Lercanidipine, enalapril and their combination in the treatment of elderly hypertensive patients: placebo-controlled, randomized, crossover study with four ABPM.

This double-blind, placebo-controlled, four-way balanced design crossover study included hypertensive patients aged 60-85 years with mean office-measured sitting systolic blood pressure (SBP) 160-179 mm Hg and daytime SBP > or =135 mm Hg. After a 2-week run-in period, during which previous medications were discontinued, each patient received the following four treatments in randomized order for 4 weeks each: lercanidipine 10 mg (L), enalapril 20 mg (E), lercanidipine 10 mg plus enalapril 20 mg (L/E) and placebo (P). At the end of each treatment period, office trough blood pressure (BP) was measured and a 24-h Ambulatory Blood Pressure Monitoring (ABPM) was performed. Seventy-five patients (mean age 66 years, office BP 168/92 mm Hg, daytime SBP 151 mm Hg) were randomized and 62 completed the study with four valid post-baseline ABPMs. The administration of P, L, E and L/E was associated with a mean 24-h SBP of 144, 137, 133 and 127 mm Hg, respectively. All active treatments significantly reduced the mean 24-h SBP in comparison with placebo, but L/E was significantly more effective than L and E alone. Similarly, office SBP was significantly more reduced with L/E (-16.9 mm Hg) than with L (-5.0 mm Hg) or E (-5.9 mm Hg). A BP <140/90 mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events. In conclusion, combination therapy with L/E has additive antihypertensive effects on both ambulatory and office BP in elderly patients and is well tolerated.

Exercise capacity and hemodynamics in persons aged 20 to 50 years with systemic hypertension treated with diltiazem and atenolol.

Hemodynamic responses and exercise capacity were studied during maximal exercise in 25 young hypertensive persons (mean age 40 years) taking placebo, diltiazem (mean 216 mg/day) and atenolol (mean 80 mg/day). The study was a crossover, double-blind, randomized trial, each medication period lasting 2 months. Sitting blood pressure (BP) was 160 +/- 19/109 +/- 8 mm Hg after run-in. Both drugs decreased BP significantly, diltiazem by 10/ 11 mm Hg and atenolol by 16/14 mm Hg (difference not significant between drugs). During exercise there were no differences among patients taking placebo, diltiazem and atenolol in peak workload and rating of perceived exertion. Atenolol significantly attenuated the increase in heart rate, BP and heart rate-BP product at each workload. Diastolic BP during exercise was significantly lower (6 to 10 mm Hg) during diltiazem therapy than during placebo at each workload. Thus, both diltiazem and atenolol decrease rest BP significantly without impairing exercise capacity.

Cerivastatin gender effect: sub-analyses of results from a multinational, randomised, double-blind study. Cerivastatin Study Group.

We previously reported the results of a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day and cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 +/- 8.9% in women, compared with a mean decrease of 37.0 +/- 0.9% in men (p < 0.046). This paper reports the results of further sub-analyses from this study. Overall in the per-protocol (PP) population, 71.5% (n = 73) of women taking cerivastatin 0.4 mg had an LDL-C decrease of > 40%, compared with 38.0% (n = 76) of men taking the same dose. In the cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the cerivastatin 0.4 mg PP group: -41.3% in males vs. -48.3% in females. In the cerivastatin 0.2 mg group, the decrease in LDL-C/HDL-C ratio from baseline to endpoint did not markedly differ between genders: -37.0% for males vs. -37.3% for females. Categorial analysis of the LDL-C/HDL-C ratio found that 90% of PP patients taking cerivastatin 0.4 mg, and 84% of PP patients taking cerivastatin 0.2 mg, had a low CHD risk (defined as a LDL-C/HDL-C ratio < or = 3) after 8 weeks of treatment. The 6th and 95th percentiles of the distribution of LDL-C reduction from baseline revealed that 90% of PP patients taking cerivastatin 0.4 mg had an LDL-C reduction of between 22% and 56%. The mean LDL-C reduction for this 90% subset of patients was 40.1%. The same analysis for PP patients taking cerivastatin 0.2 mg found that 90% had an LDL-C reduction of between 13% and 49%. The mean LDL-C reduction in this 90% subset of patients was 31.5%. Of the patients taking cerivastatin 0.4 mg and valid for treatment according to National Cholesterol Education Program (NCEP) criteria, 71% (149/211) achieved NCEP targets for LDL-C at Week 16.

