Neil Chapman

Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration.

BACKGROUNDnThis programme of overviews of randomised trials was established to investigate the effects of angiotensin-converting-enzyme (ACE) inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients. We did separate overviews of trials comparing active treatment regimens with placebo, trials comparing more intensive and less intensive blood-pressure-lowering strategies, and trials comparing treatment regimens based on different drug classes.nnnMETHODSnThe hypotheses to be investigated, the trials to be included, and the outcomes to be studied were all selected before the results of any participating trial were known. Individual participant data or group tabular data were provided by each trial and combined by standard statistical techniques.nnnFINDINGSnThe overview of placebo-controlled trials of ACE inhibitors (four trials, 12,124 patients mostly with coronary heart disease) revealed reductions in stroke (30% [95% CI 15-43]), coronary heart disease (20% [11-28]), and major cardiovascular events (21% [14-27]). The overview of placebo-controlled trials of calcium antagonists (two trials, 5520 patients mostly with hypertension) showed reductions in stroke (39% [15-56]) and major cardiovascular events (28% [13-41]). In the overview of trials comparing blood-pressure-lowering strategies of different intensity (three trials, 20,408 patients with hypertension), there were reduced risks of stroke (20% [2-35]), coronary heart disease (19% [2-33]), and major cardiovascular events (15% [4-24]) with more intensive therapy. In the overviews comparing different antihypertensive regimens (eight trials, 37,872 patients with hypertension), several differences in cause-specific effects were seen between calcium-antagonist-based therapy and other regimens, but each was of borderline significance.nnnINTERPRETATIONnStrong evidence of benefits of ACE inhibitors and calcium antagonists is provided by the overviews of placebo-controlled trials. There is weaker evidence of differences between treatment regimens of differing intensities and of differences between treatment regimens based on different drug classes. Data from continuing trials of blood-pressure-lowering drugs will substantially increase the evidence available about any real differences that might exist between regimens.

Association of Mean Platelet Volume With Risk of Stroke Among 3134 Individuals With History of Cerebrovascular Disease

Background and Purpose— Mean platelet volume (MPV) is positively associated with measures of platelet activity and may be a useful indicator of the risk of vascular events in a variety of patient groups. Methods— The association of MPV with the risk of stroke was assessed in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). All participants had a history of cerebrovascular disease at baseline, and analyses were adjusted for the effects of potential confounders. Results— The study followed 3134 individuals for an average of 3.9 years (mean age, 65 years; 71% male; average MPV, 10.0 fL). Three hundred eighty-three individuals had 402 stroke events, and 160 had major coronary events. MPV was positively associated with the risk of stroke, with an 11% increased relative risk (95% CI, 3% to 19%) of stroke per femtoliter greater MPV. There was no clear association of MPV with the risk of major coronary events (9% decreased relative risk; 95% CI, −23% to 7%). Perindopril did not alter MPV. Conclusions— MPV is an independent predictor of the risk of stroke among individuals with a history of stroke or transient ischemic attack. The measurement of MPV may add useful prognostic information for clinicians managing patients with a history of cerebrovascular disease.

The ACE Gene I/D Polymorphism Is Not Associated With the Blood Pressure and Cardiovascular Benefits of ACE Inhibition

Abstract—The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE I/D genotypes were measured in 5688 of 6105 individuals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The DD genotype was significantly (P <0.0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline; neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.

Perindopril-based blood pressure lowering in individuals with cerebrovascular disease: consistency of benefits by age, sex and region.

Objective To assess the consistency of the benefits of blood pressure lowering on secondary stroke risk by age, sex and geographic region of recruitment. Design Randomized, placebo-controlled trial. Participants were randomized to the angiotensin-converting enzyme (ACE) inhibitor perindopril (plus the diuretic indapamide if not indicated or contraindicated) or to placebo(s) over a mean follow-up of 3.9 years. Main analyses used Cox proportional hazards models on an intention-to-treat basis. Subgroup results were standardized for the proportion (42%) taking single-drug therapy. Setting A total of 172 centres in Asia, Australia, New Zealand and Europe. Participants Patients (n = 6105) with a history of stroke or transient ischaemic attack, of whom 50% were aged over 65 years at baseline, 30% were women and 39% were from Asia. Main outcome measures Stroke, coronary heart disease and major vascular events. Results Overall, treatment reduced stroke by 28% [95% confidence interval (CI) 17–38%] and major vascular events by 26% (16–44%), with separately significant reductions across subgroups defined by age (< or ⩾ 65 years), sex and region (Asia or not). Treatment was safe and well tolerated, and the absolute benefits were large; 5 years’ treatment would be expected to avert at least one major vascular event among every 20 patients in all age, sex and region subgroups. There was some evidence of particularly large benefits among younger participants and those from Asia. Conclusions Blood pressure lowering reduces secondary stroke risk, with large absolute benefits across groups defined by age, sex and geographic region.

