Treatment of hypertension associated with stable angina pectoris: favourable interaction between new metoprolol formulation (OROS) and nifedipine.

This was a double-blind, within-patient, crossover study to evaluate the effects of a new formulation of metoprolol on blood pressure (BP) and myocardial ischemia. Twenty outpatients with mild to moderate essential arterial hypertension, chronic stable angina pectoris and positive exercise test, after a 2-week baseline placebo period, were randomized to receive long-acting metoprolol (OROS) 14/190 mg o.d., nifedipine SR 20 mg b.i.d. or their combination in a sequence of a 3 x 3 Latin square design. Two patients withdrew from the study (1 for adverse event during metoprolol and 1 for rise of BP during nifedipine). Nifedipine, metoprolol and their combination significantly reduced the weekly number of angina attacks and nitroglycerin consumption with respect to baseline. The total number of ischemic events (at 24-hour ECG monitoring) significantly decreased after each treatment with respect to baseline. Twenty-four hours mean systolic and diastolic BP were reduced by both nifedipine alone and metoprolol alone; the combination of the two drugs led to a further decrease in both systolic and diastolic BP. The duration of silent ischemic episodes was significantly reduced by nifedipine and combination but not by metoprolol. On the other hand 24 hours symptomatic attacks/patient were significantly reduced by beta-blocker and combination, but not by nifedipine. Metoprolol alone and administered with nifedipine caused a decrease, with respect to placebo baseline, in 24-hour mean heart rate (HR) and reduced the increase of HR and systolic BP at the onset of ST depression during symptomatic ischemic episodes. The effort time and time to ST = -1 mm at treadmill were significantly increased by treatment with nifedipine alone, with metoprolol alone and with their combination, but the combination was more effective than the individual therapies. ST depression at peak exercise was significantly reduced by each treatment. The slopes of correlations between the ST-segment variation and systolic BP, HR and rate-pressure product during exercise, significantly decreased after all treatments with respect to placebo baseline, more with the combination therapy than with nifedipine alone and metoprolol alone. In conclusion, based on our results the favourable interaction of metoprolol OROS and nifedipine given concomitantly, is likely to be due to a better control, respect to each individual therapy, of the pathogenetic mechanism of myocardia ischemia: BP and HR increases during exercise and during symptomatic ischemic episodes are controlled by the beta-blocker and coronary vasoconstriction during silent ischemia is prevented by the calcium-antagonist.

Management of the patient with left ventricular hypertrophy.

The management of left ventricular hypertrophy (LVH) presupposes that the patient is identified by echocardiography and is carefully evaluated for risk stratification, taking into consideration possible associated complications. The role of non-pharmacological treatment is limited, except in obese patients. Drug treatment, especially using calcium antagonists, angiotensin converting enzyme inhibitors and beta-blockers, has proved to be effective in reducing LVH. These drugs are also effective in controlling, if not reversing, the associated pathophysiological changes and complications, such as impaired systolic and diastolic function, and ventricular arrhythmias. There is, however, no evidence of any beneficial effect on myocardial ischaemia. The desirable goal is LVH regression, but it may not be achievable in over 50% of patients, and it is not possible to identify patients in whom regression is likely. Regression, or control of each sequelae, could prevent sudden death, the evolution of hypertensive heart disease leading to heart failure and, probably, myocardial infarction. Patients must be followed carefully during and, particularly, at the beginning of the antihypertensive therapy which has to be gradually introduced. At best, blood pressure must be reduced while avoiding hypotension. The strategy of antihypertensive treatment has to be reconsidered on the basis of the presence of LVH and could lead to decreased cardiovascular morbidity and mortality of patients with LVH.

A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris.

The antianginal activities of nicorandil, 10 and 20 mg bid, and metoprolol, 100 mg bid, were compared in patients with stable effort angina pectoris in a randomized, double-blind parallel group study lasting 7 weeks. Twenty patients were enrolled into the trial and 16 patients completed the study. To evaluate the anti-ischemic effects of the two drugs, a treadmill exercise test was performed after a 1-week placebo run-in period and 6 weeks of treatment. On the same occasions, weekly sublingual nitroglycerin consumption and the number of anginal attacks were also recorded in the patient's diary. The total duration of exercise increased significantly with both nicorandil, 10 and 20 mg, and metoprolol (p < 0.01). Similar improvements were observed in the time to onset of ischemia with both treatments (p < 0.01). The double product at maximal comparable workload (MAX 1) was reduced with the two drugs (p < 0.05 for nicorandil and p < 0.01 for metoprolol), while at the maximal exercise time (MAX 2) it was reduced with metoprolol (p < 0.01) and slightly but not significantly increased with both doses of nicorandil. Weekly sublingual nitroglycerin consumption and anginal attacks were also significantly reduced a similar manner by both treatments (p < 0.01). In conclusion, nicorandil, 10 and 20 mg bid, exerted an anti-ischemic effect comparable with that of metoprolol in patients with stable effort angina pectoris.

