months of treatment. When taken together, these trials show that angiotensin converting enzyme inhibitors produce a significant 7% relative risk reduction in mortality (P < 0.006), which corresponds to an absolute difference of about five fewer deaths per 1,000 patients treated. The benefits may be greater in higher-risk patients (e.g. those with previous myocardial infarction, heart failure or large infarcts). These results demonstrate that for a wide range of patients without clear contraindications, angiotensin converting enzyme inhibitors started early in acute myocardial infarction prevent further deaths in the first few weeks when added to standard therapy (aspirin, thrombolytic therapy and beta-blockers). The early benefits seen with ACE inhibitors seems to persist for at least the first year. The clinical implications of these results are discussed.
Angiotensin-Converting Enzyme Inhibitors↗
Adjunctive therapy for myocardial infarction.
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Adrenergic beta-Antagonists↗
Ten-year results of the randomized control trials of coronary artery bypass graft surgery: tabular data compiled by the collaborative effort of the original trial investigators. Part 2 of 2.
This metaanalysis has some important general implications for conducting studies to evaluate other treatments as well as for patient management. To avoid missing clinically important differences (eg, 15-20% differences in mortality at 5 years) between the methods of revascularization, study populations should be several times larger than those in our metaanalysis, should include a high proportion of the types of patients for whom surgery is known to be superior to medical therapy, and should be complemented by a systematic overview. We recommend that researchers running large randomized trials consider prospective collaboration with researchers from other trials with a common protocol.
Adult↗
Ten-year results of the randomized control trials of coronary artery bypass graft surgery: tabular data compiled by the collaborative effort of the original trial investigators. Part 1 of 2.
OBJECTIVE: To make available 10-year mortality data compiled and analyzed on patients with stable coronary heart disease (angina not severe enough to necessitate surgery) from all studies in which patients were randomized to initial coronary artery bypass graft (CABG) surgery or initial medical treatment and to determine whether the effects are influenced by the extent of coronary artery disease and degree of left-ventricular function. Data and analyses are presented in tabular form; text is published simultaneously in Lancet. METHODS: We collected individual patient data using standardized forms and, whenever possible, uniform definitions. We used Mantel-Haentel methods to combine data. Restricted means analyses were applied to quantify the extension in survival, and logistic regression analyses were applied to assess whether any baseline covariate affected the treatment differences. RESULTS: Of 2,649 patients, 1,324 were assigned to receive CABG surgery and 1,325 to the medical group. Mean age was 50.8 years; 98.8% were men. 93.7% of the CABG group underwent surgery. 25% of the medical group had undergone surgery at 5 years, 33% at 7 years, and 41% at 10 years. Initial CABG surgery reduced mortality significantly at 5 years (10.2% vs 15.8%; OR = 0.61; P < 0.001), 7 years (15.8% vs 21.7%; OR = 0.68; P < 0.001), and 10 years (26.4% vs 30.5%; OR = 0.83; P < 0.03). Risk reductions were most pronounced in patients with left-main disease compared to those with 3- or 1-2-vessel disease (at 5 years OR = 0.32, 0.58, and 0.77, respectively). CONCLUSIONS: Initial CABG surgery compared to initial medical management reduces mortality, especially in high- and medium-risk patients.
Adult↗
Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration.
We carried out a systematic overview using individual patient data from the seven randomised trials that have compared a strategy of initial coronary artery bypass graft (CABG) surgery with one of initial medical therapy to assess the effects on mortality in patients with stable coronary heart disease (stable angina not severe enough to necessitate surgery on grounds of symptoms alone, or myocardial infarction). 1324 patients were assigned CABG surgery and 1325 medical management between 1972 and 1984. The proportion of patients in the medical treatment group who had undergone CABG surgery was 25% at 5 years, 33% at 7 years, and 41% at 10 years: 93.7% of patients assigned to the surgery group underwent CABG surgery. The CABG group had significantly lower mortality than the medical treatment group at 5 years (10.2 vs 15.8%; odds ratio 0.61 [95% CI 0.48-0.77], p = 0.0001), 7 years (15.8 vs 21.7%; 0.68 [0.56-0.83], p < 0.001), and 10 years (26.4 vs 30.5%; 0.83 [0.70-0.98]; p = 0.03). The risk reduction was greater in patients with left main artery disease than in those with disease in three vessels or one or two vessels (odds ratios at 5 years 0.32, 0.58, and 0.77, respectively). Although relative risk reductions in subgroups defined by other baseline characteristics were similar, the absolute benefits of CABG surgery were most pronounced in patients in the highest risk categories. This effect was most evident when several prognostically important clinical and angiographic risk factors were integrated to stratify patients by risk levels and the extension of survival at 10 years was examined (change in survival -1.1 [SE 3.1] months in low-risk group, 5.0 [4.2] months in moderate-risk group, and 8.8 [5.4] months in high-risk group; p for trend < 0.003). A strategy of initial CABG surgery is associated with lower mortality than one of medical management with delayed surgery if necessary, especially in high-risk and medium-risk patients with stable coronary heart disease. In low-risk patients, the limited data show a non-significant trend towards greater mortality with CABG.
