Age-Adjusted Stroke Incidence Increase: Could Angiotensin AT1 Receptor Antagonists Enhance Stroke Prevention?
To the Editor:
A series of articles recently published in Stroke strongly suggest that age-adjusted stroke incidence is increasing. After a marked decline since the 1960s, the stroke mortality rate has plateaued since 1990 in both Japan1 and the United States.2 The in-hospital case-fatality rate for stroke, however, is declining in the United States,3 mainly because of better acute stroke treatment, although detection of milder cases of stroke through neuroimaging improvement may contribute to this trend.4 On the contrary, the age-adjusted stroke hospitalization rate increased by 18.6% between 1988 and 1997 in the United States.3 Even though the institution of more lenient criteria for hospitalization may partially explain it, this phenomenon strongly suggests an actual increase of age-adjusted stroke incidence,4 which could account for the leveling off of the stroke mortality rate despite the decrease of stroke case-fatality. Since the increased rate of hospitalization after stroke was limited to elderly patients >65 years, we quite agree with Tu4 that the stroke incidence increase may be due to more successful prevention of coronary heart disease (CHD) by increasing a population at higher risk for stroke, since CHD per se increases this risk.5 However, we are more reluctant to admit the role of aging per se, since the stroke hospitalization rate and therefore the suggested stroke incidence increase are age-adjusted. Furthermore, it should be noted that the prevalence increase of associated CHD was stable during the study period, in contrast to the prevalence of associated hypertension (33.6%; P=0.05), heart failure (31%; P=0.09), and diabetes (17.4%; P=0.17).
This significant increase in hypertension comorbidity is intriguing because the National Health and Nutrition Examination Survey (NHANES) III phases I and II showed only a slight decrease of well-controlled hypertension prevalence (from 29% to 27%) in the United States during the study period.6 Therefore, we would like to know the diagnosis criteria of hypertension used in their study and, in particular, whether the diagnosis was based on actual blood pressure data or only on the notion of a treated hypertension.
As indicated by Tu,4 suboptimal prevention of strokes may explain this incidence increase, and since hypertension control is plateauing in the United States and still improving in Japan,1 this raises the issue of stroke prevention efficiency by blood pressure (BP)-lowering drugs. The recent publication of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial7 has indeed clearly demonstrated that the BP-independent stroke protective effect of antihypertensive drugs is quite different according to their pharmacological class: in patients with a history of stroke and either normotension or hypertension, perindopril alone nonsignificantly decreased the risk of stroke recurrence by 5% in this trial,7 whereas for the same BP decrease, indapamide significantly decreased this risk by 29% in the Poststroke Antihypertensive Treatment Study (PATS).8 This almost 6-fold greater stroke risk reduction with a diuretic than with an ACE inhibitor is reminiscent of the almost 3-fold better stroke prevention observed in the MRC trial,9 with high doses of bendrofluazide as compared with propranolol, which led Brown and Brown to hypothesize that angiotensin II might be stroke protective.10 Finally, 2 recent metaanalyses11,12⇓ have concluded that calcium antagonists (long-acting dihydropyridines and the short-acting diltiazem) were more stroke protective than conventional treatment by beta-blockers and/or thiazides. This brief review of the stroke-protective effect of the 4 major classes of antihypertensive drugs suggests that diuretics and calcium antagonists, which stimulate the renin angiotensin and sympathetic (RAS) systems,13,14⇓ have a greater BP-independent stroke protective effect than beta-blockers and angiotensin-converting enzyme inhibitors (ACEI), both of which decrease angiotensin II formation,13 at least in hypertensive patients or in normotensive patients with a history of stroke but with a low prevalence of CHD (<16%). Indeed, in the unique Heart Outcomes Prevention Evaluation (HOPE) trial, performed in patients with a high prevalence of CHD (80%),15 ramipril has been shown to have a BP-independent protective effect not only for cardiac events but also for strokes.