Antihypertensive effects of verapamil, captopril and their combination at rest and during dynamic exercise.

In order to investigate the antihypertensive effects of verapamil (CAS 52-53-9) and captopril (CAS 62571-86-2), administered alone or in combination therapy, the blood pressure and heart rate effects of these two drugs at rest and during dynamic exercise were evaluated in a double blind study in 30 moderate or severe essential hypertensive patients. After a 30-day placebo wash-out period, 15 patients (age 60.6 +/- 8.0 years, mean +/- SD) were allocated to verapamil sustained-release treatment (120 mg b.i.d. for the first month of therapy and 240 mg b.i.d. for the second one) and 15 patients (age 58.4 +/- 10.0 years) to captopril treatment (25 mg b.i.d. and 50 mg b.i.d. for the first and second month of therapy, respectively). At low dosage both verapamil and captopril significantly (p less than 0.001) and markedly reduced blood pressure values. Goal diastolic blood pressure of 90 mmHg was achieved in 40% and 20% of patients in the verapamil group and in the captopril group, respectively, at high dosage. In contrast to captopril, verapamil induced a significant and dose-dependent heart rate reduction and markedly attenuated the pressor and tachycardiac responses to dynamic exercise. The combination of verapamil 240 mg b.i.d. plus captopril 50 mg b.i.d. was then administered to patients, whose blood pressure was not satisfactorily controlled by monotherapy. This regimen allowed a better blood pressure control both at rest and during exercise than on monotherapy and induced a complete blood pressure normalization in 62% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic interactions between diuretics and calcium antagonists in the treatment of hypertensive patients.

To investigate the hypotensive and hemodynamic effects of plain and extended-release (ER) formulations of felodipine added to a diuretic in the treatment of moderate essential hypertension, we studied 18 patients in a randomized, double-blind, cross-over study. Blood pressure (BP), heart rate (HR), hemodynamics (bioimpedance), foot volume (Archimedes' principle), and symptoms were evaluated after a 1-month placebo washout, after 1-month's treatment with a fixed combination of hydrochlorothiazide 50 mg plus amiloride 5 mg (HA), and then after felodipine 5 mg twice daily (F) or felodipine ER 10 mg daily (FER) (double-blind phase), each given for 2 weeks in a randomized sequence together with the diuretic. All measurements were performed at the end of the dosing interval. At baseline, supine SBP/DBP was 175.6 +/- 12.9/113.4 +/- 8.1 mmHg; HR was 77.3 +/- 7.0 beats/min; CO was 5.3 +/- 1.4 l/min; SVR was 2166 +/- 707 dynes sec. cm5, and foot volume was 433 +/- 195 ml (FV). HA induced a reduction (p less than 0.05) in BP; one patient had a DBP = 90 mmHg and was excluded from the combination study; eight patients had a DBP reduction of greater than or equal to 10 mmHg (responders), and their blood pressure was mainly reduced by a fall in SVR. HR, CO, and FV were unchanged. The addition of felodipine to a diuretic induced a further significant (p less than 0.001) reduction in BP with respect to HA alone, with no differences between F and FER. All patients had a DBP fall greater than 10 mmHg, which had no relationship to their response to the diuretic.(ABSTRACT TRUNCATED AT 250 WORDS)

Effort blood pressure control in the course of antihypertensive treatment.