Efficacy and safety of cerivastatin, 0.2 mg and 0.4 mg, in patients with primary hypercholesterolaemia: a multinational, randomised, double-blind study. Cerivastatin Study Group.

Elevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg. This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of cerivastatin 0.4 mg/day with that of cerivastatin 0.2 mg/day in patients with primary hypercholesterolaemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive cerivastatin 0.4 mg (n = 332) or 0.2 mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 +/- 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 +/- 0.9% in the 0.2 mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 +/- 8.9% in women, compared with a decrease of 37.0 +/- 0.9% in men (p < 0.046). In the PP group as a whole, total cholesterol decreased by 26.0 +/- 0.5% from baseline in the 0.4 mg group, compared with a decrease of 21.6 +/- 0.7% in the 0.2 mg group (p < 0.0001). Both doses were well tolerated; only eight (2.4%) patients in the 0.4 mg group and five (3.1%) patients in the 0.2 mg group withdrew owing to adverse events. Cerivastatin 0.2 mg/day and 0.4 mg/day was found to lower low-density lipoprotein cholesterol and total cholesterol levels in a dose-dependent manner, with both doses exhibiting a good safety profile.

Strenuous physical activity, aspirin and heat stress increase urinary dolichols: evidence for lysosomal origin of urinary dolichols.

Strenuous physical activity, aspirin and heat stress (Finnish sauna) were all found to significantly increase urinary dolichol excretion. In contrast, serum dolichol concentration studied before and after aspirin and sauna, was not affected. A similar aspirin-induced increase, as seen in urinary dolichol concentration, was also observed in the urinary excretion of two lysosomal enzymes--beta-hexosaminidase and beta-glucuronidase. In contrast, the excretion of two non-lysosomal enzymes--lactate dehydrogenase and leucine aminopeptidase--was not affected. The lack of correlation between serum and urinary dolichols, and the parallel increase in urinary dolichols and the activities of the lysosomal enzymes suggest that urinary dolichols may be derived from the lysosomes of the renal cells. We conclude that the finding of increased urinary dolichol concentrations in some relatively common conditions limits the clinical use of urinary dolichols as a diagnostic tool in neuronal ceroid lipofuscinosis or alcoholism.

Efficacy and Tolerability of Nisoldipine Coat-Core vs Diltiazem Retard in Combination with a Beta-Blocker in Patients with Stable Exertional Angina Pectoris.

A randomised, double-blind, placebo-controlled, parallel-group trial with forced titration study to investigate possible equivalence of efficacy and tolerability between nisoldipine coat-core (CC) 40mg once daily, and diltiazem retard 120mg twice daily, was carried out in 176 patients with stable angina pectoris who were already receiving beta-blocker therapy. A total of 164 patients were included in the tolerability analysis and 135 patients were evaluable for efficacy (nisoldipine CC, n = 69; diltiazem retard, n = 66). During bicycle exercise tolerance tests, time to 1mm ST-segment depression, total exercise time, and time to angina were assessed at baseline and at the end of the treatment period. The number of angina attacks and of consumed nitroglycerin tablets were recorded in weekly diaries. Time to onset of 1mm ST-segment depression increased by 69.4 +/- 100.0 seconds with nisoldipine CC and by 65.9 +/- 87.6 seconds with diltiazem retard. The two treatment regimens were equally effective in time to onset of 1mm ST-segment depression, time to angina pectoris, and in exercise duration. A beneficial effect on angina attacks and nitroglycerin consumption was achieved with both treatments. Patient compliance, as assessed by the number of returned tablets, was high, at over 80%. Six patients withdrew from the treatment because of adverse events. Mild and transient adverse events were reported by 24 patients during treatment. One patient experienced a severe circulatory shock on the combination of diltiazem retard and atenolol. Peripheral oedema and headache were more common on nisoldipine CC. We concluded that the two treatments were equally efficacious and tolerated in patients with stable angina pectoris.

