Elsevier

The Lancet

Volume 351, Issue 9118, 13 June 1998, Pages 1755-1762
The Lancet

Articles
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

https://doi.org/10.1016/S0140-6736(98)04311-6Get rights and content

Summary

Background

Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.

Methods

18 790 patients, from 26 countries, aged 50–80 years (mean 61·5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure ⩽90 mm Hg, 6264 to ⩽85 mm Hg, and 6262 to ⩽80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.

Findings

Diastolic blood pressure was reduced by 20·3 mm Hg, 22·3 mm Hg, and 24·3 mm Hg, in the ⩽90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82·6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86·5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group ⩽80 mm Hg compared with target group ⩽90 mm Hg (p for trend=0·005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0·03) and all myocardial infarction by 36% (p=0·002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0·001).

Interpretation

Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.

Introduction

The background and rationale of the Hypertension Optimal Treatment (HOT) Study have been presented previously in some detail.1 In brief, it is well documented that treatment of hypertension reduces cardiovascular morbidity and mortality.2, 3 However, it is obvious that treated patients with hypertension remain at a greater risk of developing cardiovascular complications than matched normotensive individuals.4, 5 One possible explanation could be that the blood pressure of the patients with hypertension has not been lowered to strictly normotensive levels.6 Indeed, epidemiological surveys in various parts of the world indicate that less than 30% of patients with hypertension have their blood pressure brought down below 140/90 mm Hg.7, 8 In addition, concerns have been expressed that too vigorous reduction in blood pressure may be associated with increased cardiovascular risk—the so-called J-curve concept.9, 10, 11, 12 The issue of how far blood pressure should be lowered to achieve the greatest benefit, in terms of reduced cardiovascular morbidity and mortality, has been a matter of scientific debate.13 The real issue is not whether the relation between achieved blood pressure and cardiovascular events is J-shaped (it must be), but whether there are additional benefits, or risks, in lowering blood pressure of patients with hypertension to fully normotensive levels—ie, between 70 mm Hg and 85 mm Hg diastolic blood pressure—or whether there is little further benefit in lowering diastolic blood pressure much below 90 mm Hg.14 This issue needed to be addressed in a randomised and prospective trial and this was one of the reasons for doing the present study.

Another possible approach to improving treatment benefits in patients with hypertension is that of associating antihypertensive therapy with correction of other cardiovascular risk factors. Acetylsalicylic acid (aspirin) has been shown to reduce the incidence of stroke and myocardial infarction when given long term to healthy individuals or patients with previous cardiovascular events15, 16, 17 but its effects in individuals without a history of cardiovascular disease have been less clear and more controversial.18, 19 However, no intervention studies with acetylsalicylic acid have been done in patients with hypertension, possibly because the use of acetylsalicylic acid has been associated with a small increase in the risk of cerebral haemorrhage; a risk that could be greater in hypertension.

The principal aims of this study were: to assess the association between major cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) and the target blood pressures ·90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg during antihypertensive treatment; to assess the association between major cardiovascular events and the diastolic blood pressure achieved during treatment; and to find out whether the addition of low doses of acetylsalicylic acid to antihypertensive treatment reduces the rate of major cardiovascular events.

Section snippets

Study population and organisation

The patient population in the HOT Study has been described previously.20 In brief, 19 193 patients from 26 countries, aged 50–80 years (mean 61·5 years), with hypertension and a diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target blood pressure and acetylsalicylic acid or placebo. Because of the suspicion of incorrect inclusion or data handling at one centre, 403 patients were excluded early in the trial. Patients were recruited from

Study population

6264 patients were given the diastolic blood-pressure target of ⩽90 mm Hg, 6264 a target of ⩽85 mm Hg, and 6262 a target of ⩽80 mm Hg (figure 1). In addition, 9399 patients were randomly assigned acetylsalicylic acid and 9391 patients were assigned placebo. A total of 491 (2·6%) patients were lost to follow-up. Most were lost early in the study—eg, 130 patients did not return for any of the follow-up visits. The loss in terms of patient years was 1269 (1·8%). The loss of patients in the three

Blood-pressure effects of treatment

An important finding is that substantial reductions in blood pressure can be achieved with a treatment regimen based on the long-acting calcium antagonist, felodipine. Even in patients who were receiving treatment before enrolment (52·6%) there was a striking further reduction in blood pressure with the treatment regimen used.20 The overall reductions in diastolic and systolic blood pressures are striking—eg, in comparison with those reported in the meta-analysis by Collins and colleagues2 (5–6

Conclusion

The principal results of the HOT Study demonstrate the benefits of lowering blood pressure in patients with hypertension to 140 mm Hg systolic and 85 mm Hg diastolic, or lower. Efforts to lower blood pressure further, down to 120 mm Hg systolic and 70 mm Hg diastolic, appear to give little further benefit, but do not cause any significant additional risk. Active lowering of blood pressure was particularly beneficial in the subgroup of patients with diabetes mellitus. On the whole, the rate of

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