In 30 patients with mild hypertension (diastolic blood pressure, 95 to 105 mmHg), the antihypertensive effect of rilmenidine 1 mg was compared in a double-blind study, with the effect of hydrochlorothiazide 25 mg. Patients not satisfactorily controlled received a combined therapy on the same doses of the two drugs used. Rilmenidine and hydrochlorothiazide induced a significant reduction (p = 0.01) of supine and erect systolic/diastolic blood pressure 23 hours after drug intake with no change in heart rate. This effect was due to a reduction in cardiac output (bioimpedance method) significant (p = 0.05) only for rilmenidine. Both drugs controlled the increase of effort systolic blood pressure in comparison with placebo on systemic vascular resistance treadmill exercise testing. Effort cardiac output was increased by each treatment in comparison with baseline values. Both at rest and on exertion, there was no effect on systemic vascular resistance induced by the two drugs. In a second group of 10 patients with moderate hypertension (diastolic blood pressure, 105 to 115 mmHg), rilmenidine 1 mg was administered in order to evaluate its efficacy and hemodynamic effects (bioimpedance and radionuclide ventriculography), at rest and during a lying cycloergometer effort test. The drug induced a significant decrease in blood pressure at rest and on exertion four hours after drug intake. This effect was due to a reduction (p = 0.05) in systemic vascular resistance, whereas cardiac output and heart rate remained unchanged. Our results show that the reduction in systolic/diastolic blood pressure induced by rilmenidine 1 mg is comparable with that induced by the well-known antihypertensive drug hydrochlorothiazide in mild hypertension. In moderate hypertension, the 1-mg dose appears to be insufficient in controlling the blood pressure in all patients. The drug exerts its antihypertensive effect through the normalization of the altered hemodynamic parameters of hypertension (high cardiac output and/or increased systemic vascular resistance). Rilmenidine also respects the physiologic increase in blood pressure and cardiac output on exertion.

Treatment of hypertensive patients with ventricular arrhythmias: comparison and combination of beta-blocker and anti-arrhythmic therapy.

The effect of therapy with atenolol and tocainide, separately or in combination, was studied in 20 patients with hypertension and concomitant ventricular arrhythmias. Patients were given 400 mg tocainide, three times daily, 100 mg atenolol, once daily (plus 25 mg hydrochlorothiazide and 2.5 mg amiloride diuretics if required) and a combination of these treatments. Tocainide alone significantly reduced the incidence of ventricular arrhythmias without affecting atrial arrhythmias. It also controlled exercise-induced arrhythmias in 7/13 (54%) patients. Atenolol significantly reduced atrial arrhythmias and had a good effect on exercise-induced arrhythmias (reduced in 75% of patients), but it did not have a significant effect on ventricular arrhythmias. In 13 patients, despite normalization of blood pressure by atenolol, it was necessary to combine antihypertensive therapy (atenolol) with anti-arrhythmic therapy (tocainide) in order to reduce ventricular arrhythmias. All drugs were well tolerated. It is concluded that, in certain patients, specific anti-arrhythmic treatment may be necessary to control ventricular arrhythmias in hypertensive patients despite normalization of blood pressure by beta-blockers.

Blood pressure and cardiac morphology in young children of hypertensive subjects.

Our aim was to assess echocardiographic parameters and the effort blood pressure of 50 children of hypertensives with respect to 50 children of normotensives. Systolic and diastolic blood pressures at rest were comparable between the two groups. Left ventricular mass index (LVMI), interventricular septum and posterior wall thicknesses were higher in children of hypertensives (P less than 0.01). Systolic blood pressure was higher in children of hypertensives at maximal effort until 5 min of recovery (P less than 0.01). Similarly, diastolic blood pressure was higher at 1 and 2 min of recovery (P less than 0.01). Direct correlations of mean diastolic wall thickness (r = 0.39, P less than 0.01) and LVMI (r = 0.33, P less than 0.05) with percentage effort systolic blood pressure increases were found in children of hypertensives but not in children of normotensives. In conclusion, we confirmed early cardiac alterations and a tendency for effort hypertension in children of hypertensives. The relationship between these data could be explained either by effort systolic overload or by a common response to an increased adrenergic stimulus.

Atenolol and amiodarone: a comparative study of their anti-ischaemic effect.

