John B. Kostis

Effect of Enalapril On Myocardial-infarction and Unstable Angina in Patients With Low Ejection Fractions

An association between raised renin levels and myocardial infarction has been reported. We studied the effects of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, on the development of myocardial infarction and unstable angina in 6797 patients with ejection fractions < or = 0.35 enrolled into the two Studies of Left Ventricular Dysfunction (SOLVD) trials. Patients were randomly assigned to placebo (n = 3401) or enalapril (n = 3396) at doses of 2.5-20 mg per day in two concurrent double-blind trials with the same protocol. Patients with heart failure entered the treatment trial (n = 2569) and those without heart failure entered the prevention trial (n = 4228). Follow-up averaged 40 months. In each trial there were significant reductions in the number of patients developing myocardial infarction (treatment trial: 158 placebo vs 127 enalapril, p < 0.02; prevention trial: 204 vs 161 p < 0.01) or unstable angina (240 vs 187 p < 0.001; 355 vs 312, p < 0.05). Combined, there were 362 placebo group patients with myocardial infarction compared with 288 in the enalapril group (risk reduction 23%, 95% CI 11-34%; p < 0.001). 595 placebo group patients developed unstable angina compared with 499 in the enalapril group (risk reduction 20%, 95% CI 9-29%, p < 0.001). There was also a reduction in cardiac deaths (711 placebo, 615 enalapril; p < 0.003), so that the reduction in the combined endpoint of deaths, myocardial infarction, and unstable angina was highly significant (20% risk reduction, 95% CI 14-26%; p < 0.0001). Enalapril treatment significantly reduced myocardial infarction, unstable angina, and cardiac mortality in patients with low ejection fractions.

Diabetes mellitus, a predictor of morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD) trials and registry

Diabetes is an independent predictor of morbidity and mortality in patients with symptomatic heart failure, patients with asymptomatic left ventricular dysfunction (defined as an ejection fraction of 35% or less), and in a broader registry population with less stringent entry criteria. Although the SOLVD Trials made a major clinical contribution by proving the value of enalapril, diabetes remains a significant predictor of outcome even after adjusting for treatment with enalapril.

Baseline Quality of Life as a Predictor of Mortality and Hospitalization in 5,025 Patients With Congestive Heart Failure

This study examined the independent relation of health-related quality of life (HRQL) to mortality and congestive heart failure (CHF)-related hospitalizations in patients with an ejection fraction of < 0.35 followed for a mean of 36.5 months. A brief HRQL questionnaire was administered at baseline to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) trial. Participants had an ejection fraction of < 0.35 and either symptomatic CHF (treatment trial, n = 2,465) or asymptomatic CHF (prevention trial, n = 2,560). Baseline assessment of HRQL predicted mortality and CHF-related hospitalizations in symptomatic and asymptomatic patients randomized to enalapril and placebo treatment. Domains that were the stronger univariate predictors of mortality and CHF-related hospitalizations were activities of daily living (relative risk [RR] for mortality: 1.163, p < 0.000; for hospitalization: 1.215, p < 0.000), general health (RR for mortality: 1.205, p < 0.000; for hospitalization: 1.188, p < 0.000), and social functioning (RR for mortality 1.098, p < 0.000; for hospitalization: RR 1.156, p < 0.000). In the multivariate model, activities of daily living (RR for mortality 1.41, p < 0.000; for hospitalization: RR 1.43, p < 0.002), general health (RR for mortality 1.21, p < 0.000; for hospitalization RR 1.16, p < 0.013) and heart failure symptoms (RR for mortality 1.02, p < 0.025; for hospitalization RR 1.03, p < 0.004) were found to be independent risk factors. HRQL independently predicted mortality and CHF-related hospitalizations after adjustment for ejection fraction, age, treatment, and New York Heart Association classification in patients with an ejection fraction of < 0.35, randomized to enalapril and placebo treatment. HRQL provides additional clinical information regarding disease course and outcome that is not captured by traditional indexes of clinical status.

Delay in Presentation and Evaluation for Acute Stroke Stroke Time Registry for Outcomes Knowledge and Epidemiology (S.T.R.O.K.E.)

Background and Purpose—Early treatment is a critical determinant of successful intervention in acute stroke. The study was designed to find current patterns of stroke care by determining delays in time from onset of signs or symptoms to arrival at the emergency department and to initial evaluation by physicians and by identifying factors associated with these delays. Methods—Data were prospectively collected by nurses and physicians from patients, patients’ family members, and medical records from 10 hospitals of the Robert Wood Johnson Health System in New Jersey. Results—A total of 553 patients who presented with signs or symptoms of acute stroke were studied. Thirty-two percent of patients arrived at the emergency department within 1.5 hours of stroke onset. Forty-six percent of patients arrived within 3 hours and 61% within 6 hours. Delays in arrival time were significantly associated with sex, race, transportation mode, and history of cardiovascular disease. Patients arriving by ambulance were more l...

Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial

IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206062.

Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group.

