[Comparison of preventive effect of "new" and "old" antihypertensive agents]. / Sammenlikning av forebyggende effekt av "nye" og "gamle" blodtrykksmedisiner.

BACKGROUND: Until recently no morbidity-mortality study had examined the effects of newer drugs like angiotensin-converting enzyme inhibitors, calcium-antagonists and alpha-blockers compared to "old" but well-proven thiazide diuretics and beta-blockers in the treatment of essential hypertension. MATERIAL AND METHODS: The prospective and randomized clinical trials CAPPP, STOP-2, NORDIL, INSIGHT and one arm of ALLHAT, with a total of approximately 58,000 middle-aged or elderly hypertensive patients have been assessed. RESULTS: The primary outcome, composite cardiovascular (CV) death, cerebral stroke and myocardial infarction, in one study with heart failure, or composite fatal coronary heart disease and myocardial infarction, was equal in all trials. INTERPRETATION: According to current evidence, prevention of cardiovascular disease in hypertension is the same irrespective of the class of drug.

Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.

BACKGROUND: Calcium antagonists are a first-line treatment for hypertension. The effectiveness of diltiazem, a non-dihydropyridine calcium antagonist, in reducing cardiovascular morbidity or mortality is unclear. We compared the effects of diltiazem with that of diuretics, beta-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients. METHODS: In a prospective, randomised, open, blinded endpoint study, we enrolled 10,881 patients, aged 50-74 years, at health centres in Norway and Sweden, who had diastolic blood pressure of 100 mm Hg or more. We randomly assigned patients diltiazem, or diuretics, beta-blockers, or both. The combined primary endpoint was fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death. Analysis was done by intention to treat. FINDINGS: Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups (reduction 20.3/18.7 vs 23.3/18.7 mm Hg; difference in systolic reduction p<0.001). A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group (16.6 vs 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87-1.15], p=0.97). Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group (6.4 vs 7.9 events per 1000 patient-years; 0.80 [0.65-0.99], p=0.04) and fatal and non-fatal myocardial infarction in 183 and 157 patients (7.4 vs 6.3 events per 1000 patient-years; 1.16 [0.94-1.44], p=0.17). INTERPRETATION: Diltiazem was as effective as treatment based on diuretics, beta-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death.

Cardiac conduction with diltiazem and beta-blockade combined. A review and report on cases.

Sinus arrest or atrioventricular block are rare but serious adverse effects of diltiazem. The risk of developing such adverse reactions may be somewhat exacerbated by concomitant beta-adrenergic blocker therapy. In patients with hypertension or coronary heart disease, combination therapy with diltiazem and a beta-blocker usually enhances therapeutic benefit relative to monotherapy, but adverse effects attributable to this combination, especially in patients with left ventricular dysfunction or latent cardiac conduction deficits, may be limiting. Therefore, such combination therapy may not be suitable in patients with atrioventricular block grade I, bradycardia or hypotension, and patients on the combined therapy should always have their blood pressure, heart rate and atrioventricular conduction on ECG monitored. If combination therapy with diltiazem and propranolol or metoprolol is commenced, or in the case of impaired renal function, an adjustment of the beta-blocker dosage may be required. Clinical studies on the combined use of diltiazem and beta-adrenergic blockers mostly concern the treatment of angina pectoris in patients with coronary heart disease. Although very few cases of severe bradycardia and conduction abnormalities have been reported in patients with uncomplicated hypertension on diltiazem and beta-blockade combination, there seems to be a potential for the occurrence of significant conduction disturbances with the combined treatment, and precautions should apply also for hypertensive populations.

[Status of ongoing controlled clinical trials on hypertension]. / Status for pågående kontrollerte kliniske hypertensjonsforsøk.

Antihypertensive treatment with diuretics and/or beta-blockers lowers stroke and coronary heart disease morbidity and mortality. However, although the newer antihypertensives induce effective control of blood pressure and regression of hypertensive organ damage, it has not been proven whether they reduce mortality. Ongoing clinical trials such as STOP II, CAPPP, NORDIL, INSIGHT, ALLHAT and LIFE test whether antihypertensive regimens with ACE-inhibitor, calcium-blocker, alpha-blocker and Angiotensin II-antagonist are equally good or possibly even better than diuretics and beta-blockers in preventing cardiovascular complications. The HOT trial clarifies how much the diastolic blood pressure should be lowered, and whether a small dose of aspirin has a protective effect when combined with optimal control of blood pressure. These studies should give better guidelines for the treatment of hypertension.

Female preponderance for lisinopril-induced cough in hypertension.

In a double-blind double-dummy multicenter study, patients with mild to moderate essential hypertension were randomized to receive either nifedipine (n = 416, 47.6% women) or lisinopril (n = 412, 50% women), and side effects were registered by specific questioning, by spontaneous reports, and by use of visual analog scales. Cough was spontaneously reported to occur in 8.5% with lisinopril compared to 3.1% with nifedipine. Women treated with lisinopril reported cough spontaneously three times more often than men, 12.6% v 4.4%, whereas no differences between the sexes were observed during the placebo period or during nifedipine treatment. Similar gender differences were observed during specific questioning. Furthermore, nonsmokers reported an increase in cough more often than did smokers.

