Published online before print December 2, 2002, doi: 10.1161/01.STR.0000044950.15362.A4
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(Stroke. 2003;34:8.)
© 2003 American Heart Association, Inc.
Letters to the Editor |
Converting Enzyme Inhibitor or AT1-Receptor Blocker for Decreasing Long-Term Mortality in Patients With Stroke History and Renal Dysfunction?
Department of Nephrology, CHU Hôpital Sud, 80054 Amiens Cedex 1, Paris, France
To the Editor:
Having concluded their cohort study with the suggestion that renal dysfunction was an independent risk factor of mortality in patients having had a stroke, MacWalter et al1 strongly recommend the use of angiotensin-converting enzyme inhibitor (ACEI) to decrease this mortality. They base their recommendation on the HOPE study, in which ramipril comparatively with placebo significantly decreased mortality in both patients with and patients without renal dysfunction,2 and on the PROGRESS study. We think, however, that the use of the results of these 2 studies are not entirely appropriate for supporting this exclusive recommendation, alternative recommendation of diuretics and/or AT1-receptor blockers (ARB) having in our opinion at least equal or even greater evidence basis.
As regards the use of the HOPE trial, we fear that it is not appropriate to extrapolate its results to the kind of population the authors have studied because the baseline characteristics of the 2 studies are quite different regarding the prevalence of coronary heart disease, which was 80% in HOPE and only 15% in their cohort study, whereas the magnitude of stroke history prevalence was the opposite (11% and 100%, respectively). Cardiac death was therefore probably much more prevalent in HOPE (given that heart complication incidence was 5 times higher than that of stroke) than in their cohort study (for which the nature of death is not defined).
As regards the use of PROGRESS trial,3 it is also not quite appropriate despite comparable baseline prevalence of coronary heart disease (CHD) (16% and 15%, respectively) and of stroke history (100%), because the stroke recurrence preventive effect of the ACEI perindopril per se was mainly related with its synergistic blood pressure (BP)–lowering action when given in association with indapamide, its own BP-independent stroke protective effect being even actually negative.
Indeed the PROGRESS trial is composed of 2 separate studies having independently randomized to placebo and to either perindopril alone or its association with indapamide, so the results of these 2 studies should be discussed separately, all the more that they are quite different. In the first study, perindopril alone did not significantly decrease the stroke recurrence risk (-5%) despite a 5-mm Hg SBP decrease, whereas in the second study its association with indapamide decreased it by 43% while the SBP decrease was 12 mm Hg. According to the PROGRESS authors, this BP decrease would account for a stroke recurrence risk decrease of only 33%. It seems therefore logical to ascribe the 10% BP-independent stroke recurrence protective effect of this association exclusively to its diuretic component. This interpretation is further supported by the comparison of the stroke recurrence risk decrease with indapamide alone in the PATS trial,4 also performed in patients with a history of stroke, which was 29% and not only 5% as with perindopril alone, while the SBP decrease was the same (5 mm Hg), so that the BP-independent stroke recurrence risk with perindopril comparatively with indapamide is 24% higher. Therefore, when the authors recommend ACEI on the basis of PROGRESS, it seems necessary that they add "in association with a diuretic."
Considering the results of the recent clinical outcome trials with ARB, we propose that this latter class should also be considered, in preference to ACEI, especially in patients with a history of stroke associated with renal dysfunction. Indeed, this new antihypertensive class has been shown to have not only some BP-independent renoprotective effects5,6 as well as ACEI, but also BP-independent stroke protective effect in patients with low prevalence of CHD (<16%), whereas in these populations ACEI alone have been shown to be associated either with no BP-independent stroke protective effect3 or even with increased stroke risk.7 Indeed, the LIFE trial8 has demonstrated that an ARB like losartan decreases the risk of stroke by 25% compared with iso-antihypertensive dose of atenolol,8 while giving the same protection against cardiac complications. Furthermore, in the UKPDS 39 study,9 atenolol and captopril have been shown to have this same BP-independent brain and heart protective effect. Therefore it may be presumed that losartan has a greater BP-independent stroke protective effect than ACEI while having the same protective effect against cardiac complication.
We recognize, however, that our proposal urgently needs an actual formal demonstration by a direct head-to-head comparison of an ARB with an ACEI (in association with thiazide) in patients with a higher risk of stroke than of CHD as in populations with either a history of stroke (and normal or elevated BP) or of hypertension with high risk of stroke because of age or left ventricular hypertrophy as in LIFE but a low prevalence of CHD.
References
1. MacWalter RS, Wong SY, Wong KY, et al. Does renal dysfunction predict mortality after acute stroke? A 7-year follow-up study. Stroke. 2002; 33: 1630–1635.
2. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134: 629–636.
3. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6150 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033–1041.[CrossRef][Medline] [Order article via Infotrieve]
4. PATS Collaborating Group. Post-stroke Antihypertensive Study. Chin Med J. 1995; 108: 710–717.[Medline] [Order article via Infotrieve]
5. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869.
6. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345: 851–860.
7. Hansson L, Lindholm L, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the captopril prevention project (CAPPP) randomised trial. Lancet. 1999; 353: 611–616.[CrossRef][Medline] [Order article via Infotrieve]
8. Dahlöf B, Devereux R, Kjeldsen S, et al. 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.[CrossRef][Medline] [Order article via Infotrieve]
9. Holman R, et al, for the UKPDS group. Efficacy of atenolol and captopril in reducing the risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ. 1998; 317: 713–720.
Department of Medicine, Ninewells Hospital & Medical School, Dundee, Scotland, UK
Department of Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee, Scotland, UK
Department of Physical Medicine & Rehabilitation, Inonu University Faculty of Medicine, Turgut Ozal Medical Centre, Malatya, Turkey
Response
Prof Fournier et al’s contention that AT1-receptor blockers (ARBs) may be as good as or better than ACE inhibitors (ACEI) may be true, but we know of no large trials in which ARBs have actually been given to stroke patients, whereas PROGRESS1 and HOPE2 represent, despite their imperfections, a large database on the effect of ACEIs in stroke survivors. This is why we recommended ACEIs in stroke survivors.
We accept contention by Fournier et al that ARBs are an exciting group of drugs and may also prove to have a protective effect on renal function. In a comparative study of 3 years’ treatment in hypertensive individuals, both enalapril and losartan did appear to reduce blood pressure, diminish left ventricular hypertrophy, and protect renal function.3 The losartan group also had a reduction of uric acid levels. We have shown recently that serum urate concentrations were associated with cardiac death after stroke, independent of many other risk factors, such as pulse pressure, glucose, cholesterol, and creatinine.4 This may partially account for the additional beneficial effect seen in the ARB group.
We would like to dispute Fournier et al’s belief that PROGRESS was in fact 2 separate trials.1 Patients were randomized to perindopril or placebo after an initial trial of tolerance of perindopril. The addition of indapamide was at the discretion of the investigator and was not controlled by a randomization process. Therefore, it is impossible to attribute the outcome differences to the effects of any particular treatment. The trial was powered only to demonstrate a difference between active treatment (perindopril or perindopril plus indapamide) versus placebo. The Post-stroke Antihypertensive Treatment Study (PATS)5 may give support to a diuretic effect in terms of end-point reduction but not renal protection. This study was in a Chinese population whose risk factors are possibly different from those of a Western population, and, importantly, the full results of this study have not been reported. It is not clear if thiazide diuretics are renoprotective. In UKPDS 39, captopril was associated with development of less proteinuria than atenolol, although the small numbers involved fail to reach significance.6 A meta-regression analysis in diabetic patients has shown that ACEIs are associated with a reduction in proteinuria compared with beta-blockers, although blood pressure control is similar.7
We agree that further studies may help clarify the respective roles in renal protection of ACEIs, ARDs, diuretics, and other antihypertensive medications in various groups of patients. These trials should include hypertensive and normotensive patients. We share the opinion of Fournier et al that a large comparative randomized trial examining the effects of the different classes of drugs is required in stroke patients to help clarify the position.
Currently the largest database on stroke patients and these drugs comes from the PROGRESS and HOPE studies, which give good support to the use of ACEIs in stroke survivors.
References
1. Perindopril Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033–1041.[CrossRef][Medline] [Order article via Infotrieve]
2. Mann JFE, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134: 629–636.
3. De Rosa ML, Cardace P, Rossi M, Baiano A, de Cristofaro A. Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients. J Hum Hypertens. 2002; 16: 133–140.[CrossRef][Medline] [Order article via Infotrieve]
4. Wong KY, MacWalter RS, Fraser HW, Crombie I, Ogston SA, Struthers AD. Urate predicts subsequent cardiac death in stroke survivors. Eur Heart J. 2002; 23: 788–793.
5. PATS Collaborating Group. Post-stroke antihypertensive treatment study: a preliminary result. Chin Med J (Engl). 1995; 108: 710–717.[Medline] [Order article via Infotrieve]
6. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complication in type 2 diabetes: UKPDS 39. BMJ. 1998; 317: 713–720.
7. Kasiske BL, Kalil RSN, Ma JZ, Lio M, Keane WF. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med. 1993; 118: 129–138.
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