CONTEXT Heart failure is often preceded by isolated systolic hypertension, but the effectiveness of antihypertensive treatment in preventing heart failure is not known. OBJECTIVE To assess the effect of diuretic-based antihypertensive stepped-care treatment on the occurrence of heart failure in older persons with isolated systolic hypertension. DESIGN Analysis of data from a multicenter, randomized, double-blind, placebo-controlled clinical trial. PARTICIPANTS A total of 4736 persons aged 60 years and older with systolic blood pressure between 160 and 219 mm Hg and diastolic blood pressure below 90 mm Hg who participated in the Systolic Hypertension in the Elderly Program (SHEP). INTERVENTION Stepped-care antihypertensive drug therapy, in which the step 1 drug is chlorthalidone (12.5-25 mg) or matching placebo, and the step 2 drug is atenolol (25-50 mg) or matching placebo. MAIN OUTCOME MEASURES Fatal and nonfatal heart failure. RESULTS During an average of 4.5 years of follow-up, fatal or nonfatal heart failure occurred in 55 of 2365 patients randomized to active therapy and 105 of the 2371 patients randomized to placebo (relative risk [RR], 0.51; 95% confidence interval [CI], 0.37-0.71; P<.001; number needed to treat to prevent 1 event [NNT], 48). Among patients with a history of or electrocardiographic evidence of prior myocardial infarction (MI), the RR was 0.19 (95% CI, 0.06-0.53; P=.002; NNT, 15). Older patients, men, and those with higher systolic blood pressure or a history of or electrocardiographic evidence of MI at baseline had higher risk of developing heart failure. CONCLUSION In older persons with isolated systolic hypertension, stepped-care treatment based on low-dose chlorthalidone exerted a strong protective effect in preventing heart failure. Among patients with prior MI, an 80% risk reduction was observed.

J-curve revisited: an analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial

AIM In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. METHODS AND RESULTS We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. CONCLUSION In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke).

Sex differences in the management and long-term outcome of acute myocardial infarction. A statewide study. MIDAS Study Group. Myocardial Infarction Data Acquisition System.

BACKGROUND We wished to evaluate whether differences in the rate of invasive cardiac procedures between men and women with acute myocardial infarction are associated with different short- and long-term mortality. METHODS AND RESULTS The database (Myocardial Infarction Data Acquisition System, MIDAS) included all discharges for the years 1986 and 1987 with the diagnosis of acute myocardial infarction in New Jersey, based on the New Jersey hospital discharge data system (MIDS/UB-82). Accuracy of the data was evaluated by auditing 726 randomly selected charts. The variables examined included age, sex, race, comorbidity (anemia, chronic liver disease, cancer, chronic obstructive pulmonary disease, diabetes, hypertension, prior myocardial infarction), complications (left ventricular dysfunction, arrhythmias, conduction defects), insurance status, performance of cardiac catheterization, percutaneous transluminal coronary angioplasty, or coronary artery bypass graft surgery, and survival up to 3 years. Women were older, had longer hospital stay, and were more likely than men to have anemia, diabetes, hypertension, left ventricular dysfunction, and Medicare or Medicaid insurance coverage. They were less likely than men to be admitted to a hospital equipped to perform invasive procedures or to have chronic obstructive pulmonary disease, chronic liver disease, prior myocardial infarction, or arrhythmias. After adjustment for these differences, women were less likely than men to have cardiac catheterization. Cardiac catheterization was associated with lower mortality. Women up to age 70 had higher 3-year death rates than men after adjustment for age, race, comorbidity, complications, and insurance type. This difference between men and women was somewhat diminished after the performance of cardiac catheterization and revascularization was taken into account. Unadjusted mortality was high in this study group. CONCLUSIONS Women with acute myocardial infarction are less likely to have invasive cardiac procedures and have higher 3-year adjusted death rate up to age 70 than men.

The Princeton III Consensus Recommendations for the Management of Erectile Dysfunction and Cardiovascular Disease

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. The third Princeton Consensus met November 8 to 10, 2010, and had 2 primary objectives. The first objective focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic work-up. The second objective focused on reevaluation and modification of previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD. The Panels recommendations build on those developed during the first and second Princeton Consensus Conferences, first emphasizing the use of exercise ability and stress testing to ensure that each mans cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED, and second highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.

Prognostic significance of ventricular ectopic activity in survivors of acute myocardial infarction

Twenty-four hour ambulatory electrocardiography was performed on 3,290 survivors of acute myocardial infarction participating in the Beta-Blocker Heart Attack Trial (BHAT). History of myocardial infarction before the qualifying event, congestive heart failure and age were independently associated with the frequency and complexity of ventricular premature beats. Of the 1,640 patients randomized to placebo therapy, 163 died (76 suffered sudden death) during a 25 month average follow-up period. Ventricular ectopic activity was an independent predictor of total mortality after taking into consideration 16 other prognostic factors describing past history, risk factors, physical examination and laboratory investigations. Seven categoric definitions of ventricular ectopic activity predicted mortality, with similar odds ratios ranging from 2.27 to 2.69. A reciprocal relation of the sensitivity and specificity of each definition in predicting mortality was observed. Three clinical criteria (ST depression, cardiomegaly and prior infarction) allowed stratification of patients into four subsets with respective mortality rates of 35.5% (three criteria present), 19.0% (two criteria), 11.5% (one criterion) and 4.7% (none). Presence of ventricular ectopic activity (greater than or equal to 10 ventricular premature beats/h or pairs, ventricular tachycardia or multiform complexes) was associated with higher mortality rates in all four risk strata. The relative risk was higher (3.86) in the lowest risk stratum (mortality 2.4% without and 9.1% with ventricular ectopic activity). Thus, in survivors of acute myocardial infarction, ventricular ectopic activity was more pronounced in patients with prior myocardial infarction and congestive heart failure. It predicted mortality independently of other factors. Although mortality ratios were similar for all seven arrhythmia definitions, a reciprocal relation between sensitivity and specificity of the definitions in predicting mortality existed; ventricular ectopic activity was associated with increased mortality in all risk strata, but with a higher risk ratio in the numerically larger, low risk subset.