Efficacy and safety of cerivastatin and pravastatin in the treatment of primary hypercholesterolemia.

In this randomized, double-blind, parallel group study, the efficacy and safety of cerivastatin (0.3 mg) and pravastatin (20 mg) were compared in 402 patients with primary hypercholesterolemia with and without documented coronary heart disease or peripheral vascular disease. After 8 weeks of treatment, cerivastatin provided significantly greater reductions than pravastatin in low-density lipoprotein (LDL)-cholesterol (31.1% vs. 26.0%; p < 0.0001) and total cholesterol (21.1% vs. 17.8%; p < 0.0001). A greater proportion of patients treated with cerivastatin than pravastatin achieved > 30% and > 40% reductions from baseline in LDL-cholesterol. Both agents also increased high density lipoprotein-cholesterol and reduced triglycerides. Overall, 65.1% of patients treated with cerivastatin and 63.3% of patients with pravastatin achieved LDL-cholesterol goals defined by the National Cholesterol Education Program. Both drugs were well tolerated, with most adverse events being mild. These results demonstrate that cerivastatin (0.3 mg) is a highly effective 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, which enables a large proportion of patients to achieve clinically meaningful reductions in LDL-cholesterol.

A study of the efficacy and safety of irbesartan in combination with conventional therapy, including ACE inhibitors, in heart failure. Irbesartan Heart Failure Group.

Because heart failure therapy with angiotensin-converting enzyme (ACE) inhibitors may not be optimal, owing to persistent levels of angiotensin II occurring through incomplete blockade and alternate pathways, the benefit of adding irbesartan, an angiotensin receptor antagonist, to conventional therapy, including ACE inhibitors, was examined. In this multicentre, randomised, double-blind, placebo-controlled study, 109 patients with heart failure (New York Heart Association functional class II and III) and left ventricular ejection fraction (LVEF) < or = 40% received stable doses of ACE inhibitors and diuretics before and throughout the study. Irbesartan was titrated as tolerated to 150 mg once daily in all patients. Exercise tolerance time (ETT), LVEF and clinical status were assessed at baseline and after 12 weeks. Compared with placebo, irbesartan in combination with conventional therapy, including ACE inhibitors, produced favourable trends in ETT and LVEF and was well tolerated in patients with mild to moderate heart failure.

Comparative effects of candesartan cilexetil and losartan in patients with systemic hypertension. Candesartan Versus Losartan Efficacy Comparison (CANDLE) Study Group.

The antihypertensive efficacy and tolerability of the novel angiotensin-II (A-II) receptor blocker candesartan cilexetil and the prototype A-II receptor blocker, losartan, were compared in an 8-week, multicenter, double-blind, randomized, parallel-group, titration-to-effect study of 332 adults (42% women, 12% black) with systemic hypertension (sitting diastolic blood pressure [DBP] 95-114 mmHg, inclusive). In patients with a mean trough (24 +/- 3 hours after dose) sitting DBP of 90 mmHg or higher after 4 weeks of once daily administration of candesartan 16 mg or losartan 50 mg, dose was titrated up to candesartan 32 mg or losartan 100 mg once daily. The candesartan regimen was significantly more effective than the losartan regimen in reducing trough sitting DBP at week 8 (11.0 mmHg versus 8.9 mmHg). Candesartan also produced numerically greater reductions in secondary blood pressure parameters, including sitting systolic blood pressure (SBP), trough standing DBP and SBP, and peak (6 +/- 2.5 hours after dose) sitting and standing DBP and SBP. Responder rates (sitting DBP < 90 mmHg or reduction in blood pressure of > or = 10 mmHg) and control rates (sitting DBP <90 mmHg) were higher with candesartan (64% versus 54% and 54% versus 43%, respectively). A total of 1.9% of the patients taking candesartan and 6.5% of those taking losartan discontinued prematurely because of adverse events or lack of efficacy.

Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. The Quinapril Heart Failure Trial Investigators.

OBJECTIVES: This study was performed to assess the efficacy, safety and clinical consequences of abrupt cessation of quinapril therapy in a placebo-controlled, randomized, double-blind withdrawal trial. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy has assumed a pivotal role in the treatment of chronic heart failure. Quinapril hydrochloride, a nonsulfydryl angiotensin-converting enzyme inhibitor, has shown beneficial clinical effects in previous studies. METHODS: After > or = 10 weeks of single-blind quinapril therapy, 224 patients with New York Heart Association class II or III heart failure were randomized in double-blind fashion to continue quinapril (n = 114) or to receive placebo (n = 110) for 16 weeks. Changes in treadmill exercise time, New York Heart Association functional class, quality of life and symptoms of heart failure were assessed. RESULTS: Patients withdrawn to placebo had a significant deterioration in exercise tolerance (median change -16 s with placebo vs. +3 s with quinapril, p = 0.015). New York Heart Association functional class (p = 0.004) and quality of life were improved and signs and symptoms of congestive heart failure were lessened in those remaining on quinapril therapy compared with those receiving placebo. During double-blind treatment, 18 patients were withdrawn from the placebo group because of worsening heart failure compared with 5 patients withdrawn from quinapril treatment (p < 0.001). Rather than a precipitous deterioration of clinical status or early incidence of adverse events, withdrawal from quinapril was associated with steady worsening of heart failure, beginning 4 to 6 weeks after randomization to placebo. CONCLUSIONS: Quinapril is effective and safe for maintaining clinical stability in patients with moderate congestive heart failure. Withdrawal of quinapril from patients with heart failure results in a slow progressive decline in clinical status.

