Dilevalol compared with propranolol and placebo for systemic hypertension

Dilevalol is a new antihypertensive agent that is both a vasodilator, through its beta 2-agonist action, and a nonselective beta antagonist. Two multicenter, double-blind studies were performed: study 1 compared dilevalol administered once-daily with either dilevalol or propranolol every 12 hours; study 2 compared dilevalol administered once daily with placebo. Both studies had a placebo run-in period to establish that the baseline supine diastolic blood pressures were consistent in the mild to moderate severity range (95 to 115 mm Hg) at 2 consecutive visits for study 1 and in the mild severity range (95 to 105 mm Hg) in study 2. Patients then were randomized to the double-blind titration phase, during which doses were titrated over a 9-week period to achieve a supine diastolic blood pressure of less than 90 mm Hg and a decrease from baseline of greater than or equal to 10 mm Hg. Patients were then maintained on a fixed dose for 2 months (study 1) or for 1 month (study 2). Dilevalol given once daily was as effective in reducing supine diastolic blood pressure as dilevalol every 12 hours and propranolol every 12 hours (study 1) and was superior to placebo (p less than 0.001) (study 2). In both studies, dilevalol given once daily was effective and well tolerated. The side-effect profile of dilevalol was similar to that of placebo and different from that of propranolol. Treatment with dilevalol resulted in significantly less fatigue (p less than 0.05), bradycardia (less than 50 beats/minute) and mental depression than with propranolol, but significantly (p less than 0.05) more diarrhea/loose stools.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipids, vascular disease, and dementia with advancing age. Epidemiologic considerations

Elevated plasma lipid and lipoprotein levels are associated with an increased risk of cardiovascular disease in middle-aged men and women. It is still not clear, however, whether lipid and lipoprotein abnormalities continue to be risk factors for cardiovascular disease in the elderly population. It is not even clear what normal lipid values are in the elderly, and whether diet or drug therapy should be advised on the basis of lipid values established in middle-aged populations. Ischemic heart disease does remain the leading cause of death in the elderly, and there is now preliminary evidence from epidemiologic studies that relative elevations of levels of lipid and lipoprotein fractions in an elderly population might be associated with an independent and increased risk of coronary heart disease, stroke, and possibly dementia. Intervention studies are about to begin that will assess various lipid-and lipoprotein-modifying therapies and their ability to reduce vascular disease risk in the elderly.     

Diabetes Mellitus in the Aging: Epidemiologic and Therapeutic Considerations

Diabetes mellitus is prevalent in older persons and a major risk factor for the development of cardiovascular disease. Impaired glucose tolerance without overt diabetes has also been shown to be associated with an increased risk of cardiovascular disease. Elderly patients with non-insulin-dependent diabetes mellitus are at increased risk for both symptomatic and asymptomatic myocardial infarction, and appear to have worse outcomes than nondiabetic persons with these same conditions. Older diabetic persons also have a greater risk than nondiabetics of developing systemic hypertension and stroke. Treatment of diabetes in the elderly can be divided into treatment of the hyperglycemia itself and treatment of other cardiovascular risk factors. It is unknown whether treatment of hyperglycemia in older patients will decrease the risk of cardiovascular and cerebrovascular disease, but it is proposed that treating diabetes along with other commonly associated risk factors for cardiovascular disease may provide the best outlook for such patients.     

beta-Blockade therapy for supraventricular tachyarrhythmias after coronary surgery: a propranolol withdrawal syndrome?

A high incidence of cardiac arrhythmias and hypertension has been noted after coronary artery bypass surgery in patients previously treated with oral propranolol. Forty-two patients undergoing coronary bypass surgery had propranolol withdrawal 10 hours before surgery and were randomized into a group treated with propranolol immediately postoperatively, and a nontreatment group. Patients treated with prophylactic propranolol had a significantly lower incidence of postoperative supraventricular arrhythmias compared to patints who received no prophylaxis. All the arrhythmias responded rapidly to 1 mg of intravenous propranolol therapy, whether it was used as a primary treatment or as a supplement to prophylactic propranolol. The findings suggest that (1) there is a high incidence of supraventricular arrhythmias and sinus tachycardia after coronary artery bypass which might reflect an abrupt propranolol withdrawal, and (2) that perioperative prophylactic or supplementary propranolol therapy will successfully prevent or treat most of these arrhythmias.     