Carvedilol and atenolol once daily in the treatment of hypertension.

Fifty milligrams of carvedilol and 100 mg atenolol were administered in a random order once a day for 2 months to 43 patients with mild to moderate hypertension, in a double-blind crossover study. Blood pressure, heart rate and peripheral blood flow parameters (n = 11) were recorded 2 and 24 h after the drug administration. Supine blood pressure was the same 2 h after both carvedilol and atenolol administration, but carvedilol caused a greater decrease in standing systolic blood pressure 2 h after the administration (P less than 0.05). The heart rate decreased less with carvedilol (P less than 0.01). There was no difference in the effects exerted by the two therapies on systolic blood pressure and the heart rate 24 h after drug administration, but the diastolic blood pressure was higher in patients given carvedilol (92 versus 88 mmHg; P less than 0.05). Forearm blood flow, forearm vascular resistance and calf blood flow did not change significantly with either of the therapies. In conclusion, 50 mg carvedilol once a day is an effective antihypertensive therapy, though its duration of action did not reach that of 100 mg atenolol once a day. Peripheral vasodilation was similar with both therapies.

Response of R wave amplitude to postural changes and to exercise. A study of healthy subjects and patients surviving acute myocardial infarction.

The effects of postural changes and bicycle ergometer exercise tests on R wave amplitude were studied in 10 sedentary and 21 physically active healthy men as well as in 158 male survivors of myocardial infarction. In the latter group recordings were made 6-8 weeks, 5 months and 12 months after the infarction, and also the effect of physical activity during the first post-infarction year on the R wave height responses was studied. At rest in the supine position the R wave amplitudes in the three groups studied were almost similar, but in the sitting position at rest and at the beginning of the exercise the R wave amplitudes were significantly higher in physically active healthy men than in sedentary healthy men or infarction patients. Physical training during the first post-infarction year induced only negligible changes in the R wave amplitude response to postural changes and exercise. The mechanisms which may underlie these different responses of R wave amplitude to postural changes and to exercise are discussed.

The Finnish sauna and cardiovascular diseases.

From time to time it has been claimed that the thermal stress caused by sauna bathing can be harmful to persons with cardiovascular disorders. Furthermore, elderly persons in general, who have experienced no symptoms from bathing, have also been cautioned. However, several studies carried out in Finland did not confirm the adverse effects of bathing on the elderly and cardiovascular patients. The controversial results obtained in Finnish and in some foreign studies are at least partly due to the different test conditions. The typical Finnish sauna bath is safe, and even patients who have recovered from acute myocardial infarction can enjoy the sauna without incurring any harmful cardiovascular effects.

Double-blind titrated-dose comparison of metoprolol and propranolol in the treatment of angina pectoris.

The effectiveness of metoprolol in relieving angina pectoris was compared with that of propranolol at equipotent dosages in a series of 20 patients. Before double-blind periods propranolol was given in gradually increased dosages to obtain a maximal effect for each individual patient. The responses were monitored using subjective assessment based on attack rate and nitroglycerin consumption, as well as objective maximal exercise testing. Both compounds significantly increased the exercise tolerance on a bicycle ergometer, and relieved angina as assessed subjectively. No significant differences were found between the responses to metoprolol and propranolol. The mean increase in exercise tolerance amounted to 36% with metoprolol. Biochemical monitoring revealed no harmful effects. Two cases of rebound phenomenon were observed at the transition from metoprolol to placebo. It was concluded that metoprolol is a useful new cardio-selective beta-blocking compound equipotent to propranolol in the treatment of angina pectoris.

