BMJ 2002;324:699-702 ( 23 March )

Papers

Use of ramipril in preventing stroke: double blind randomised trial

Editorial by Schrader and Lüders

Jackie Bosch, assistant professor ^a, Salim Yusuf, professor of medicine ^a, Janice Pogue, senior statistician ^a, Peter Sleight, professor emeritus ^b, Eva Lonn, associate professor of medicine ^a, Badrudin Rangoonwala, medical consultant ^c, Richard Davies, associate professor ^d, Jan Ostergren, researcher ^e, Jeff Probstfield, professor of medicine ^f,  on behalf of the HOPE Investigators.

^a Canadian Cardiovascular Collaboration, McMaster University, 237 Barton St E, Hamilton, ON, Canada L8L 2X2, ^b Cardiac Department, John Radcliffe Hospital, Oxford OX3 9DU, ^c Dahlien Weg 11, D65719 Hofheim-Taunus, Germany, ^d University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, ON, Canada K1Y 4W7, ^e Karolinska Institute, Stockholm, Sweden SE-171 77, ^f University of Washington, 1124 Columbia Street, Seattle, WA 98104, USA

Correspondence to: J Bosch jackie{at}ccc.mcmaster.ca

	Abstract

Top Abstract Introduction Design and methods Results Discussion References

Objective: To determine the effect of the angiotensin converting enzyme inhibitor ramipril on the secondary prevention of stroke.
Design: Randomised controlled trial with 2×2 factorial design.
Setting: 267 hospitals in 19 countries.
Participants: 9297 patients with vascular disease or diabetes plus an additional risk factor, followed for 4.5 years as part of the HOPE study.
Outcome measures: Stroke (confirmed by computed tomography or magnetic resonance imaging when available), transient ischaemic attack, and cognitive function. Blood pressure was recorded at entry to the study, after 2 years, and at the end of the study.
Results: Reduction in blood pressure was modest (3.8 mm Hg systolic and 2.8 mm Hg diastolic). The relative risk of any stroke was reduced by 32% (156 v 226) in the ramipril group compared with the placebo group, and the relative risk of fatal stroke was reduced by 61% (17 v 44). Benefits were consistent across baseline blood pressures, drugs used, and subgroups defined by the presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension. Significantly fewer patients on ramipril had cognitive or functional impairment.
Conclusion: Ramipril reduces the incidence of stroke in patients at high risk, despite a modest reduction in blood pressure.

What is already known on this topic Treatment with aspirin and lowering blood pressure reduce the incidence of stroke What this study adds Ramipril, an angiotensin converting enzyme inhibitor, reduces strokes in patients at high risk whose blood pressure is not elevated, despite only a modest lowering of blood pressure The benefits are observed even when patients receive aspirin and other blood pressure lowering treatments

	Introduction

Top Abstract Introduction Design and methods Results Discussion References

Stroke is the second leading cause of death in the world and of disability in developed countries.^1-4 In North America, 550 000 new strokes occur each year and there are approximately five million people who have had a stroke, 60% of whom have some residual disability. ^{4 5} Stroke is also responsible for a substantial proportion of deaths and disability in developing countries.⁶ Strokes can be prevented by lowering blood pressure in people with hypertension and by the use of antiplatelet agents in people with vascular disease. ^{7 8} Although a person's risk of stroke increases with blood pressure, the population attributable risk of stroke is greatest at pressures that would not currently be treated with drugs.⁹ We therefore need additional strategies that lower the risk of stroke across a broad range of patients at high risk.

Angiotensin converting enzyme inhibitors have been shown to block the activation of the renin-angiotensin system in the plasma as well as in the vascular wall. Recent experimental and human data suggest that angiotensin converting enzyme inhibitors reduce proliferation of vascular smooth muscle; enhance endogenous fibrinolysis; have the potential to stabilise plaques; and decrease angiotensin II mediated atherosclerosis, plaque rupture, and vascular occlusion.¹⁰ Angiotensin converting enzyme inhibitors therefore have the potential to lower the risk of ischaemic vascular events, including strokes, through mechanisms that are independent of lowering blood pressure.

We provide a detailed analysis of the impact of ramipril, an angiotensin converting enzyme inhibitor, on stroke, its subtypes, and the related disability and report the effects in various subgroups of patients in the heart outcomes prevention evaluation (HOPE) study.

	Design and methods

Top Abstract Introduction Design and methods Results Discussion References

The HOPE study was a double blind randomised trial with a two by two factorial design, in which participants were randomised to receive up to 10 mg of ramipril, 400 IU of vitamin E, both, or matching placebos.¹¹

Participants
Participants were aged 55 or over and were at high risk of cardiovascular events because of previous coronary artery disease, cerebrovascular disease, or peripheral arterial disease or diabetes plus one additional risk factor. Patients were excluded if they were taking either an angiotensin converting enzyme inhibitor or vitamin E; had heart failure or a known left ventricular ejection fraction of less than 0.40, known proteinuria, or uncontrolled hypertension; or had had a previous stroke or a myocardial infarction less than one month before enrolment in the study.

