Published online before print April 17, 2003, doi: 10.1161/01.STR.0000069267.19971.7D
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(Stroke. 2003;34:1334.)
© 2003 American Heart Association, Inc.
Controversies in Stroke |
Blood Pressure–Lowering for Secondary Prevention of Stroke: ACE Inhibition Is Not the Key
From the Centre for Vascular Research, University of Nottingham, Nottingham, UK.
Correspondence to Prof Philip M. Bath, University of Nottingham, Division of Stroke Medicine, City Hospital Campus, Nottingham, NG5 1PB, UK. E-mail philip.bath{at}nottingham.ac.uk
Key Words: angiotensin-converting enzyme inhibitors • blood pressure • randomized controlled trials • stroke prevention
The questions that need to be addressed in this debate are 3-fold. First, do antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors, prevent recurrent stroke and other vascular events? Second, is this effect dependent on their blood pressure (BP)–lowering properties? And last, are potentially beneficial non-BP effects limited to ACE inhibitors? The answers are straightforward: antihypertensive drugs do prevent further vascular events; the effect is dependent on the degree to which BP is lowered; and most antihypertensive drug classes, not just ACE inhibitors, exhibit multimodal vascular activity beyond their effects on BP, although whether these are important remains to be established. The rest of the article fleshes out these assertions.
Seven randomized controlled trials have assessed whether antihypertensive drugs prevent recurrence in patients with previous stroke or transient ischemic attack (TIA).1 Two trials (2193 patients) used a ß-receptor antagonist (ß-RA, atenolol), recorded a small fall in BP (5/3 mm Hg), and were neutral, ie, there was no protective vascular effect.2,3 Three trials (6216 patients) studied a diuretic4–6; the largest of these, PATS (5665 patients), reported that indapamide reduced BP by 6/3 mm Hg and stroke recurrence by 29%.6 Finally, 2 trials used an ACE inhibitor. The HOPE study recruited a total of 9541 subjects with vascular disease, of whom 1013 had a prior stroke or TIA.7 Ramipril reduced subsequent stroke by 32% across the whole trial and had a small reported effect (3/1 mm Hg) on BP; however, this reduction is probably an underestimate for 2 reasons: (1) ramipril was mostly taken in the evening while BP was measured the next day, ie, some 12 to 18 hours or 2 to 3 half-lives later; and (2) a substudy of HOPE reported a 10/4 mm Hg fall in 24-hour ambulatory BP.8 The latest trial, PROGRESS (6105 patients), reported that perindopril-based therapy reduced stroke recurrence.9 These 7 trials varied not just in the intervention but in other significant design aspects; notably, both HOPE and PROGRESS recruited patients irrespective of their BP and gave ACE inhibitors on top of other antihypertensive drug classes. No studies have investigated other drug classes including alpha receptor antagonists, angiotensin receptor antagonists (ARA), calcium channel blockers (CCB), and centrally acting drugs.
A meta-analysis of these studies and limited to patients with prior cerebrovascular disease found that the use of antihypertensive therapy reduced subsequent stroke, nonfatal stroke, myocardial infarction, and combined vascular outcomes (stroke, myocardial infarction, vascular death).1 Importantly, the rates of both stroke and combined vascular outcome fell in parallel with the magnitude of effect on BP.1 This relationship between BP and vascular events was also found in an earlier meta-analysis of trials involving patients with any type of vascular disease10; it also occurred in PROGRESS, in which dual antihypertensive therapy (perindopril and indapamide) was superior to mono therapy (perindopril) in reducing both BP (12.3/5.0 mm Hg versus 4.9/2.8 mm Hg) and stroke recurrence (relative risk reduction 43% versus 5%).9
This is not to say that differences do not exist between drug classes in the prevention of various vascular events following stroke or TIA—diuretics reduced stroke but not myocardial infarction, ACE inhibitors reduced myocardial infarction but not stroke, and ß-RA did not appear to moderate any outcome.1 Although some of these findings might reflect the limited data size (<16 000 subjects across all drug classes), similar differential effects have been found in the primary prevention of vascular disease whereby CCB prevent stroke more than myocardial infarction and ACE inhibitors do the opposite.
A current vogue in vascular prevention is to ascribe beneficial drug effects to their multiple modes of action, eg, statins not only lower lipids but have moderating effects on the vessel wall and circulating blood cells. Several antihypertensive classes of drugs (including ACE inhibitors, ARA, ß-RA, and CCB) are also multimodal in their action, having anti-inflammatory, antiplatelet, antiproliferative, and neuroprotective activity. Whether these effects are vital over and above BP lowering remains unanswered, but it is nevertheless unreasonable to suggest that the non-BP effects of ACE inhibitors are special or limited to that class because they are present in other antihypertensive drugs.
The key to the secondary prevention of stroke through lowering blood pressure is by using agents that have been shown to be effective in randomized controlled trials, ie, the practice of evidence-based medicine. The current data unequivocally support the use of diuretics (in particular, indapamide), ACE inhibitors (perindopril, ramipril), and especially their combination. ß-RA appear to be ineffective, at least when used alone, and other drug classes have no data for this indication and may, therefore, also be ineffective until shown otherwise. Nevertheless, many patients with a raised BP need multiple drug treatment, in addition to nonpharmacological measures, and other agents should be added to a diuretic and ACE inhibitor to further lower BP after stroke or TIA. Finally, treatment should be started irrespective of baseline levels of BP once the patient’s medical state has stabilized poststroke, typically after 1 to 2 weeks.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1. Rashid PA, Leonardi-Bee J, Bath PM. Lowering blood pressure after stroke or transient ischaemic attack to prevent recurrence: a systematic review of randomised controlled trials. Cerebrovasc Dis. 2002; 13 (suppl 3): 92.Abstract.
2. The Dutch TIA Study Group. Trial of secondary prevention with atenolol after transient ischaemic attack or nondisabling ischaemic stroke. Stroke. 1993; 24: 543–548.
3. Eriksson S, Olofsson B-O, Wester P-O. Atenolol in secondary prevention after stroke. Cerebrovasc Dis. 1995; 5: 21–25.
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5. Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA. 1974; 228: 409–418.
6. PATS Collaborating Group. Post-stroke antihypertensive treatment study: a preliminary result. Chin Med J. 1995; 108: 710–717.[Medline] [Order article via Infotrieve]
7. The Heart Outcome Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
8. Svensson P, de Faire U, Sleight P, Yusuf S, Ostergren J. Comparative effects of ramipril on ambulatory and office blood pressures: a HOPE substudy. Hypertension. 2001; 38: e28–e32.
9. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358: 1033–1041.[CrossRef][Medline] [Order article via Infotrieve]
10. Staessen JA, Wang J-G, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet. 2001; 358: 1305–1315.[CrossRef][Medline] [Order article via Infotrieve]
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