INSIGHT and NORDIL

Stephen MacMahon and Bruce Neil1MacMahon S Neal B Differences between blood-pressure-lowering drugs.Lancet. 2000; 356: 352-353Summary Full Text Full Text PDF PubMed Scopus (27) Google Scholar present a well balanced commentary about the INSIGHT2Brown MJ Palmer CR Castaigne A et al.Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in The International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT).Lancet. 2000; 356: 366-372Summary Full Text Full Text PDF PubMed Scopus (1131) Google Scholar and NORDIL3Hansson L Hedner T Lund-Johansen P et al.Randomised trial of effects of calcium antagonists compared with diuretics and ß-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.Lancet. 2000; 356: 359-365Summary Full Text Full Text PDF PubMed Scopus (858) Google Scholar trials. We look eagerly towards the results of the collaborative meta-analysis of the 35 trials in which calcium antagonists, ACE inhibitors, angiotensin II antagonists, diuretics, or β-blockers have been compared. The difficulty with such a meta-analysis will be, however, to take into account the fact that in the most recent comparative studies, calcium antagonists and ACE inhibitors have been compared with conventional therapy such as thiazides or β-blockers in the first step, and associated with both in a second step, whereas in a second step, ACE inhibitors have been associated with thiazides4Hansson L Lindholm L Niskanen L et al.Effect of angiotensin-converting inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomised trial.Lancet. 1999; 353: 611-616Summary Full Text Full Text PDF PubMed Scopus (1930) Google Scholar and the dihydropyridine calcium antagonists with β-blockers. These confounding associations will make it difficult to answer whether ACE inhibitors in hypertensive patients are less strokeprotective than diuretics, as feared by J M Brown and T Brown in 1986 after the MRC trial in middle-aged people with hypertension showed three-fold better protection of stroke with thiazides at high doses than with propranolol. MacMahon and Neal seem reassuring by stating that the greater stroke risk with captopril than with conventional therapy in the Captoril Prevention Project4Hansson L Lindholm L Niskanen L et al.Effect of angiotensin-converting inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomised trial.Lancet. 1999; 353: 611-616Summary Full Text Full Text PDF PubMed Scopus (1930) Google Scholar was largely or possibly entirely accounted for by the higher baseline and follow-up blood pressure in the captopril group. This difference was, however, only 2·2 mm Hg and 1·7 mm Hg for systolic and diastolic blood pressure, respectively, which was similar to that seen in the Heart Outcomes Prevention Evaluation (HOPE) study5Heart Outcomes Prevention Evaluation (HOPE) Study InvestigatorsEffects of angiotensin-converting-enzyme inhibitor on death from cardiovascular causes, myocardial infarction and stroke in high-risk patients.N Engl J Med. 2000; 342: 145-153Crossref PubMed Scopus (8258) Google Scholar (3 mm Hg and 1·5 mm Hg between the ramipril and the placebo group). Since this latter difference in HOPE was thought to account for a difference in stroke risk of only 13%, we propose to make the same correction for the increase in stroke risk with captopril. The bloodpressure-independent higher stroke risk in the on-treatment analysis is, therefore, still 43-13 (30%), which might not be marginal. Dismissal of this 30% difference might not be justified because in the acute brain ischaemia induced in the gerbil by unilateral carotid ligation, enalaprilat premedication decreases survival, whereas losartan improves it. Since the previous preadministration of these two drugs also decreases survival, non-angiotensin I receptor stimulation is suggested to be of crucial importance in the case of acute cerebral-artery occlusion to favour rapid recruitment of pre-established collateral circulation. The absence of this rescue mechanism might account for worse stroke protection seen with β-blockers and captopril than with diuretics in hypertensive patients without advanced atherosclerosis. This hypothesis does not contradict the stroke protection given by high doses of ramipril in the HOPE study in patients with symptomatic atherothrombotic disease, in whom the atherosclerotic plaque destabilisation favoured by angiotensin II would be prevented by this highly tissue specific ACE inhibitor, even in the absence of any significant decrease in blood pressure. INSIGHT and NORDILAuthors' reply Full-Text PDF INSIGHT and NORDILAuthors' reply Full-Text PDF