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EDITORIALS: Joachim Schrader and Stephan Lüders Preventing stroke BMJ 2002; 324: 687-688 [Full text]

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Are other classes of drugs effective

john sharvill   (25 March 2002)

Ramipril in stroke prevention: benefits were considerably overstated

Andrew P Wakeman, Jacqueline G Wakeman   (25 March 2002)

Tolerance of remipril

pervez Asghar, 4600   (26 March 2002)

Is there HOPE for 2.5mg?

Peter David Burrill   (26 March 2002)

There are outcome data on A2As in hypertension

FD Richard Hobbs   (22 May 2002)

Are other classes of drugs effective 25 March 2002
john sharvill, gp Deal Kent Send response to journal: Re: Are other classes of drugs effective	This article is certainly persuasive. However what is not stated(and I realise is available elsewehere) is the effect of overall mortality in HOPE and the absolute, as opposed to relative,risk reduction. Also is it known what the risk reduction using low dose thiazides is in this same group of people?
Ramipril in stroke prevention: benefits were considerably overstated 25 March 2002
Andrew P Wakeman, Director of Public Health Burntwood, Lichfield and Tamworth Primary Care Trust, Guardian House, Rotten Row, Lichfield WS13 6JB, Jacqueline G Wakeman Send response to journal: Re: Ramipril in stroke prevention: benefits were considerably overstated	EDITOR - In commenting on the HOPE study, Schrader and Luders1 claim that ramipril “substantially decreased the risk of stroke” and that “In HOPE, fatal stroke was reduced by 61%, non-fatal stroke was reduced by 24%”…The former statement overstates the effect of the drug and the latter statement is quite simply incorrect. Whilst the relative risk reduction of fatal stroke and non-fatal stroke in the trial was 61% and 24% respectively, the absolute risk reduction (ARR), which is the clinically relevant outcome measure, was reduced only by 1.5% and 0.9% respectively. Since the follow up period of the trial was an average of 4.5 years, these “substantial” results are equivalent to an overall reduction of only 0.33% and 0.2% per annum respectively in the occurrence of fatal and non-fatal stroke. This demonstrates the pitfalls that can arise when the results of intervention trials are presented only in terms of relative risk reduction but recommendations are made in terms of alleged clinical benefits.2 Although patients in the trial were labelled “high risk”, participants only demonstrated an absolute risk of 4.9% for any stroke over the follow up period. This confirms the importance of hypertension control as one of the main public health interventions in preventing stroke. In addition, it is already proven that antiplatelet agents are an effective secondary prevention strategy in high risk patients3 and that anticoagulants effectively prevent stroke in those with atrial fibrillation.4 Whilst stroke is an important cause of mortality and disability in the United Kingdom and the search for new cost-effective solutions to reducing death and disability must continue, we doubt the results of the HOPE trial warrant Bosch et als recommendation5 that “patients who are at high risk of stroke should be treated with ramipril irrespective of their blood pressure levels.” Perhaps the authors intuitively accept this when they choose only to present the trial outcomes in terms of relative risk reduction. A.P. Wakeman Director of Public Health Burntwood, Lichfield & Tamworth Primary Care Trust, Guardian House, Rotten Row, Lichfield WS13 6JB Corresponding author e-mail address: andrew.wakeman@talk21.com J.G. Wakeman General Practitioner Langton Medical Group, St Chad's Health Centre, Dimbles Lane, Lichfield WS13 7HT 1. Schrader J, Luders S. Preventing stroke. BMJ 2002; 324:687-8 2. McQuay H, Moore A. Using numerical results from systematic reviews in clinical practice. Ann Intern Med 1997;126:712-720 3. Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy – 1: prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106 4. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Arch Intern Med 1994;154:1449-1457 5. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B et al. Use of ramipril in preventing stroke: double-blind randomised trial. BMJ 2002;324:699-702
Tolerance of remipril 26 March 2002
pervez Asghar, classified medical specialist C.M.H. jhelum pakistan., 4600 Send response to journal: Re: Tolerance of remipril	I will be much more hesitant in using remipril in my normotensive patients because of exagerrated response of ACE inhibitors in our patients. It is not at all possible to reach 10mg with out significant hypotension. I think it will be difficult for them to tolerate even 2.5mg.
Is there HOPE for 2.5mg? 26 March 2002