Anticoagulation in myocardial infarction: Modem approach to an old problem

The role of routine anticoagulation in acute myocardial infarction continues to be a source of controversy. There is currently strong evidence to suggest that conventional anticoagulation will prevent the formation of most deep vein thrombi and subsequent pulmonary embolization. Anticoagulant agents also appear to reduce the incidence of emboli from cardiac mural thrombi to peripheral arteries. Patients without a predisposition to bleeding are unlikely to have hemorrhagic complications in the hospital after usual doses of anticoagulant drugs. In patients with severe hypertension, prior gastrointestinal bleeding, carcinoma or advanced age, small dose heparin therapy appears to reduce the incidence of venous thrombosis and probably of pulmonary emboli as well. Its value in preventing peripheral arterial embolization has not been defined. Anticoagulation with standard “large” doses is an effective means of preventing the risks of pulmonary and peripheral emboli during the in-patient phase of acute myocardial infarction. Small dose heparin therapy provides an excellent alternative to conventional anticoagulation when there is more than a negligible risk of hemorrhage. There is little evidence at this time to support the use of long-term anticoagulation beyond the acute phase of myocardial infarction.     

Diltiazem, nifedipine, and their combination in patients with stable angina pectoris: effects on angina, exercise tolerance, and the ambulatory electrocardiographic ST segment

The efficacy and safety of oral nifedipine and diltiazem were compared in 20 patients with stable angina pectoris with use of a placebo run-in, randomized, double-blind titration to maximal effect crossover protocol. The effects of treatment withdrawal were also analyzed. All patients received placebo for 2 weeks and were then randomly assigned to receive either diltiazem or nifedipine. A 2 week drug titration phase in which patients received either diltiazem (180 to 360 mg/day) or nifedipine (30 to 120 mg/day) in three divided doses was followed by a 1 week maintenance phase. Patients then received placebo for 1 to 2 weeks, followed by crossover to the other treatment regimen and a second placebo washout period of 1 week. Patients (n = 13) who remained symptomatic on both diltiazem and nifedipine during the monotherapy periods entered a 3 week combination treatment phase, followed by a final 1 week placebo washout period. Frequency of angina, nitroglycerin consumption, exercise tolerance (Naughton protocol), and frequency of daily episodes of ST segment deviations on the electrocardiogram (1 mm of ST segment depression persisting for at least 1 min with and without chest pain) on an ambulatory electrocardiographic monitor were assessed during the baseline placebo, active monotherapy, placebo withdrawal, and combination treatment phases. Plasma drug levels were also measured. Compared with initial placebo values, the frequency of angina and the amount of nitroglycerin treatment were reduced by both diltiazem (p less than .001) and nifedipine (p less than .02). Diltiazem was more effective than nifedipine in reducing angina (p less than .02). Exercise duration increased with both drugs (p less than .0001). Diltiazem was significantly better than nifedipine in reducing the episodes of ST segment depression on the ambulatory monitor (p less than .01). Diltiazem reduced the resting heart rate (p less than .01); both drugs reduced the resting blood pressure and rate-pressure product. Overall, combination therapy was more effective in patients who did not maximally respond to diltiazem or nifedipine alone with respect to anginal and exercise variables and in reducing blood pressure at rest and during exercise. Plasma drug levels could not predict an individual patient's treatment response. Diltiazem may increase nifedipine drug levels when the drugs are combined. Fewer side effects were observed with diltiazem than nifedipine; the most side effects were seen with combination treatment. There were no apparent withdrawal effects observed with either treatment regimen.(ABSTRACT TRUNCATED AT 400 WORDS)     

Tolerance, rebound, and time-zero effect of nitrate therapy.