Blood pressure monitoring for assessing the duration of action of antihypertensive treatment.

The duration of antihypertensive action of the alpha-adrenergic blocking agent, prazosin, was studied in 12 hypertensive patients in whom twice-daily doses of this agent were found to be effective and well tolerated during a preliminary titration period. The patients then entered a cross-over phase of study. On a randomized basis, they were given prazosin either twice daily for eight weeks followed by an eight-week period in which they received the same total dose once daily (each morning), or they were given the treatment for a once-daily period followed by a twice-daily period. Using the conventional sphygmomanometer, there were no significant differences in blood pressures for the patients as a whole between the measurements during once-daily dosage (measured approximately 24 hours after the last administration of drug) and those during twice-daily dosage (measured approximately 12 hours after the last administration); but for both methods of administration, blood pressures were significantly lower than pre-treatment values. Automated whole-day ambulatory blood pressure monitoring showed a tendency for blood pressures to be lower with once-daily than with twice-daily treatment during the first 12 hours after the morning doses were given, but there was a reversal of this pattern during the early morning hours preceding the next dose. However, for at least half of the patients these differences were only minimal. Thus, prazosin may be effective in some patients as once-daily treatment, especially after several weeks of therapy. Moreover, automated whole-day blood pressure monitoring appears to be a valuable technique for guiding dosage requirements for patients on an individual basis.

Effect of antihypertensive therapy on the circadian blood pressure pattern.

This study employed 24-hour automated ambulatory blood pressure monitoring to evaluate whole-day patterns of blood pressure in age-matched groups of normotensive volunteers, untreated hypertensive patients, and hypertensive patients treated with prazosin. As would be expected, overall systolic and diastolic blood pressures were found to be lowest in the normotensive subjects and highest in the untreated hypertensive patients. The systolic and diastolic blood pressure values for patients receiving prazosin twice daily were significantly lower than in the untreated patients; they were slightly, but not significantly, higher than the values recorded for the normotensive volunteers. The data from 24-hour monitoring revealed no between-group differences in the actual circadian rhythm of the blood pressure. This finding established that the blood pressure pattern for hypertensive patients treated with prazosin was parallel to that for normal individuals. Thus, prazosin administered twice daily reduces blood pressure throughout a full 24-hour period in a fashion that maintains the normal circadian pattern of the blood pressure.

Randomized, double-blind comparison of transdermal clonidine with oral propranolol.

The antihypertensive effect of transdermal clonidine (TC) vs. oral propranolol (OP) was evaluated in 32 patients with mild essential hypertension (mean BP 150/95 mm Hg). The protocol consisted of a 4-week pretreatment washout period, a 2- to 6-week titration, a 4-week maintenance phase, and a 1-week postwashout phase. BP control (diastolic BP less than 90 mm Hg) was achieved in 15 out of 17 transdermal patients, and in 12 out of 14 propranolol subjects. Comparable decreases in systolic/diastolic BP were noted (-19/15 mm Hg for TC vs. -24/13 mm Hg for OP). No rebound symptoms were reported after sudden cessation of the transdermal system during the post-treatment washout. Side effects were recorded in 3 out of 17 TC patients, and in 3 out of 15 OP patients with 1 OP dropout. A mild transient erythematous rash developed in 2 TC and 2 OP (placebo patch) patients. We conclude that the safety and efficacy of TC is comparable to OP for monotherapy in mild hypertensives.

Hemodynamic profiles of antianginal agents.

The 3 main classes of antianginal drugs are nitrates, beta blockers, and calcium channel blockers. Nitrates have been viewed classically as affecting myocardial demand by reducing intraventricular volume and lowering the filling pressure of the left ventricle. They have been used increasingly to improve oxygen supply in myocardial ischemia by increasing coronary blood flow and actually causing coronary vasodilatation, and by having an effect on endothelial competence. Beta blockers are used to decrease myocardial blood flow by reducing myocardial demand, with reduction of myocardial contractility, afterload, and heart rate. No major improvement of oxygen supply is seen with this class of medication, and in fact, there is some potential for augmenting coronary vasoconstriction. Calcium channel blockers not only reduce myocardial demand by reducing afterload and, in some cases, heart rate, but similar to nitrates, they enhance myocardial oxygen supply.

Effects of digitalis on the exercise electrocardiogram in normal adult subjects.