Adult↗
The impact of left ventricular dysfunction on outcomes with the implantable defibrillator.
Implanted cardioverter defibrillators (ICDs) are very effective in the treatment of life-threatening ventricular arrhythmias. Among patients with severe left ventricular (LV) dysfunction, ICDs can defibrillate at energies similar to those in patients with well-preserved LV function; the perioperative mortality rate with transvenous systems is low, even in patients with a low ejection fraction (EF). In patients whose EF is < 30%, sudden death and total mortality rates are relatively low. However, at most only 50% of deaths in patients with low EFs are sudden, and life in these patients may be only slightly prolonged by successful defibrillator shocks. The true value of ICDs in these patients can be determined only by comparison with optimal medical therapy in randomized controlled studies. The Canadian Implantable Defibrillator Study randomly assigns patients with ventricular fibrillation or ventricular tachycardia to ICD or amiodarone. Current patient profiles show that most of these patients have poor LV function (mean EF, 33.6%), and most receive optimal medical therapy. Results of this and other studies will clarify the benefits from ICDs in these patients with severe heart disease.
Anti-Arrhythmia Agents↗
Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction.
Although converting-enzyme inhibitors are useful for the treatment of congestive heart failure (CHF), there are concerns about adverse reactions especially on initiation of therapy. In the Studies of Left Ventricular Dysfunction, enalapril, 2.5 mg twice per day was given on an open-label outpatient basis for 7 days (mean 6.1, range 2 to 7, and median 7) as a prerandomization drug challenge to 7487 patients with left ventricular dysfunction (ejection fraction < or = 0.35). Four hundred forty-four (5.93%) patients reported side effects, including symptoms attributed to hypotension (in 166 patients [2.2%]). The majority (346 [77.9%] of 444 and 129 [77.7%] of 166 with symptoms attributed to hypotension) of patients who reported side effects were willing to participate in the study and to continue receiving enalapril. Thus only 98 (1.3%) of 7487 patients (0.5% because of symptoms attributed to hypotension) were not willing to continue because of side effects. Women and patients of CHF class III or IV were more likely to report side effects. In conclusion, enalapril is well tolerated by patients with left ventricular dysfunction; treatment can be initiated on an outpatient basis in the majority of patients.
Enalapril↗
Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril: the Studies of Left Ventricular Dysfunction. The SOLVD Investigators.
OBJECTIVES: This study was performed to assess the quality of life of patients with left ventricular dysfunction for up to 2 years after randomization to enalapril or placebo. BACKGROUND: Previous reports have documented that survival of patients with congestive heart failure can be extended by the angiotensin-converting enzyme inhibitor enalapril. However, it is unknown whether enalapril has a long-term favorable impact on the quality of life in patients with heart failure. METHODS: A brief quality of life questionnaire assessing the quality of life was administered at baseline and at 6 weeks, 1 year and 2 years of follow-up to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). Participants had an ejection fraction < or = 0.35, no other serious illnesses and either symptomatic heart failure (treatment trial, n = 2,465) or asymptomatic left ventricular dysfunction (prevention trial, n = 2,560). RESULTS: Among the 14 scales of quality of life, better scores at one or more follow-up intervals were noted in 6 scales in the treatment trial and in 1 scale in the prevention trial among patients assigned to enalapril. Consistent superiority with enalapril at two consecutive follow-up intervals was noted in the treatment trial for social functioning and dyspnea but for no scale in the prevention trial. However, an average of 40% of quality of life responses were missing at 2 years of follow-up because of death or failure to complete the questionnaire. In the treatment trial, survivors with more severe heart failure were less likely to complete the questionnaire. CONCLUSIONS: Modest benefits in quality of life for > or = 1 year occurred when patients with left ventricular dysfunction and symptomatic heart failure were treated with enalapril. No apparent beneficial or adverse effect on quality of life was observed with enalapril in asymptomatic patients with left ventricular dysfunction.
Activities of Daily Living↗
Role of angiotensin converting enzyme inhibitors in patients with left ventricular dysfunction and congestive heart failure.
We now have conclusive data that ACE inhibitors reduce mortality, morbidity, and symptoms in patients with low ejection fraction and/or heart failure. Therefore, ACE inhibitors should be routinely used in all such patients, as long as there are no clear contraindications. Routine use of ACE inhibitors will lead to prolongation of survival and a reduction in the number of hospitalizations for heart failure and ischaemic events. The reduction in costs associated with the prevention of these events is likely substantially to offset the cost of the use of these therapies. Therefore, ACE inhibitors should be instituted as early as possible in patients with LV dysfunction.
Angiotensin-Converting Enzyme Inhibitors↗