Peter David Burrill, Specialist in Pharmaceutical Public Health North Derbyshire Health, Scarsdale, Newbold Road, Chesterfield, S41 7PF Send response to journal: Re: Is there HOPE for 2.5mg?	Indeed ramipril does seem to have beneficial effects on cardiovascular events in high risk individuals, especially if suffering from type 2 diabetes (HOPE and MicroHOPE). The study by Bosch et al may add to the story but the NNTs, ranging from 53(combined stroke and TIA) to 167 (fatal stroke), are quite high. What particularly intrigues me in the editorial by Schader and Luders is the statement "the effect of a 10mg dose, as used in the HOPE study, was better than 2.5mg". On what do they base this? In the orignal HOPE study, on page 146 under the heading 'Study Design',it says "A substudy compared a low dose of ramipril (2.5mg per day) with a full dose (10mg per day) or placebo; there were 244 patients in each group.The results of the placebo-controlled study of full-dose ramipril are given here." At the bottom of Table 3 (page 148) it states "In the substudy, 34 of 244 patients (13.9%) assigned to a low dose of ramipril (2.5mg per day) reached the composite endpoint, as compared with 31 of 244 assigned to take 10mg of ramipril per day (12.7%) and 41 of 244 assigned to placebo (16.8%)." This does not seem to be discussed anywhere else in the paper. No p- values are quoted but intuitively the two doses of ramipril look close and significantly different from placebo. Is it possible that 2.5mg is as effective as 10mg per day? We need to know as the financial implications are significant. More patients could receive and benefit from ramipril from a given budget if this were true. Less profit for the manufacturer though! The authors rightly point out that we cannot assume that similar outcomes would occur with other ACEIs. Indeed, in the recently published PROGRESS study, in the patients treated with perindopril alone, stroke risk was NOT different from that in those who received single placebo. Nor was the risk of major vascular events despite BP lowering by a mean of 5/3 mmHg.
There are outcome data on A2As in hypertension 22 May 2002
FD Richard Hobbs, Head of Department University of Birmingham, B15 2TT Send response to journal: Re: There are outcome data on A2As in hypertension	Editor: In their Editorial (1) on the latest publication from the HOPE study (2), Schrader and Lüders state that "Angiotensin I antagonists have yet to prove similar long-term benefits" on prevention of vascular events as those seen with ramipril [I assume that the authors meant to refer to angiotensin II antagonists]. Almost simultaneously, the results of the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study (3) provided just such evidence. In LIFE, 9193 patients aged between 55 and 80 years with essential hypertension and left ventricular hypertrophy (LVH), an independent cardiovascular risk factor, were randomly assigned to receive an antihypertensive regime based on losartan or atenolol. Over 4.5 years of follow-up there was a significant reduction in the composite primary endpoint of cardiovascular mortality and morbidity in the losartan-based group compared with the atenolol-based group (13% relative risk reduction, p = 0.021). There was a particularly striking reduction in fatal and non-fatal stroke (25% relative risk reduction, p = 0.001). Reductions in blood pressure were similar in both groups (mean pressures at last visit were 144.1/81.3 and 145.4/80.9 in the losartan and atenolol groups respectively), and adjustment for the small differences between groups did not affect the significance of the result. In the sub-group of patients with diabetes, losartan also significantly reduced all-cause mortality compared with atenolol (39% relative risk reduction p = 0.002)(4). An important feature of LIFE is that it is an active comparator, rather than placebo-controlled, trial using atenolol, a widely prescribed antihypertensive and a member of a class of drugs with demonstrated effects on cardiovascular mortality and morbidity when used as antihypertensive therapy (5) (although outcome data on atenolol alone are somewhat limited). Additional therapy with a hydrochlorothiazide diuretic was allowed and most patients took a diuretic in addition to the study drug. The LIFE study design was therefore close to 'real world' conditions where a combination of drugs and non-pharmacological measures is normally required to provide satisfactory control of blood pressure. Importantly, LIFE confirmed, like the HOT trial before it, that it is possible to achieve current blood pressure targets in ambulant community populations if patients are triaged to up-titrated drug doses and combination treatments. Based on this new evidence, losartan, dosed at up to 100 mg daily and in association with a low-dose thiazide, showed major benefits over the active comparator atenolol with significantly increased protection against stroke in an older hypertensive population with LVH. These data may prove to have as many implications for the beta-blocker atenolol as they do for losartan. Professor FDR Hobbs References 1. Schrader J, Lüders S. Preventing stroke. BMJ 2002;324:687-688. 2. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B et al. on behalf of the HOPE Investigators. Use of ramipril in preventing stroke: double blind randomised trial. BMJ 2002;324:699-702. 3. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U et al. for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. 4. Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U et al. for the LIFE study group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:1004-1010. 5. Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-838. Competing interest: Professor Hobbs has delivered talks and consultancy to several companies with cardiovascular products including Aventis and MSD, the respective sponsors of the HOPE and LIFE studies.