Controversy continues regarding the effects of administration of digitalis upon the exercise electrocardiogram. Thus, maximal treadmill exercise tests were performed before and two weeks after administration of 0.25 mg of digoxin daily in 15 normal subjects (documented by cardiac catheterization and coronary arteriographic studies). Administration of digitalis induced abnormal findings on exercise tests in all 14 subjects with serum levels of digoxin greater than or equal to 0.5 ng/ml; however, at workloads greater than 75 to 90 percent of maximal predicted heart rate, the changes in the ST segment reverted to a normal configuration in all subjects, thereby providing differentiation of digitalis-induced ST-segment alterations from those due to myocardial ischemia at maximal treadmill stress.

Multifactor evaluation of the determinants of ischemic electrocardiographic response to maximal treadmill testing in coronary disease.

Despite widespread use of treadmill stress in the detection of coronary disease, detailed information relating the important features of coronary pathoanatomy to the ischemic response noted on the electrocardiogram is lacking. Accordingly, 91 consecutive patients undergoing graded maximal exercise tests (MEXT) who were found to have clinical stenosis (larger than or equal to 75 per cent luminal narrowing) of at least one of the three major coronary arteries on coronary arteriography were evaluated. Positive MEXT was defined as larger than or equal to 0.1 mV horizontal or downsloping S-T segment depression larger than or equal to 0.08 second beyond J point. Over-all sensitivity of positive MEXT was 59 of 91 (65 per cent) patients; 11 of 26 (42 per cent) with single vessel stenosis, 20 of 30 (66 per cent) with two vessel disease and 28 of 35 (80 per cent) with three vessel disease. In patients with two vessel disease, the frequency (p less than 0.05) of positive MEXT was greater in those with (15 of 21;71 per cent) than in those without (five of nine; 55 per cent) stenosis of the left anterior descending artery. Concerning the site of intravessel stenosis, the frequency of positive MEXT was greater (p less than 0.05) with stenosis proximal to the left anterior descending artery in patients with one vessel disease. Quantification of total numbers of intra- and intervessel stenoses revealed 2.7 stenoses in the 59 patients with positive MEXT in contrast (p less than 0.01) to 1.9 in 32 patients with negative MEXT. Similarly, graded luminal narrowing index of severity of total stenoses per patient was 9.9 in those with positive MEXT compared (p less than 0.01) to 6.1 in those with negative MEXT. The poststenotic myocardial perfusion index, estimated by graded distal vessel opacification per major vessel disease, was only 1.5 in those with positive MEXT contrasted (p less than 0.01) to 2.4 in those with negative MEXT. These data indicate that sensitivity of positive MEXT in patients with coronary disease is most closely determined by the number of major coronary vessels involved, the total number of major vessels stenosed, the severity of total stenoses and poststenotic distal vessel perfusion. Less important factors are the precise site of intravessesl stenosis and the specific major coronary artery involved, although stenosis proximal to the left anterior descending artery favored positive MEXT. Unimportant variables were the quality of collateral vessels, ventricular function and prior inferior infarction. Angina occurred more frequently in those with positive MEXT, and marked degree of positive MEXT indicated stenosis proximal to the left anterior descending artery.

Improvement of symptoms in patients with sick sinus syndrome by spontaneous development of stable atrial fibrillation.

Fifty-six patients with symptomatic chronic sinus bradycardia because of sick sinus syndrome (SSS) were followed for periods from one month to 11 years (average 3-2 years). Eleven developed stable atrial fibrillation persisting for 8 to 61 months; 52 had permanent demand pacemakers implanted before atrial fibrillation commenced. In the 11 patients with atrial fibrillation, 10 had adequate ventricular rate, 8 with rates greater than 100 beats/min requiring digoxin for rate control. The 8 patients with atrial fibrillation with pacemakers remained asymptomatic for 13 to 18 months without requiring reimplantation; battery failure occurred in 2 whose rapid ventricular rates were controlled by digoxin. In the other 6 patients with pacemakers who developed atrial fibrillation, adequate ventricular rates persisted resulting in overdrive suppression. No patient had systemic embolisation. The previous duration of symptomatic sinus bradycardia was longer in patients developing atrial fibrillation (average 5-5 years) compared (P less than 0-01) with patients without atrial fibrillation (1-9 years). Further, premature atrial contractions occurred in all 11 patients before atrial fibrillation in contrast to only 21 of the 45 patients without atrial fibrillation. It is concluded that occurrence of atrial fibrillation in SSS with symptomatic sinus bradycardia provides a natural cure of symptoms caused by bradycardia. These data indicate that permanent ventricular pacing may not be necessary if persistent atrial fibrillation develops in SSS.

Purification of canine plasma renin by affinity chromatography.

An affinity column for the purfication of canine plasma renin was prepared using goat anti-renin (dog kidney) gammaG gloublins. The antiserum was prepared against a purified kidney renin preparation. The anti-renin globulins were coupled to cyanogen bromide activated Sepharose. Using the anti-renin globulin-coupled Sepharose as an immuno-adsorbant, a method was devised allowing purification of plasma renin to a 1,000-fold purity.