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mm Hg was recorded in 18% of patients with L, 19% with E and 45% with L/E. Two patients on P and two on L/E were withdrawn from the study due to adverse events.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.

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.

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.

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.

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)

Alcohol and sauna bathing: effects on cardiac rhythm, blood pressure, and serum electrolyte and cortisol concentrations.

The effect of heavy drinking and sauna bathing on cardiac rhythm, blood pressure, and serum electrolyte and cortisol concentrations was studied in 10 healthy male volunteers. Sauna bathing induced a comparable, significant increase in heart rate with and without alcohol consumption. During sauna bathing without alcohol, systolic blood pressure remained at the baseline level, whereas sauna and alcohol together decreased systolic blood pressure markedly from 136 +/- 4 to 113 +/- 3 mmHg (P less than 0.01). Neither sauna alone, nor sauna combined with alcohol intake, increased the frequency of premature ventricular complexes. Serum potassium, calcium and cortisol concentrations changed slightly during sauna, but alcohol consumption did not contribute further to this. In conclusion, sauna bathing, even in combination with heavy drinking, does not appear to provoke cardiac arrhythmias in healthy young men. However, the risk of hypotension is increased when sauna bathing is combined with alcohol consumption.

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.

Prognostic value of an exercise test one year after myocardial infarction.

An exercise test was performed in 306 patients who had had acute myocardial infarction one year previously. The five year cumulative coronary heart disease mortality was 40.0%, when the test had to be discontinued because of ventricular arrhythmias but only 13.0% if discontinued because of fatigue (P less than 0.05). If the maximum work load was less than 80 W the mortality was 30.7% compared with 16.6% in patients who exercised at least 80 W (P less than 0.01). If maximum systolic blood pressure was less than or equal to 150 mmHg mortality was 40.3% compared with 8.5% in patients with greater than 200 mgHg (P less than 0.001). The mortality was 38.2% in patients having single monoform ventricular ectopic beats at a rate of three or more per minute or multiform, paired or early cycle ventricular ectopic beats or ventricular tachycardias: this compared with 14.1% (P less than 0.001) in patients having no or only single monoform ventricular ectopic beats at a rate of less than three per minute. ST-segment depression in univariate testing had no prognostic value. When both exercise test and clinical variables were used in survival analysis (Cox's regression) the most important variable was heart volume and after that ventricular arrhythmias. In multivariate regression analysis ST segment depression also had additional prognostic value. Thus ventricular arrhythmias turned out to be the most important prognostic factor measured during exercise test.

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.

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.

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.

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.

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.