Clifton R. Lacy

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...

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.

Coronary vasoconstriction induced by mental stress (simulated public speaking)

Abstract The present study demonstrates that potent mental stress, such as that produced in response to the simulated public speaking task, results in an increase in heart rate and blood pressure, and vasoconstriction of normal coronary artery segments in patients with and without angiographically demonstrable coronary artery disease.

Trial of Nonpharmacologic Intervention in the Elderly (TONE): Design and rationale of a blood pressure control trial☆

National and international policy-making organizations advocate nonpharmacologic therapies to reduce blood pressure (BP). However, data to support such recommendations in older persons are virtually nonexistent. The Trials of Nonpharmacologic Intervention in the Elderly (TONE) is a randomized, controlled trial that will test whether weight loss or a reduced sodium (Na) intake or both can maintain satisfactory BP control, without unacceptable side effects, after withdrawal of antihypertensive drug therapy. Medication-treated hypertensives (aged 60 to 80 years) with a systolic BP less than 145 mm Hg and a diastolic BP less than 85 mm Hg who are taking one antihypertensive medication are randomly assigned to one of four groups: (1) weight loss alone, (2) reduced Na intake alone, (3) combined weight loss and reduced Na intake, or (4) usual life-style (control group). Overweight participants are randomized to one of these four groups, while nonoverweight individuals are assigned to either the reduced Na intake or the usual life-style group. The interventions, tailored to the needs of older persons, use behavioral approaches to accomplish intervention-specific goals (weight loss > or = 10 lb, daily Na intake < or = 80 mEqa). Three months after the start of intervention, antihypertensive drug therapy is withdrawn. The primary trial end point is a BP of 150/90 mm Hg or higher, resumption of antihypertensive drug therapy, or the occurrence of a BP-related clinical complication during 2 to 3 years of follow-up. It is anticipated that TONE findings may identify an effective and acceptable nonpharmacologic approach to control hypertension in the increasingly large number of older persons treated with antihypertensive drug therapy.

Recruitment in the Trial of Nonpharmacologic Intervention in the Elderly (TONE)

OBJECTIVE: To compare the effectiveness of different approaches to participant enrollment in a behavior modification trial.

The relationship of plasma renin activity to clinic and ambulatory blood pressure in elderly people with isolated systolic hypertension

Eighty-one untreated elderly patients with clinic-defined isolated systolic hypertension (ISH) and 39 normotensive elderly subjects underwent 24-h ambulatory blood pressure monitoring. Before the ambulatory blood pressure monitoring, EDTA-anticoagulated venous blood was obtained from seated subjects for determination of plasma renin activity. Ambulatory blood pressure and heart rates were determined at 15–30-min intervals by a validated, portable non-invasive technique (Spacelabs 5200). Ambulatory blood pressure variability was defined for each subject as the standard deviation and the coefficient of variation of the ambulatory blood pressure. The mean awake systolic blood pressure was much lower than the clinic-determined value in the ISH group (P < 0.001), but only slightly so in the normotensive group. Forty-two per cent of the clinic-defined ISH group had mean awake ambulatory systolic blood pressures below the 90th percentile of the normotensive group. A discrepancy between office and ambulatory blood pressures was not associated with blood pressure variability, heart rate or plasma renin activity.

Association of calcium channel blocker use with increased rate of acute myocardial infarction in patients with left ventricular dysfunction

The Studies of Left Ventricular Dysfunction (SOLVD) assessed the effect of enalapril in patients with systolic left ventricular dysfunction (LVD). We performed retrospective analyses of the association between calcium channel blocker (CCB) use and fatal and nonfatal myocardial infarction (MI) in these patients. MI occurred in 11.5% of 845 patients receiving CCBs versus 7.5% of 2551 patients not receiving CCBs in the enalapril group and in 14.4% of 874 patients receiving CCBs versus 9.3% of 2527 patients not receiving CCBs in the placebo group. By multivariate Cox regression analysis, adjusting for comorbidity, cause and severity of LVD, heart failure, and concomitant drug use, CCB use was an independent predictor of MI (relative risk [RR] 1.37, confidence interval [CI] 1.14 to 1.63). The increase in MI risk was greater among patients with a higher heart rate (RR 1.46, CI 1.14 to 1.86) and lower blood pressure (RR 1.45, CI 1.14 to 1.86). The adjusted risk ratio for all-cause mortality associated with CCB use was 1.14 (CI 1.00 to 1.28; p = 0.0454). In this analysis of patients with LVD, CCB use was associated with significantly increased risk of fatal or nonfatal MI.