Arrhythmias and ST segment deviation during prolonged exhaustive exercise (ski marathon) in healthy middle-aged men.

To evaluate the occurrence of arrhythmias and silent ischaemia during a prolonged exhaustive exercise in cold climate conditions, we monitored 37 healthy middle-aged men (age 40-56 years) who were randomly selected from participants of a ski marathon. Completing the 75-90 km race took 7-12 h. The highest and lowest mean hourly heart rates during skiing were 150 +/- 9 (mean +/- SD) and 138 +/- 11 beats.min-1. The maximum heart rate was 161 +/- 9 beats.min-1, and occurred in most skiers during the first hour. Ventricular premature complexes (VPCs) were present in 33 of 37 men (89%) with a median frequency of five beats during skiing (range 0-425). Complex forms occurred in eight men (22%), and atrial ectopics appeared in 33 of 35 participants (94%). The frequency of the arrhythmias did not increase over the skiing period. At control monitoring during a representative period the highest mean hourly heart rate was 74 +/- 12 beats.min-1 and VPCs were seen in 21 men (57%) at a median frequency of one beat during the control period (range 0-338) and complex forms occurred in three men (8%). Three men had asymptomatic ST segment depression of 0.2-0.3 mV lasting 2-10 min during the first hour of skiing. One of them had marginal ST segment depression (0.1 mV) at exercise electrocardiography, but all had normal results at exercise thallium scintigraphy and echocardiography. Thus, arrhythmias were significantly (P < 0.001) increased in middle-aged men during exhaustive prolonged exercise as compared to those observed during a similar period of time of normal daily life.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduction in sudden deaths by a multifactorial intervention programme after acute myocardial infarction.

375 consecutive patients below 65 years who had an acute myocardial infarction (AMI) took part in a randomised rehabilitation and secondary prevention trial (part of a W.H.O.-coordinated project) designed to study the effects of a multifactorial intervention programme on morbidity, mortality, return to work, &c. After three years' follow-up the cumulative coronary mortality was significantly smaller in the intervention group than in the controls (18.6% versus 29.4%, p = 0.02). This difference was mainly due to a reduction of sudden deaths in the intervention group (5.8% versus 14.4%, p less than 0.01). The reduction was greatest during the first six months after AMI. 18.1% in the intervention group and 11.2% in the controls (p less than 0.10) presented with non-fatal reinfarctions. The number of patients with new Q-QS findings at the end of the three years was, however, almost the same in both groups. The results suggest that organised aftercare during the first six months after AMI with special emphasis on optimum medical control and health education contributes significantly to a reduction in the number of sudden deaths.

Effects of alcohol ingestion on cardiac rhythm in patients with ischaemic heart disease.

The effect of alcohol on cardiac rhythm was examined in ten male volunteers with a history of acute myocardial infarction. ECG monitoring with a portable ECG recorder was carried out for a period of 48 hours. After a control period of 15-18 hours an exercise test was performed and repeated after a standard dose (0.5 g/kg b.wt.) of alcohol. Then the patients were allowed to drink alcohol freely for two and half hours. The third exercise test was performed on the second morning. Heart rate at rest and sitting on a bicycle was highest in the third test, during the "hangover" period (p less than 0.05). With a submaximal work load heart rate, and also the heart rate-blood pressure pressure product, were highest after a standard dose of alcohol in the second test (p less than 0.05 and less than 0.01 respectively). The number of ectopic beats showed no significant difference in repeated exercise tests. On tape recordings, however, five of the ten patients experienced changes in cardiac rhythm after alcohol. In two patients the number of ectopic beats increased, the third patient had three successive ventricular ectopic beats after alcohol ingestion and in the fourth patient multiple sinus arrests occurred. In one patient a higher heart rate after alcohol ingestion abolished the ventricular ectopic focus seen during the control period.