Intervention
After a run-in phase in which patients received 2.5 mg ramipril daily for 7-10 days, serum creatinine and potassium levels were measured. Participants then started a 10-14 day course of placebo. Those who tolerated and adhered to this regimen were then randomised to receive either placebo or 2.5 mg ramipril daily for one week, followed by placebo or 5.0 mg ramipril for a further three weeks. One month after randomisation the patient's serum creatinine and potassium were measured; if these were satisfactory the patient continued on either placebo or 10 mg ramipril for the remainder of the study. Participants were seen after six months and then every six months until the end of the study, with an average follow up of 4.5 years. Of the 10 576 patients who entered the run-in phase, 9541 were randomised and outcome results were available on 9539 (99.9%).

Outcome measures
The primary outcome was the composite end point of myocardial infarction, stroke, or cardiovascular death.¹² This analysis focuses on stroke.

Investigators reported the occurrences of stroke or transient ischaemic attack at follow up visits. The investigators used a simple six point scale to record if there was full recovery, persistent symptoms, some functional impairment, functional impairment necessitating the assistance of others to perform activities of daily living, or inability to perform activities of daily living even with help at seven days or at discharge if earlier. Classification of a stroke as either ischaemic or haemorrhagic was confirmed for 84% of strokes by computed tomography or magnetic resonance imaging within 14 days of onset or by autopsy. All other strokes were classified as being of uncertain aetiology.

Statistical analysis
We estimated survival curves according to the Kaplan-Meier procedure and compared treatments by using the log rank test.¹³ Because of the factorial design, we stratified all analyses for the randomisation to vitamin E or placebo. We conducted subgroup analyses by using tests for interactions in the Cox regression model.

Study organisation
The study was conducted in 267 hospital clinics in 19 countries. It was coordinated by the Canadian Cardiovascular Collaboration in Hamilton, Canada.

	Results

Top Abstract Introduction Design and methods Results Discussion References

Baseline characteristicsPatients were on average 66 (SD 7) years old and had a mean systolic blood pressure of 139 (20) mm Hg and a mean diastolic blood pressure of 79 (11) mm Hg.¹⁴ Seven thousand four hundred and seventy seven (80%) patients had a history of coronary artery disease, 1013 (11%) had previous stroke or transient ischaemic attack, 4051 (43%) had peripheral arterial disease, 3577 (38%) had diabetes, and 4355 (46%) had hypertension; 7074 (76%) patients were taking aspirin or other antiplatelet agents, and 2658 (28%) were taking lipid lowering agents.

Changes in blood pressureBlood pressure decreased on average by 3.8 mm Hg systolic and 2.8 mm Hg diastolic in the ramipril group and by 0.66 mm Hg systolic and 1.1 mm Hg diastolic in the placebo group. The mean baseline blood pressure of participants who developed a stroke was 143/79 mm Hg compared with 139/79 mm Hg in patients who did not have a stroke.

Incidence of stroke and transient ischaemic attacksThe total number of strokes, the number of fatal strokes, and the number of non-fatal strokes were all lower in the ramipril group than in the placebo group (table 1). A total of 190 (4.1%) patients in the ramipril group had a transient ischaemic attack compared with 227 (4.9%) in the placebo group (0.83, 0.68 to 1.00; P=0.052). Patients taking ramipril had a significantly reduced combined risk of stroke and transient ischaemic attack (n=315, 6.8%) compared with those on placebo (405, 8.7%) The relative risk was 0.77 (0.66 to 0.89; P=0.0004). Because of clear benefit, the study was terminated early on 22 March 1999. 

View this table: [in this window] [in a new window]   Table 1. Impact of ramipril on stroke subdivided by non-fatal and fatal stroke, subtype of stroke, and presence or absence of functional impairment. Values are numbers (percentages) unless stated otherwise

View larger version (13K): [in this window] [in a new window]   Kaplan-Meier estimates of the development of stroke by treatment group. The relative risk of developing stroke in the ramipril group compared with the placebo group was 0.68 (95% confidence interval 0.56 to 0.84; P=0.0002).

Outcome by type of strokeFewer patients in the ramipril group than in the placebo group had an ischaemic stroke, a haemorrhagic stroke, or a stroke of uncertain origin (table 1).

Functional and cognitive outcomesSignificantly fewer patients on ramipril than on placebo had functional impairment, particularly in terms of cognition, motor weakness, speech, and swallowing (tables 1 and 2).

View this table: [in this window] [in a new window]   Table 2. Details of cognitive and motor changes (24 hours after stroke) associated with stroke in patients with an event.* Values are numbers (percentages) unless stated otherwise

Results by baseline blood pressure and in other subgroupsThe beneficial treatment effects were consistently seen regardless of baseline blood pressure and in all the subgroups examined (drugs used and presence or absence of previous stroke, coronary artery disease, peripheral arterial disease, diabetes, or hypertension).

	Discussion

Top Abstract Introduction Design and methods Results Discussion References

Our results show that prolonged treatment with ramipril is effective in reducing fatal and non-fatal stroke and transient ischaemic attack in a broad group of patients at high risk of stroke but with relatively normal blood pressure. The impact is seen early, and the benefit continues to increase throughout the study period. The reduction is consistent across different subtypes of stroke and in various subgroups examined and is independent of the modest reduction in blood pressure seen with ramipril.