Angiotensin-Converting Enzyme Inhibitors: A Comparative Review

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensin-converting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention. The ACE inhibitors, therefore, are capable of lowering blood pressure primarily by promoting vasodilitation and reducing intravascular fluid volume. Captopril, the first orally active, commercially available ACE inhibitor, is a sulfhydryl-containing compound. Captopril was followed by the introduction of enalapril and lisinopril, two non-sulfhydryl ACE inhibitors. The pharmacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively short duration of action, whereas enalapril and lisinopril have slower onset and relatively long duration of action. Captopril is an active ACE inhibitor in its orally absorbable parent form. In contrast, enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of activity. Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces. Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remaining parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension. In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure, and pulmonary artery pressure. These drugs may produce improvement in cardiac output and stroke volume and, with chronic administration, may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefit as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status. Although only captopril and enalapril are currently approved by the Food and Drug Administration for the treatment of CHF, early data with lisinopril suggest beneficial effects comparable to those of captopril. Several unapproved, experimental uses for ACE inhibitors have recently been reported and include treatment of proteinuria, scleroderma renal crisis, idiopathic edema, Raynauds syndrome, and hypertensive emergency. The ACE inhibitors as a group are generally effective and well tolerated in most patients, although the adverse effect profile may vary somewhat among individual agents.

Time trends in the occurrence and outcome of acute myocardial infarction and coronary heart disease death between 1986 and 1996 (a New Jersey statewide study)

Most reports of the decrease in age-adjusted coronary heart disease (CHD) are based on databases with upper age cut-offs that exclude approximately half of the events. We report changes in rates of acute myocardial infarction (AMI) and of out-of-hospital coronary death between 1986 and 1996 among New Jersey residents > or =15 years old. Data on patients discharged with the diagnosis of AMI from nonfederal acute care hospitals in the state (n = 270,091) and all records in the New Jersey death registration files with CHD (n = 172,175) listed as the cause of death from 1986 to 1996 (total study n = 442,266) were analyzed. The rate of hospitalized AMI cases in the state remained essentially unchanged during these 11 years, whereas in-hospital and 30-day case fatality among all age groups and both sexes declined. Age-adjusted CHD rates showed a decrease in fatal events, a smaller decrease in total events, and a slight increase in nonfatal events. The proportion of fatal CHD events occurring out-of-hospital decreased especially among men. The median age at occurrence of events increased by 1 year. Despite a decrease in CHD mortality, the rate of nonfatal events increased, especially among persons > or =75 years old. Thus, the decrease in age-adjusted CHD mortality is not all due to treatment and true prevention of CHD, but the disease simply occurs at an older age.

DPI 201-106 for severe congestive heart failure

DPI 201-106 is a new oral inotropic agent that exerts its effects through a novel mechanism of action, namely, by enhancing sensitivity of myofilaments to calcium and prolonging inward sodium current. In a double-blind, randomized, placebo-controlled fashion, single oral doses (80 and 100 mg) of DPI 201-106 were administered to 15 patients with severe congestive heart failure. Dose-dependent increases in cardiac index (25%, p = 0.016), left ventricular stroke work index (24%, p = 0.018), left ventricular stroke volume index (32%,p = 0.005) and QTc interval (7%, p = 0.009) were observed. Significant effects on heart rate and systemic arterial pressure were not observed. Positive correlations of QTc interval with DPI plasma level (r = 0.64, p = 0.0001), stroke work index (r = 0.47, p = 0.0001) and ventricular ectopic activity on ambulatory electrocardiography (r = 0.49, p = 0.0001) were observed. Maximum changes occurred approximately 3 to 4 hours after ingestion and lasted more than 8 hours. Plasma drug levels were consistent with a 2-compartment model exhibiting first-order absorption and elimination kinetics. DPI 201-106 produced hemodynamic improvement in patients with severe congestive heart failure.