[Lisinopril and nifedipine have neutral effects on lipids]. / Lisinopril og nifedipin er lipidnøytrale.

In a randomized, double blind, parallel-group, multicentre study in Norway, 97 patients with mild to moderate hypertension (mean blood pressure 159/104 mm Hg) were treated with either lisinopril 10-40 mg or nifedipine 20-80 mg and the effects on blood lipids were evaluated. Complete results of laboratory analyses are given for 80 patients. After a 4 week run-in and placebo period, antihypertensive treatment was given for the next 10 weeks. During treatment with lisinopril the changes in lipids were +2.1% for total cholesterol, +0.7% for HDL-cholesterol, +3.8% for triglycerides and -6.1% for ratio HDL/cholesterol-HDL. For nifedipine the corresponding values were -2.4% for cholesterol, -5.8% for HDL-cholesterol, +8.0% for triglycerides and +3.2% for ratio. None of these changes was statistically significant. Both lisinopril and nifedipine lowered the blood pressure significantly, 18.1/12.0 mm Hg with lisonopril (p < 0.01 for both systolic and diastolic pressure) and 8.0/8.5 mm Hg with nifedipine (p < 0.01 for both respectively). Both drugs were well tolerated. In conclusion, neither lisinopril nor nifedipine had any negative impact on lipid levels.

Effect and tolerability of combining lovastatin with nifedipine or lisinopril.

Single cardiovascular risk factor intervention is probably not sufficient to prevent atherosclerosis progression. There is a lack of data on concomitant use of hypocholesterolemic agents and antihypertensive drugs with respect to possible interactions and adverse experiences. We studied 293 patients (below 65 years of age) under treatment with either lisinopril (n = 144) or nifedipine (n = 149) for mild to moderate hypertension for 10 weeks, and with serum cholesterol above 6.5 mmol/L, who were randomized to either lovastatin 20 mg every day or placebo in a double-blind, double-dummy design for 6 weeks. Lovastatin effectively lowered cholesterol by 16% and 15% in the lisinopril and nifedipine group respectively (P < .01 compared to placebo for both groups) without any negative impact on the antihypertensive efficacy of either lisinopril or nifedipine. The drugs in combination were well tolerated and did not affect the well-being of the patients, and did not cause any more adverse effects than the antihypertensive agents alone. Liver enzymes increased slightly during lovastatin therapy, while no case of myopathy was reported. Combined therapy with lovastatin and antihypertensive therapy can be safely undertaken.

[Can treatment of hypertension prevent myocardial infarction? New controlled clinical trials are proposed]. / Kan hypertensjonsbehandling forebygge hjerteinfarkt? Nye kontrollerte kliniske forsøk igangsettes.

The only antihypertensive treatment regimen with documented effect on morbidity and mortality from stroke and coronary heart disease is based on diuretics and/or beta-blockers. However, new antihypertensive drugs are now widely used. These compounds may also prevent cardiovascular complications, but, as yet, this has not been proven. The clinical trials of the 1990s such as STOP II, CAPPP and NORDIL will test whether antihypertensive treatment with ACE-inhibitors and calcium-blockers are more effective than diuretics and beta-blockers in preventing cardiovascular complications. Also, a large-scale study (HOT) is being undertaken to examine how far diastolic blood pressure should be treated, and whether a small dose of aspirin has a protective effect when combined with good control of blood pressure. These studies will hopefully lead to better guidelines for the future treatment of hypertension.

[Cough during treatment with angiotensin-converting enzyme inhibitors is gender related]. / Hoste ved angiotensinkonverterende enzymhemning er kjønnsrelatert.

In a Norwegian, double-blind, double-dummy multicenter study, 828 patients with mild to moderate hypertension were randomized to treatment by either lisinopril or nifedipine. One of the aims of the study was to specifically investigate the frequency of side effects. Spontaneously reported coughing reached 8.5% for lisinopril, as against 3.1% for nifedipine. In two patients coughing led to withdrawal from the study, and in another three it contributed partially to discontinuation of the treatment. A significant sex difference was found for spontaneously reported coughing among patients on lisinopril; 12.6% of the women and 4.4% of the men. A similar difference between the sexes was found for specific questioning about coughing. Use of a visual analogue scale by both patient and spouse revealed similar frequency of coughing as when reported spontaneously. The reason for sex being an important determinant for lisinopril-induced coughing remains obscure.

[Treatment with lisinopril or nifedipine in essential hypertension. A Norwegian multicenter study of the effect, tolerance and quality of life of 828 patients]. / Behandling med lisinopril eller nifedipin ved essensiell hypertensjon. En norsk multisenterstudie av effekt, toleranse og livskvalitet hos 828 pasienter.