A total of 10 patients with mixed angina were entered into a study to compare the anti-ischaemic efficacy of atenolol and amiodarone. The study was divided into three parts: (a) placebo for 2 weeks; (b) 100 mg atenolol given for 8 weeks; and (c) amiodarone given for 8 weeks, divided into week 1, 200 mg three times daily; week 2, 200 mg twice daily; weeks 3 and 4, 200 mg once daily; weeks 5-8, 200 mg once daily for 5 days a week. Clinical examination, basal and multi-stage effort electrocardiograms were performed at the end of each treatment. The number of anginal attacks and the amount of trinitrin taken by the patients were significantly reduced by both drugs with no significant difference between them. Compared with placebo, both drugs induced a significant increase in work capacity and in the time to decrease the ST-segment by 1 mm. At rest, atenolol reduced systolic blood pressure, heart rate and the systolic blood pressure--heart rate product compared with placebo. Systolic blood pressure was also reduced significantly compared with patients given amiodarone. Amiodarone did not influence these parameters. At maximum effort, amiodarone reduced heart rate and the systolic blood pressure--heart rate product compared with placebo. This reduction was greater for atenolol. The ST-segment depression was comparable between patients given either test drug. Amiodarone, therefore, exerts an anti-ischaemic effect similar to that shown by atenolol with different haemodynamics: atenolol reducing myocardial oxygen demand, amiodarone having an additive increase of coronary flow. Such an effect was obtained with a lower dose of amiodarone than is commonly used.

Bisoprolol in the treatment of angina pectoris: a double blind comparison with verapamil.

In order to verify the anti-ischaemic effect of a new beta-blocking agent, bisoprolol, a double blind parallel groups trial was carried out in comparison with verapamil. 26 patients with a history of spontaneous and/or effort angina were studied. After a two-week treatment with placebo, they were randomized in two groups. One group was treated for 4 weeks with bisoprolol 10 mg o.d. and for the following 4 weeks with bisoprolol 20 mg o.d. The other group received verapamil 80 mg t.i.d. for the first 4 weeks and 120 mg t.i.d. for the remaining 4 weeks. Throughout the study isosorbide dinitrate 20 mg b.i.d. was administered and sublingual nitroglycerin was allowed when necessary. 21 patients completed the study. Both bisoprolol and verapamil significantly reduced the number of angina episodes and nitroglycerin tablets consumption, as well as ischaemic episodes recorded on Holter ECG. The total number and severity of ectopic ventricular beats were reduced too. On multistage treadmill exercise test, both drugs increased effort time and time to ST depression = 1 mm, and reduced ST depression and double-product. The effect of bisoprolol on double product was greater than that of verapamil because of the better control of heart rate. The relationship ST/double product suggested that beta-blockers act essentially through the reduction of myocardial oxygen consumption and verapamil possibly with an additive effect on coronary circulation. Radionuclide ventriculography showed no deterioration of rest ventricular function with both drugs. In conclusion, bisoprolol and verapamil showed a satisfactory anti-ischaemic effect, with good tolerability.

Muzolimine and nitrendipine in the treatment of arterial hypertension.

Thirty patients with moderate to severe hypertension (diastolic blood pressure greater than or equal to 115 mmHg), after a run-in wash out period of 15 days, were treated with muzolimine at a dosage of 20 mg once daily, given at 1 p.m., for three weeks. At the end of this period of treatment the patients with diastolic blood pressure greater than or equal to 100 mmHg started a double blind randomized study of comparison of nitrendipine, a vasodilator calcium antagonist agent, and captopril, an inhibitor of converting enzyme. The dosage was 10 mg twice daily for nitrendipine and 25 mg twice daily for captopril, the duration of each treatment being four weeks. At the end of 28 days of double blind treatment, the patients with diastolic blood pressure greater than or equal to 100 mmHg were treated with a triple combination: muzolimine plus nitrendipine plus captopril at the same dosage for a further four weeks. At the end of run-in and of each period of treatment blood pressure and heart rate were recorded in supine and erect positions and after a treadmill exercise test. At these times laboratory tests, including PRA and aldosterone, were performed. After the run-in period supine blood pressure was 189.6 +/- 13.9/123.1 +/- 7.7 mmHg. At the end of muzolimine treatment, supine blood pressure was 176.5 +/- 10.8/117.8 +/- 5.6 mmHg (p less than 0.001); at this time 4 patients had their diastolic blood pressure normalized and left the study. Thus 26 patients were randomized for comparative study.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitrendipine and atenolol: comparison and combination in the treatment of arterial hypertension.