Both nitroglycerin and long-acting nitrates have proved effective in treating acute anginal pain. In recent years, however, development of tolerance with the continuous use of these agents has been documented. A pilot study demonstrated attenuation of the therapeutic effect of high-dose, continuous transdermal nitroglycerin therapy, despite adequate plasma nitroglycerin levels. In a subsequent, larger Transdermal Nitroglycerin Cooperative Study, evidence of tolerance was detected within 24 hours of initiation of continuous nitroglycerin patch therapy at several different dose levels. Sustained pharmacologic activity has been achieved with the intermittent use of transdermal nitroglycerin, usually for 12 hours followed by a 12-hour drug-free period. When the patch is discontinued, however, some patients experience exacerbation, or rebound, of anginal symptoms and a worsening of exercise tolerance at the end of the drug-free period. Additional clinical research is therefore needed to determine the optimal intermittent dosing strategy.     

Properties of labetalol,a combined α-and β-blocking agent,relevant to the treatment of myocardial ischemia

Summary Labetalol, a combined --adrenergic antagonist, is one of the new group of -adrenergic blockers reduces peripheral and coronary vascular resistances while preserving cardiac output. Unlike -adrenergic blockers, labetalol tends to reduce heart rate during rest and exercise. The drug is a potent antihypertensive agent which has been used by mouth and by vein to treat mild, moderate, and severe hypertension, including hypertensive emergencies. Labetalol has a hemodynamic profile which makes it an attractive agent for treating myocardial ischemia. The drug reduces blood pressure, left ventricular wall tension, heart rate, and contractility while preserving or even augmenting coronary blood flow. Studies with labetalol in hypertensive patients with angina have shown it to be more effective than placebo in reducing angina attacks and blood pressure while improving exercise tolerance. The drug appears to have antianginal and antihypertensive effects comparable to atenolol and propranolol. Side effects of treatment are observed and most are related to - and -adrenergic blockade. Labetalol also appears to be effective for treatment of normotensive patients with angina and for silent myocardial ischemia. It has no apparent effects on serum lipids and lipoproteins. Labetalol appears to be a useful drug for treating the hypertensive heart and its many complications.     

Abrupt propranolol withdrawal in angina pectoris: effects on platelet aggregation and exercise tolerance.

Data collected before the initial reports of myocardial infarction following sudden withdrawal of propranolol are presented here to evaluate possible mechanisms for this phenomenon. Twenty patients with angina pectoris were randomized into placebo and propranolol (160 mg./day) treated groups and followed for 50 weeks at which time treatment was abruptly discontinued. Measurements of exercise tolerance, the product of heart rate and blood pressure at exercise end-point (HR × BP), and platelet aggregation thresholds in response to ADP and epinephrine were made before, during, and after treatment. Prior to propranolol, mean total work performance was 765 ± 125 k.p.m., HR × BP (heart rate-blood pressure product) was 16,800 ± 1,535. Mean platelet aggregation threshold with ADP was 1.32 μM¹; with epinephrine 1.26 μM¹. Patients treated with propranolol demonstrated significant improvement in exercise performance (1,790 ± 285 k.p.m., p < .01), reduction in HR × BP (12,000 ± 895, p < .01), and an elevation in platelet aggregation threshold; with ADP 3.43 μM¹ (p < .01); with epinephrine 12.9 μM¹ (p < .01). Following abrupt cessation of propranolol, exercise tolerance and HR × BP fell below pretreatment levels (630 ± 117 k.p.m. and 15,500 ± 513, respectively). Similarly platelet aggregation threshold fell to 1.0 μM¹ with ADP and 0.57 μM¹ with epinephrine. In six patients platelets were significantly more hyperaggregable than prior to therapy. Anginal frequency increased in all, but no acute infarction was observed. Abrupt withdrawal of propranolol may be deleterious in patients, sometimes causing “rebound” platelet hyperaggregability associated with increasing anginal frequency and decreasing exercise tolerance.