Benefit was seen at all values of diastolic and systolic blood pressure, including in patients with an initial blood pressure of less than 120 mm Hg systolic or less than 70 mm Hg diastolic, confirming that the beneficial effect of ramipril is not confined to those with "high" blood pressure. Angiotensin converting enzyme inhibitors have multiple mechanisms, in addition to blood pressure lowering, by which they could prevent atherosclerotic events.¹⁰ The study to evaluate carotid ultrasound with ramipril and vitamin E (SECURE) showed a dose dependent (but blood pressure independent) reduction in carotid artery intimal medial thickness.¹⁵ Furthermore, a recent analysis of the United Kingdom prospective diabetes study (UKPDS) showed that the benefits seen with an angiotensin converting enzyme inhibitor (and  blocker) were substantially larger than predicted from differences in blood pressure alone.¹⁶

Ramipril reduced not only the number of patients who had a stroke but also the fatality associated with stroke as well as functional impairment in non-fatal stroke. As stroke is the leading cause of disability in developed countries, even moderate decreases in disability would be of global importance.

The reduction in strokes was consistent across the various subgroups examined, including patients receiving antiplatelet treatment and lipid lowering drugs. The benefits of ramipril are consistent in patients with and without previous stroke, previous manifestation of any cerebrovascular disease, coronary artery disease, peripheral arterial disease, or diabetes. This suggests that our results are broadly applicable to patients at high risk of stroke with diverse presentations and a range of background treatments.

The perindopril protection against recurrent stroke study (PROGRESS) recently reported that perindopril in combination with indapamide reduced the risk of recurrent strokes by 28% in patients with previous cerebrovascular disease. ^{17 18} Taken together, these studies clearly document the benefits of an angiotensin converting enzyme inhibitor in both primary and secondary prevention, even in patients without hypertension.

Conclusions
Our results indicate that patients who are at high risk of stroke should be treated with ramipril, irrespective of their initial blood pressure levels and in addition to other preventive treatments such as blood pressure lowering agents or aspirin. Widespread use of an angiotensin converting enzyme inhibitor such as ramipril in patients at high risk of stroke is likely to have a major impact on public health.

	Acknowledgments

   Contributors: See bmj.com

	Footnotes

Funding: The HOPE study was funded by the Medical Research Council of Canada (now Canadian Institutes for Health Research), Hoechst-Marion Roussel (now Aventis), AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association, Negma, and the Heart and Stroke Foundation of Ontario. SY was supported by a senior scientist award of the Medical Research Council of Canada and a Heart and Stroke Foundation of Ontario research chair.

Competing interests: All authors have acted as consultants and have received funding for research from the above sponsors, as well as having attended and presented papers at symposia with support from the sponsoring agencies.

The full version of this article appears on bmj.com

	References

Top Abstract Introduction Design and methods Results Discussion References

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(Accepted 5 November 2001)

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Rapid Responses:

Read all Rapid Responses

Ramipril and all cause mortality

Trevor D Thompson
bmj.com, 23 Mar 2002 [Full text]

Ramipril and stroke: statistical subtleties matter

Adam Sandell
bmj.com, 23 Mar 2002 [Full text]

Ramipiril works, but does it help my patient with a T. I. A. or a stroke?

W.A.J. Hoefnagels, et al.
bmj.com, 23 Mar 2002 [Full text]

NNT too high to make routine use of Ramipril viable in primary care

John P Coffin
bmj.com, 25 Mar 2002 [Full text]

Is ramipril really organoprotective?

John S Yudkin
bmj.com, 27 Mar 2002 [Full text]

Preventing stroke with ramipril: The fine points.

Malvinder S. Parmar
bmj.com, 27 Mar 2002 [Full text]

Wonky data.

paul nederlof
bmj.com, 27 Mar 2002 [Full text]

Omitting Adverse Effects Data Paints a Rosier Picture

Yoon K Loke
bmj.com, 3 Apr 2002 [Full text]

Ramipril and stroke - Does the way of presenting results matter?

Padmanabhan Badrinath
bmj.com, 8 Apr 2002 [Full text]

Authors' statements are misleading and not supported by data

Mark Campbell, et al.
bmj.com, 10 Apr 2002 [Full text]

What about the influence of atrial fibrillation on the ramipril effect in the HOPE-study?

Claudia Stöllberger, et al.
bmj.com, 12 Apr 2002 [Full text]

These results have not been put in the proper perspective

Farokh Buhariwalla, et al.
bmj.com, 2 May 2002 [Full text]

stroke protective effect of angiotensin-II through non-AT1-receptors activation

Albert FOURNIER, et al.
bmj.com, 1 Jun 2002 [Full text]

Lessons learned from the ramipril study

Lesley J Morrison, et al.
bmj.com, 20 Jun 2002 [Full text]

Use of ramipril in preventing stroke

FOURNIER Albert, et al.
bmj.com, 20 Jun 2002 [Full text]

A trial's entire data-set should be publically available

Jeffrey Mann
bmj.com, 29 Aug 2002 [Full text]