The effectiveness and tolerability of nitrendipine (Bay e 5009) and atenolol in the treatment of mild or moderate arterial hypertension in monotherapy and in association were evaluated in a randomized double-blind study. The drugs were administered once daily at the dose of 20 mg for nitrendipine and 100 mg for atenolol. The trial consisted in two phases of monotherapy and of a combined regimen phase, whose sequence was randomly established; tablets were administered according to a double-dummy design. The results were evaluated according to the criteria of the Hypertension Detection and Follow-up Program Cooperative Group. 5/20 patients were considered "responders" after atenolol treatment, 4/20 after nitrendipine alone, and 14/20 after combined therapy. Side effects resulted mild in severity, and their incidence was lower during the association phase. The combination of atenolol and nitrendipine appears to improve the effectiveness and acceptability of both drugs.

Acebutolol and nifedipine in the treatment of arterial hypertension: efficacy and acceptability.

The antihypertensive efficacy and the acceptability of nifedipine (NI, Adalat) and the usefulness of its combination with a beta 1-selective blocking drug, acebutolol (AC), were studied in a placebo controlled trial on 15 patients with moderate hypertension. The study consisted of three phases: 1. An acute test, including the single blind comparison of three different single doses of NI (5, 10, 20 mg), alone and in combination with AC 200 mg, with placebo and with AC alone (200 mg), showed an early hypotensive effect, with no differences for the three doses of NI, reaching the maximum between 50 and 240 min, greater than the one of AC, and smaller in comparison with the one of the combinations, which didn't differ at the three doses of NI. Heart rate (HR) and side effects, instead, increased with the increasing doses of NI, suggesting a worse acceptability for the greater doses. 2. A long-term treatment, including a double-blind comparison of three separate periods of 4 weeks of treatment with NI (10 mg three times a day), AC (200 mg three times a day) and with the combination of the same doses, showed a significant reduction of systolic and diastolic blood pressure (BP) for each treatment, not significantly different at rest for the three single drugs but greater for the combined treatment, assuring also a better control of systolic BP during exercise. A reduced number of side effects was seen with the combined therapy which seems to contribute to a better compliance.(ABSTRACT TRUNCATED AT 250 WORDS)

Indapamide and atenolol in the treatment of hypertension: double-blind comparative and combination study.

Fifteen out-patients with moderate hypertension were randomly and sequentially treated with atenolol, indapamide and a combination of the two drugs after a wash-out period of at least 1 week and a 2-week placebo run-in period. The duration of treatment was 4 weeks in each case. The dosage was 2.5 mg indapamide and 100 mg atenolol, in single tablets which were taken at 11.00 hours. All the treatment regimens produced a highly significant (p less than 0.001) reduction in systolic and diastolic, supine and standing blood pressure; these reductions were not significantly different for the single drugs but were significantly greater for the combined therapy. The number of patients reaching the end-point of a diastolic blood pressure of 95 mmHg or less was the same with either atenolol or indapamide, i.e. 7 (46.6%), but was greater with the combined therapy, i.e. 10 (66.6%). A significant (p less than 0.001) reduction in pulse rate was observed with the treatments involving atenolol. Acceptability of the treatments was very good; the number of volunteered and elicited complaints during the different treatments being less compared to the placebo period, particularly for the combined treatment. No significant difference was observed in the blood biochemistry tests. The results are discussed in light of the mechanisms of action of the two drugs, which seem well integrated with each other, and the duration of the antihypertensive effect, which allows a single administration with consequent good treatment compliance.

Obesity and cardiac function.

We studied 10 obese volunteers, mean age 36.5 +/- 10.3 years, who weighed 123.56 +/- 28.7 g and were 69.96 +/- 22.5 kg overweight. The subjects did not have diabetes, arterial hypertension or signs of cardiac and respiratory failure or disease and all underwent right- and left-heart catheterization. cardiac output and stroke volume were high, according to increased oxygen consumption and to the degree of obesity. Ventricular end-diastolic and atrial pressures ranged from normal to high and correlated with body weight, signs of volume overloading and reduced left ventricular (LV) compliance. The mean pulmonary artery pressure was elevated and correlated well with weight, pulmonary resistance being normal; mean aortic pressure did not correlate with weight, and systemic arterial resistance tended to have a negative correlation. The LV function curve showed impaired ventricular function, particularly for the heaviest subjects, in whom Vmax and the ratio of the stroke work index to LV end-diastolic pressure were reduced. These indexes correlated well with each other and both correlated negatively with the degree of obesity. In contrast, maximal dP/dt was normal and did not correlate with excess weight. These observations show that depressed LV function is already present in relatively young obese people, even if they are free from signs of cardiopathy and other associate diseases. The degree of impairment of heart function seems to parallel the degree of obesity.