How is it possible to explain the opposite link between stroke prevention and the activation of the RAS systems according to the low or high prevalence of CHD? A possible explanation may rely on the duality of the angiotensin receptors: the AT1 receptors responsible for the vasoconstrictive and proatherothrombotic effects of angiotensin II and the non–AT1 receptors (like AT2 and AT4 receptors), for which stimulation has been shown to decrease the severity of neurological outcomes in acute brain ischemia in rodents, through either more rapid collateral circulation recruitment16 or increased neuronal resistance to anoxia.17 The stimulation of these brain protective mechanisms by the RAS system–stimulating diuretics or calcium antagonists may explain their greater BP-independent stroke protective effect compared with that of beta-blockers and ACEI in populations with low initial prevalence of CHD. On the contrary, in populations with a high CHD prevalence (80%), as in the HOPE trial, the deleterious effect of blunting these non–AT1-mediated beneficial mechanisms is canceled out by the beneficial effect of blunting the AT1-mediated proatherothrombotic effect. This is all the more likely to occur when high doses of a tissular-specific ACEI such as ramipril are used, since they will efficiently prevent destabilization of highly prevalent atherosclerotic plaques. This resulted in a 3-times-greater prevention of cardiac events than of strokes (227 versus 70).15 Since myocardial infarctions and heart failures are per se major risk factors of strokes,5 it is very likely that a great proportion of stroke prevention in the HOPE trial was attributed to this highly effective cardiac event prevention.
Since ACEI and AT1 receptor antagonists (AT1RA) have comparable anti-atherothrombotic effects in experimental animals,18 whereas AT1RA stimulate angiotensin II formation by blunting the AT1-mediated negative feedback of renin secretion and, therefore, non–AT1-mediated anti-ischemic mechanisms, AT1RA may have a cutting edge over ACEI by better preventing stroke. To prove this superiority, we propose to compare these 2 drugs in patients at higher risk for stroke than for CHD, ie, in elderly hypertensive patients or in patients with a history of stroke but low prevalence of CHD.
If AT1RA are proven superior to ACEI in stroke prevention, their association with low-dose diuretics might become the most eligible treatment for global primary and secondary cardiovascular prevention, which might help to forestall the predicted worldwide increase in stroke.19
- ↵Liu L, Ikeda K, Yamori Y. Changes in stroke mortality rates for 1950 to 1997: a great slowdown of decline trend in Japan. Stroke. 2001; 32: 1745–1749.
- ↵Howard G, Howard V, Katholi C, Oli MK, Huston S. Decline in US stroke mortality: an analysis of temporal patterns by sex, race and geographic region. Stroke. 2001; 32: 2213–2220.
- ↵Fang J, Alderman MH. Trend of stroke hospitalization, United States 1988–1997. Stroke. 2001; 32: 2221–2226.
- ↵Tu J. Are we winning the battle against stroke ? Stroke. 2001; 32: 2226.Editorial comment.
- ↵Mooe T, Olofson B, Stegmayr B, Erikson P. Ischemic stroke: impact of a recent myocardial infarction. Stroke. 1999; 30: 997–1001.
- ↵Lenfant C, Rocella E. A call to action for more aggressive treatment of hypertension. J Hypertens. 1999; 17 (suppl 1): S3–S7.
- ↵PATS collaborating group. Post-stroke Antihypertensive Study. Chinese Med J. 1995; 108: 710–717.
- ↵MRC Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J. 1985; 291: 97–104(metaanalysis BMJ. 1988;296:1565–1570).
- ↵Staessen J, Wang J, Thiss L. Cardiovascular protection and blood pressure reduction: a metaanalysis. Lancet. 2001; 258: 1305–1315.
- ↵Kaplan N. Treatment of hypertension: drug therapy.In: Clinical Hypertension, 7th ed. Baltimore, Md: Williams & Wilkins; 1998: 181–263.
- ↵Blume A, Funk A, Gohlke P, Unger T, Culman J. AT2 receptor inhibition in the rat brain reverses the beneficial of AT1 receptor blockade on neurological outcome after focal brain ischemia. Hypertension. 2000; 36: 656.
- ↵Sarti C, Rastenyte D, Cepitis Z, Tuomilehto J. International trends in mortality from strokes 1968 to 1994. Stroke. 2000; 31: 1588–1601.