Biomedical subjects
Publications and source records attributed to S Yusuf.
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BACKGROUND: Chronic heart failure (CHF) is an increasing burden to health care. Pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors and beta blockers improve survival and reduce hospitalizations in patients with low left ventricular ejection fraction (LVEF). Despite these therapies, morbidity and mortality remains problematic. Furthermore, 30% to 50% of patients with CHF have a preserved LVEF. It is not known if treatments are of benefit in this group. DESIGN: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) is a program designed to investigate the clinical usefulness of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in a broad spectrum of patients with symptomatic heart failure. Patients with systolic dysfunction, tolerant or intolerant to an ACE-inhibitor, and patients with preserved systolic function are included. Specifically, the CHARM program consists of 3 independent, parallel, placebo-controlled studies in patients with (1) LVEF less than or equal to 40%, ACE-inhibitor treated (n = 2,300); (2) LVEF less than or equal to 40%, ACE-inhibitor intolerant (n = 1,700); (3) LVEF greater than 40%, not treated with ACE inhibitors (n = 2,500). The 3 studies will be combined to evaluate the effect of candesartan cilexetil on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization. Other endpoints include the effects on myocardial infarction, all-cause hospitalization, and resource utilization. CHARM is intended to randomize 6,500 patients with symptomatic heart failure from 26 countries in Europe, the United States, Canada, South Africa, and Australia. The CHARM program started to enroll patients in March 1999. The follow-up period is a minimum of 2 years. The study is expected to end in the third quarter of 2002.
AIMS: The reported prevalence of angiotensin-converting enzyme (ACE) inhibitor use in patients with heart failure varies considerably. Recent reports suggest that many patients who could benefit from such therapy are not receiving ACE inhibitors. The Study of Patients Intolerant of Converting Enzyme Inhibitors (SPICE) Registry was established to understand better the demographics, characteristics, and contemporary use of ACE inhibitors in an international registry. METHODS AND RESULTS: Between August 1996 and April 1997, each of 105 study centres from eight countries in North America and Europe was invited to review retrospectively the medical records of 100 consecutive patients with left ventricular ejection fractions </=35%. The median age of the 9580 Registry patients was 66 years, 26% were women, the median ejection fraction was 27%, and the primary aetiology of left ventricular dysfunction was ischaemic (63%). Eighty percent of patients were receiving ACE inhibitors. The most common reason for non-use of ACE inhibitors was intolerance (9%). CONCLUSION: The SPICE Registry provides a contemporary description of the demographics and management of patients with documented left ventricular systolic dysfunction. The contemporary use of ACE inhibitors (80%) appears to be higher than previously reported and the main reason for non-use is perceived intolerance (9%).
Over the past 200 years, digoxin has been commonly used to treat patients with congestive heart failure. Clinical trials have demonstrated the benefits of the use of digoxin on exercise tolerance, ejection fraction, and neurohormone production. The Digoxin Investigators Group trial has recently provided strong evidence for the long-term benefits of digoxin on morbidity for patients with heart failure. This article will review the evidence of the benefits of digoxin and its current role in the treatment of patients with congestive heart failure.
OBJECTIVE: To assess the relationship between nondiabetic glucose levels and cardio vascular risk. RESEARCH DESIGN AND METHODS: Three independent searches using MEDLINE (1966-1996), followed by a manual search of the references from each retrieved article, were conducted by two physicians and one medical librarian. Data had to be reported in at least three quantiles or intervals so that the nature of the relationship between glucose and cardiovascular events (i.e., linear or nonlinear) could be explored, and to ensure that any incremental cardiovascular risk was consistent across quantiles or intervals. RESULTS: Analyzed studies comprised 95,783 people (94% male) who had 3,707 cardiovascular events over 12.4 years (1,193,231 person-years). Studies reporting fasting glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5), and casual glucose levels (n = 4) were included. The glucose load used varied from 50 to 100 g. The highest glucose interval for most studies included glucose values in the diabetic range. The relationship between glucose levels and the risk of a cardiovascular event was modeled for each study and the beta-coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75 mg/dl), a fasting and 2-h glucose level of 6.1 mmol/dl (110 mg/dl) and 7.8 mmol/l (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95% CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively. CONCLUSIONS: The progressive relationship between glucose levels and cardiovascular risk extends below the diabetic threshold.