Comparison of potassium alone and potassium-magnesium supplementation in patients with heart failure using hydrochlorothiazide.

Supplementation of potassium alone and in combination with magnesium was compared in 10 patients with chronic compensated heart failure receiving hydrochlorothiazide 50 mg twice daily for the whole trial. After a 3-week run-in period, the patients were randomized to receive active supplementation for 6 weeks in a double-blind cross-over manner. A 3-week wash-out period was kept in between. Addition of 2 g potassium chloride daily (27 mmol K+) did not efficiently correct the serum potassium concentration. After the combined supplementation of 2 g potassium and 1 g magnesium (27 mmol K+ and 17 mmol Mg2+ daily), both serum potassium and magnesium concentrations increased statistically significantly during the first 2 weeks of treatment. After a longer treatment of 6 weeks, the effect of combined supplementation was less clear, even though a trend toward a better maintenance of serum potassium was still evident.

Long-term reduction in sudden deaths after a multifactorial intervention programme in patients with myocardial infarction: 10-year results of a controlled investigation.

Three-hundred and seventy-five unselected patients below 65 years of age and with acute myocardial infarction participated in a controlled investigation aimed at studying the effects of a multifactorial intervention programme on morbidity, mortality and risk factor control. After ten years' follow-up the significantly lower sudden death and coronary mortality observed three years after myocardial infarction still persisted in the intervention group (188 patients) compared with the control group (187 patients). The incidence of sudden death in the intervention group was 12.8% compared with 23.0% in the controls (P = 0.01). The incidence of coronary mortality was 35.1% and 47.1%, respectively (P = 0.02). No significant difference was found in the number of patients with clinical non-fatal reinfarctions (25.6% and 19.3%, respectively). During the first year, when the mortality difference was most marked, the use of beta blockers was not significantly different between the groups. The results suggest that with a multifactorial intervention programme which starts early after the infarction and lasts for years a significant long-term reduction in sudden deaths and coronary mortality can be attained.

Reduction in sudden deaths and coronary mortality in myocardial infarction patients after rehabilitation. 15 year follow-up study.

The study was set up to evaluate the long-term effects on mortality of a comprehensive rehabilitation and secondary prevention programme lasting 3 years after acute myocardial infarction. The study group consisted of 375 consecutive, non-selected patients under 65 years of age randomly allocated to an intervention group (188 patients) or a control group (187 patients). After 15 years follow-up significantly lower incidence of sudden death (16.5% vs 28.9%, P = 0.006) and coronary mortality (47.9% vs 58.5%, P = 0.04) were seen in the intervention group compared with controls. Total mortality was 64.4% and 66.8%, respectively (ns). The incidence of cancer death was 16 in the intervention group and three in the controls. Cardiac failure, enlarged heart, New York Heart Association functional class II or more and membership in the control group were significantly associated with coronary mortality during the first 3 years, and after 3 years enlarged heart, diabetes and reinfarction were associated with late coronary death. Thus, comprehensive multifactorial intervention after acute myocardial infarction had favourable long-term effects on coronary mortality and sudden death but no effect on total mortality.

Factors related to long-term prognosis following acute myocardial infarction. Importance of left ventricular function.

Factors related to 2-year and 4-year prognosis after acute myocardial infarction were studied in a series of 158 men. Stepwise multiple discriminant analysis was applied to findings recorded during hospital admission and to results of an exercise test carried out 6-8 weeks after the infarction. The best indicators for predicting a poor prognosis in the course of the following 2 years were a low systolic blood pressure on exercise and a palpable paradoxical cardiac pulsation. During the 4-year follow-up an abnormality of P terminal force in the ECG, which reflects left atrial overload, was the main predictor of poor prognosis.