Challenges for the prevention of primary and secondary stroke: the importance of lowering blood pressure and total cardiovascular risk

It is well established that blood pressure lowering is effective for the primary prevention of stroke and other cardiovascular disorders in subjects with blood pressures as low as 140/90 mmHg, and up to 80 years of age. Despite this knowledge, blood pressure levels are controlled in less than 25% of the hypertensive population worldwide. It has taken longer to prove that blood pressure lowering is equally effective for the prevention of recurrent stroke. The results of PROGRESS (Perindopril Protection Against Recurrent Stroke Study) have confirmed that a perindopril-based regimen in subjects with cerebrovascular disease substantially reduces the incidence of secondary stroke and primary myocardial infarction. It is daunting to recall that it has taken almost two decades for beta-blockers to be widely used for the secondary prevention of myocardial infarction, since widespread use of the PROGRESS regimen would prevent more than half a million strokes worldwide each year. The real challenge now is to implement novel and effective strategies for the control of blood pressure and other cardiovascular risk factors worldwide. Strategies should include lifestyle measures, such as stopping smoking, exercise and reducing overweight. There is a real need to identify hypertensive subjects and treat them with blood pressure lowering drugs for primary prevention. In subjects with established cardiovascular disease, consideration should be given to a range of proven interventions for secondary prevention, such as blood pressure lowering, irrespective of current blood pressure, anti-platelet drugs, statins for lowering cholesterol and glycaemic control in diabetics. Among new strategies to lower overall cardiovascular risk, consideration should be given to the development of single-pill combinations of drugs of known efficacy, including various combinations of ACE inhibitors, diuretics, beta-blockers, aspirin and statins, among others.

Managing the global burden of cardiovascular disease

There is a large and increasing global burden of cardiovascular disease. Approximately 14 million individuals died of cardiovascular disease in 1990, and this is projected to rise to about 25 million by 2020. In large part, this increase can be explained on the basis of major ongoing sociodemographic changes in developing countries, and associated effects on the numbers of individuals at risk and the levels of cardiovascular risk factors. Developing countries now experience a much greater burden of cardiovascular disease than do developed countries. In addition, developing countries are expected to experience the greatest rise in cardiovascular disease burden over the next few years. Cardiovascular disease prevention programmes designed and implemented primarily in developed countries have most likely averted much premature cardiovascular disease in those countries over the past few decades. However, cardiovascular disease prevention programmes designed for developed countries are unlikely to be directly transferable to developing countries. Reliable information to inform the design and implementation of cardiovascular disease prevention programmes, tailored to the socioeconomic circumstances of developing countries, is now required. Such programmes have great potential to impact on the current and projected global epidemic of cardiovascular disease.

Effects of blood pressure lowering on cardiovascular risk according to baseline body-mass index: a meta-analysis of randomised trials.

Methods We used individual patient data from trials included in the Blood Pressure Lowering Treatment Trialists’ Collaboration to compare the eff ects of diff erent classes of blood pressure-lowering regimens for the primary outcome of total major cardiovascular events (stroke, coronary heart disease, heart failure, and cardiovascular death). We used meta-analyses and meta-regressions to assess interactions between treatment and BMI when fi tted as either a categorical variable (<25 kg/m2, 25 to <30 kg/m2, and ≥30 kg/m2) or a continuous variable.BACKGROUNDnThe cardiovascular benefits of blood pressure lowering in obese people compared with people of normal weight might depend on choice of drug. We compared the effects of blood pressure-lowering regimens on cardiovascular risk in groups of patients categorised by baseline body-mass index (BMI).nnnMETHODSnWe used individual patient data from trials included in the Blood Pressure Lowering Treatment Trialists Collaboration to compare the effects of different classes of blood pressure-lowering regimens for the primary outcome of total major cardiovascular events (stroke, coronary heart disease, heart failure, and cardiovascular death). We used meta-analyses and meta-regressions to assess interactions between treatment and BMI when fitted as either a categorical variable (<25 kg/m(2), 25 to <30 kg/m(2), and ≥30 kg/m(2)) or a continuous variable.nnnFINDINGSnAnalyses were based on 135,715 individuals from 22 trials who had 14,353 major cardiovascular events. None of the six primary comparisons showed evidence that protection varied by drug class across the three BMI groups (all p for trend >0·20). When analysed as a continuous variable, angiotensin-converting-enzyme inhibitors gave slightly greater protection for each 5 kg/m(2) higher BMI than did calcium antagonists (hazard ratio 0·93, 95% CI 0·89-0·98; p=0·004) or diuretics (0·93, 0·89-0·98; p=0·002). The meta-regressions showed no relation between BMI category and the risk reduction for a given fall in systolic blood pressure. By contrast with a previous report, we noted no relation between BMI and the efficacy of calcium antagonists compared with diuretics.nnnINTERPRETATIONnWe found little evidence that selection of a particular class of blood pressure-lowering drug will lead to substantially different outcomes for individuals who are obese compared with those who are lean.nnnFUNDINGnNone.

Progress In Reducing The Burden Of Stroke

1. The burden of stroke worldwide is growing rapidly, driven by an ageing population and by the rapid rate of urbanization and industrialization in the developing world. There are approximately 5 million fatal and 15 million non‐fatal strokes each year and over 50 million survivors of stroke alive, worldwide, today.

Blood pressure lowering in diabetes: a brief review of the current evidence and description of a new trial.

1. Diabetes is a major global public health problem. The prevalence of this disease is predicted to increase sharply in the coming decades, particularly in less‐developed regions of the world.