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BACKGROUND: Patients with peripheral vascular disease (PVD) have a three-fold increased risk of myocardial infarction, stroke and death. Recently, a number of therapies have been demonstrated to prevent morbidity or mortality in patients with PVD or other arterial disease. Given the scarcity of data on the preventive practice patterns of this high risk patient group, the in-hospital management of patients admitted to hospital for a peripheral vascular intervention was reviewed. PATIENTS AND METHODS: Charts of 195 patients with a diagnosis of peripheral arteriosclerotic disease (International Classification of Diseases, 9th revision, code 440.2) who were hospitalized at a tertiary care hospital in Ontario between June 1996 and June 1998 were reviewed. RESULTS: The average age of patients admitted was 70.6 years, and 39% of patients were women. The main reason for admission was peripheral artery bypass graft surgery in 88% (172 of 195). Fifty-four per cent (106 of 195) of patients had clinically apparent coronary or cerebrovascular disease, and 92% (180 of 195) of patients had at least one cardiovascular disease risk factor. Fewer than half of all patients (49%) were discharged on any antithrombotic therapy (antiplatelet agent or anticoagulant), and a small proportion of patients were treated with a beta-blocker (20%) and cholesterol-lowering medications (16%). CONCLUSIONS: The leading cause of morbidity and mortality in PVD patients is coronary and cerebrovascular disease. Despite this, the use of proven antithrombotic agents and other cardiac medications is suboptimal. Health professionals need to be aware of the high risk nature of the PVD population and to develop strategies to ensure that patient care is optimized.
AIM: To study the efficacy and safety of drug or therapy with recurrent events in meta-analysis of multiple clinical trials. METHODS: A nonparametric approach is proposed to estimate the rates of recurrent events for meta-analysis of trials. The method was used in meta-analysis of angiotensin-converting enzyme (ACE) inhibitor clinical trials to analyze the relative rates and the excess rates between ACE inhibitor and placebo treatment groups for endpoints of hospitalizations for CHF, hospitalizations for CHF or cardiac death, and hospitalizations for CHF or any death, respectively. RESULTS: The estimates of those three endpoints were 69%, 74%, and 76% (P < 0.01). Compared with placebo, ACE inhibitor reduced 30 cases of hospitalizations for CHF per 1000 person-years, or 40 cardiac deaths or hospitalizations for CHF per 1000 person-years (P < 0.01). CONCLUSION: The method was a simple and efficient approach to conduct meta-analysis of clinical trials with recurrent events.
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BACKGROUND: Patients with acute ischemic syndromes (AIS) suffer high rates of recurrent ischemic events despite aspirin treatment. Long-term therapy with oral anticoagulants in addition to aspirin may reduce this risk. We studied the effects of long-term warfarin at 2 intensities in patients with AIS without ST elevation in 2 consecutive randomized controlled studies. METHODS AND RESULTS: In phase 1, after the cessation of 3 days of intravenous antithrombotic therapy, 309 patients were randomized to receive fixed low-dose (3 mg/d) warfarin for 6 months that produced a mean international normalized ratio (INR) of 1.5+/-0.6 or to standard therapy. Eighty-seven percent of patients received aspirin in both groups. The rates of cardiovascular (CV) death, new myocardial infarction (MI), and refractory angina at 6 months were 6.5% in the warfarin group and 3.9% in the standard therapy group (relative risk [RR], 1. 66; 95% CI, 0.62 to 4.44; P=0.31). The rates of death, new MI, and stroke were 6.5% in the warfarin group and 2.6% in the standard therapy group (RR, 2.48; 95% CI, 0.80 to 7.75; P=0.10). The overall rate of rehospitalization for unstable angina was 21% and did not differ significantly between the groups. Four patients in the warfarin group (2.6%) and none in the control group experienced a major bleed (RR, 2.48; 95% CI, 0.80 to 7.75), and there was a significant excess of minor bleeds in the warfarin group (14.2% versus 2.6%; RR, 5.46; 95% CI, 1.93 to 15.5; P=0.001). In phase 2, the protocol was modified, and 197 patients were randomized <48 hours from the onset of symptoms to receive warfarin at an adjusted dose that produced a mean INR of 2.3+/-0.6 or standard therapy for 3 months. Eighty-five percent received aspirin in both groups. The rates of CV death, new MI, and refractory angina at 3 months were 5. 1% in the warfarin group and 12.1% in the standard group (RR, 0.42; 95% CI, 0.15 to 1.15; P=0.08). The rates of all death, new MI, and stroke were 5.1% in the warfarin group and 13.1% in the standard therapy group (RR, 0.39; 95% CI, 0.14 to 1.05; P=0.05). Significantly fewer patients were rehospitalized for unstable angina in the warfarin group than in the control group (7.1% and 17.2%, respectively; RR, 0.42; 95% CI, 0.18 to 0.96; P=0.03). Two patients in the warfarin group and 1 in the control group experienced a major bleed, and there was a significant excess of minor bleeds in the warfarin group (28.6% versus 12.1%; RR, 2.36; 95% CI, 1.37 to 4.36; P=0.004). CONCLUSIONS: Long-term treatment with moderate-intensity warfarin (INR, 2.0 to 2.5) plus aspirin but not low-intensity warfarin (INR, 1.5) plus aspirin appears to reduce the rate of recurrent ischemic events in patients with AIS without ST elevation.