In a randomized, parallel, double-blind study, lisinopril (n = 412) reduced systolic and diastolic blood pressure more than nifedipine did (n = 416) after ten weeks treatment in patients (40-70 years) with mild to moderate essential hypertension. Lisinopril was tolerated better than nifedipine, with fewer withdrawals. Adverse experiences reported after a general question on discomfort were significantly lower for lisinopril than for nifedipine. Questions referring specifically to symptoms revealed higher frequency of coughing with lisinopril, while flushing, edema, palpitations, dizziness, tiredness and rash were reported more frequently with nifedipine. Quality of life was similarly assessed by both patients and spouses. No significant differences in well-being during treatment were found for either drug, except in the case of the highest dose level of nifedipine, which caused a deterioration of well-being.

Lisinopril or nifedipine in essential hypertension? A Norwegian multicenter study on efficacy, tolerability and quality of life in 828 patients.

In a randomized, parallel, double-blind study, lisinopril (n = 412; average dose 18.8 mg) reduced systolic and diastolic blood pressure (change = 20.2/13.8 mmHg; P less than 0.01/P less than 0.01) more than nifedipine (n = 416; average dose 37.4 mg; change = 13.3/11.2 mmHg) after 10-week treatment in patients, aged 40-70 years, with mild-to-moderate essential hypertension. Lisinopril was better tolerated than nifedipine. The withdrawals from treatment were fewer in the lisinopril-treated group (11 versus 46; P less than 0.01). The frequency of adverse experiences reported after a general question of discomfort was significantly lower for lisinopril than for nifedipine (P less than 0.01). When questioned on specific symptoms, frequency of coughing was higher with lisinopril (P less than 0.01), while flushing, edema, palpitations, dizziness, tiredness and rash were reported more frequently (P less than 0.01, for all) in the nifedipine-treated group. Quality of life was assessed by both patients and spouses. No significant changes in wellbeing were observed for either drug, except for the highest dose level of nifedipine which caused a deterioration.

[The effect of doxazosin on blood pressure, lipids, fibrinogen and plasminogen activator inhibitor. A comparative study among smokers and non-smokers with essential hypertension]. / Effekten av doxazosin på blodtrykk, lipider, fibrinogen og plasminogenaktivator-inhibitor. En sammenliknende studie hos røykere og ikke-røykere med essensiell hypertensjon.

Hypertensive cigarette smokers run particularly high risk of coronary heart disease. Doxazosin, which has beneficial effects on haemodynamic factors and lipid metabolism, may be a suitable agent for treating these patients. The effects on blood pressure and metabolic parameters were investigated in a 16-week, open, parallel, comparative study comprising 64 heavy cigarette smokers and 69 non-smokers who received doxazosin after four weeks on placebo. Eight patients (three smokers and five non-smokers) dropped out due to adverse effects. Blood pressure was significantly reduced in both groups, but there was no change in heart rate. Doxazosin induced a decrease in the triglyceride, total cholesterol and LDL-cholesterol levels, and an increase in HDL-cholesterol concentration. Thus, doxazosin has favourable effects on atherogenic factors in smoking hypertensive patients. There was also a significant lowering of plasma fibrinogen levels and plasminogen activator inhibitor (PAI-1) concentration in non-smokers.

Selective alpha 1 inhibition with doxazosin in hypertensive smokers and non-smokers: haemodynamic and metabolic effects.

Hypertensive cigarette smokers have an especially high risk of coronary heart disease. Doxazosin, which has beneficial effects on haemodynamic factors and lipid metabolism, may be suitable for treating these patients. The haemodynamic and metabolic effects of doxazosin were investigated in a 16-week open, parallel, comparative study of 64 heavy cigarette smokers and 69 non-smokers after a 4-week placebo period. Of the 133 patients who entered, six patients (one smoker and five non-smokers) withdrew due to adverse events. Doxazosin significantly reduced blood pressure without reflex tachycardia in both the smokers and the non-smokers. The therapeutic success rates (reduction in sitting diastolic blood pressure to less than or equal to 90 mmHg and greater than or equal to 5 mmHg reduction, or greater than or equal to 10 mmHg reduction from baseline) were similar for the smokers (93.3%) and the non-smokers (92.5%). Doxazosin significantly decreased total cholesterol and low-density lipoprotein (LDL) cholesterol, but increased high-density lipoprotein (HDL) cholesterol and the HDL:total cholesterol ratio in both smokers and non-smokers. Doxazosin corrected the reduction in HDL cholesterol caused by smoking; compared with baseline, doxazosin increased HDL cholesterol by 19% in hypertensive smokers. The beneficial effects of doxazosin on blood pressure and the lipid profile were apparent in the change in the 10-year probability of developing coronary heart disease as calculated by the Framingham equation; the calculated risk of coronary heart disease decreased by 39% in smokers and by 33% in non-smokers. Plasma fibrinogen and plasminogen activator inhibitor, which independently contribute to atherosclerosis, were significantly reduced by doxazosin in the non-smokers but not in the smokers.