BACKGROUND: There are wide variations between countries in the use of invasive cardiac catheterisation and revascularisation procedures for patients with acute ischaemic syndromes. We studied the relation between rates of such procedures and rates of cardiovascular death, myocardial infarction, stroke, refractory angina, and major bleeding in a prospective, registry-based study in six countries with widely varying intervention rates. METHODS: 7987 consecutive patients presenting with unstable angina or suspected myocardial infarction without ST-segment elevation were recruited prospectively from 95 hospitals in six countries and followed up for 6 months. FINDINGS: The rates of all procedures were highest in patients in Brazil and the USA, intermediate in Canada and Australia, and lowest in Hungary and Poland. There were no significant differences in rates of cardiovascular death or myocardial infarction among these countries (4.7% overall [range 3.7-5.6] at 7 days; 11% overall [9-12] at 6 months). For the countries with the highest rates of invasive procedures (59%) versus the rest (21%) there was no difference in rate of cardiovascular death or myocardial infarction (adjusted odds ratio 0.88 at 7 days and 1.0 at 6 months). Rates of stroke were higher in Brazil and the USA than in the countries with lower intervention rates (adjusted odds ratio at 7 days 3.0, p=0.012; at 6 months 1.8, p=0.004) but rates of refractory angina at 7 days (0.7, p<0.001) and readmission for unstable angina at 6 months were lower (0.70, 0.63; both p<0.001). Comparison of results for hospitals without cardiac-catheterisation facilities and for those with such facilities gave adjusted odds ratios for cardiovascular death, myocardial infarction, or stroke at 6 months of 0.83 (10.6% vs 12.5%, p=0.05) and for refractory angina of 1.25 (19.3% vs 16.1%, p=0.09). INTERPRETATION: Higher rates of invasive and revascularisation procedures were associated with lower rates of refractory angina or readmission for unstable angina, no apparent reduction in cardiovascular death or myocardial infarction, but with higher rates of stroke. Randomised trials should assess the relative impact of conservative and more aggressive approaches to invasive cardiac procedures and revascularisations in patients with unstable angina.
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For a meta-analysis to give definitive information, it should meet at least the minimum standards that would be expected of a well-designed, adequately powered, and carefully conducted randomised controlled trial. These minimum standards include both qualitative characteristics--a prospective protocol, comparable definitions of key outcomes, quality control of data, and inclusion of all patients from all trials in the final analysis--and quantitative standards--an assessment of whether the total sample is large enough to provide reliable results and the use of appropriate statistical monitoring guidelines to indicate when the results of the accumulating data of a meta-analysis are conclusive. We believe that rigorous meta-analyses undertaken according to these principles will lead to more reliable evidence about the efficacy and safety of interventions than either retrospective meta-analysis or individual trials.
This report demonstrates that South Asians living in North America have elevated levels of Lp(a) compared with North American whites. Elevated Lp(a) levels may account, in part, for the tendency of South Asians to develop premature coronary heart disease (CHD).
BACKGROUND: The determinants of exercise performance are multifactorial and incompletely understood in patients with symptomatic left ventricular (LV) dysfunction, with much less information regarding asymptomatic LV dysfunction. This study assessed the hemodynamics and neurohormonal factors influencing exercise performance in patients with LV ejection fractions > or =0.35, both symptomatic and asymptomatic, enrolled in Studies of LV Dysfunction. METHODS AND RESULTS: We studied 103 patients enrolled prospectively in Studies of LV Dysfunction before randomized therapy; 38 were symptomatic and 65 had no or minimal symptoms. By using rest-exercise gated equilibrium radionuclide ventriculography and cuff blood pressure, we assessed the heart rate, LV and right ventricular (RV) volumes and ejection fractions, total peripheral resistance, the LV peak systolic pressure/end systolic volume ratio as an index of contractility, and plasma renin and norepinephrine at rest and during maximal graded supine bicycle ergometer exercise. Changes between rest and exercise were evaluated as indices of cardiovascular reserve. The cumulative workload ranged from 120 to 2,100 watt-min. At rest, the LV ejection fraction was 0.30 in asymptomatic patients and 0.25 in symptomatic patients, respectively (P < .0004). During exercise, asymptomatic patients had greater increases in heart rate, systolic blood pressure, LV ejection fraction, and cardiac output than symptomatic patients (P > or = .05). Combining all patients, the strongest univariate correlates of exercise workload were the ability to increase heart rate (r = 0.70), the pressure/volume ratio (r = 0.63), and systolic blood pressure (r = 0.55), and to decrease the total peripheral resistance (r = -0.47) with moderate correlations for the ability to increase LV and RV ejection fractions (r = 0.33 and 0.35, respectively) (P < .0008). By multivariate analysis, workload was modeled best by the changes in four factors: heart rate, systolic blood pressure, and the LV and RV ejection fractions (R2 = 0.54, P < .001). CONCLUSION: Exercise performance and its hemodynamics differed in patients with symptomatic and asymptomatic LV dysfunction. Rather than features at rest, the reserve capacities for increasing heart rate, systolic blood pressure, and the LV and RV ejection fractions were the predominant cardiac mechanisms related to greater exercise performance.
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