Nephrol Dial Transplant (2001) 16: 185-187
© 2001 European Renal Association-European Dialysis and Transplant Association
Letters
STOPPING at the CAPPP of good HOPE
Service de Néphrologie du CHU, d'Amiens, Laboratoire de Physiologie du, CHU de Limoges, France
Sir,
We have enjoyed the concise and factual review by Luft [1] of the three recent large trials evaluating angiotensin-converting enzyme inhibitors (ACEI) in primary and secondary prevention of cardiovascular events. Its humoristic title is certainly appropriate since the Heart Outcomes Prevention Evaluation (HOPE) results yield no certitude that ACEI actually provide the best cardiovascular protection in hypertensive patients without established cardiovascular complications or microalbuminuria, even in the diabetic patients. The relative risk of combined primary outcomes occurrence was not significantly decreased with ramipril in the subgroup of diabetic patients without cardiovascular disease [2]. Thus the HOPE study showed a specific cardiovascular protective effect only in a high-risk population with already established cardiovascular complications but in the absence of heart failure and hypertension (either spontaneously or because of previous administration of calcium antagonists and beta blockers). These population characteristics probably explain why the hypotensive effect of the high dose of ramipril (10 mg/day, i.e. four times the usual starting dose) was only negligible [-3 and -2 mmHg respectively, for systolic and diastolic blood pressure (BP)] and accounted for only 13 of the 32% decrease and 5 of the 20% decrease in the relative risks of stroke and myocardial infarction respectively.
Regarding the interpretation of captopril prevention project (CAPPP) and Swedish Trial in Old Patients (STOP) Hypertension-2 when comparing conventional treatment by diuretics and/or beta blockers vs ACEI or dihydropyridine in large populations of hypertensive patients (mostly without initial complication), Luft proposes the global message that ‘in patients with hypertension the single most important service we can provide is to lower blood pressure with medications to a range suggested from trials such as the Hypertension Optimal Treatment (HOT) study’ [3], implying that the primary choice of the drugs is not of significant importance. We are afraid that this implication is not totally justified, since myocardial infarction, heart failure, and stroke do not appear to be equally prevented by all antihypertensive drugs for the same BP decrease. Thus, myocardial infarcts are less well prevented by dihydropyridine than by ACEI, as shown by STOP Hypertension-2. Heart failure is less well prevented by dihydropyridine than by ACEI, as shown by STOP Hypertension-2, and by 
1 blockers than by diuretics, as shown by the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [4]. Strokes are better prevented by diuretics (especially at high dose) than by beta blockers (as shown by the Medical Research Council (MRC) trials in the middle-aged [5], the decrease in relative risk being 70 vs 27% for a BP-dependent expected decrease of 42%) or by 1 blockers, as shown by ALLHAT [4] (the stroke risk being +19% with doxazosin vs chlorthalidone at low dose for the same decrease in diastolic BP). Diuretics have never been compared directly to ACEI, but only in association with beta blockers, which have a lower stroke protective effect, whereas ACEI were associated if necessary with thiazides. The fact that a higher risk of stroke was found in CAPPP with captopril than with the conventional treatment is good evidence of the stronger stroke preventive effects of thiazides vs ACEI even though there was a higher systolic BP/DBP in the captopril group (+2.2 and +1.7 mmHg respectively). This difference in BP is of the same order of magnitude as that observed in the HOPE study, so that the BP-independent risk of stroke with captopril may be estimated at 43-13%=+30% in the treatment analysis.
This critical review of clinical trials in hypertensive patients without complications therefore supports the provocative hypothesis that stroke prevention is all the better when angiotensin II synthesis is stimulated. This hypothesis is further supported by the lack of stroke prevention in the HOT study, since a non-significant decrease of 5% was observed, instead of the 30% decrease expected on the basis of the 4 mmHg lower diastolic BP. The BP difference was not due primarily to diuretics, which stimulate angiotensin II secretion and were used in a fifth step in only 19 and 24% of the patients, but was due mainly to the more frequent use and higher doses of beta blockers and ACEI that have an inhibitory effect on angiotensin synthesis. A recent case control study also supports this hypothesis, since compared with ACEI, thiazides decreased the risk of stroke by a factor 2.8 in a hypertensive population without cardiovascular complications treated by monotherapy [6].
Pathophysiological explanations should be given to elucidate the discrepancy between the BP-independent stroke preventive effect of ACEI in patients with cardiovascular complications and the poor effectiveness of ACEI to prevent stroke in hypertensive patients. We propose that ACEI have an anti-atherothrombotic effect that becomes rapidly manifest only when the altered arterial wall is the site of local angiotensin II overproduction, linked to the overexpression of the tissular angiotensin-converting enzyme gene under the influence of oxidant stress [7]. This would occur even though the systemic renin-angiotensin endocrine system may be suppressed, as suggested by the negligible BP decrease induced by high doses of a tissue specific ACEI such as ramipril. However, this mechanism does not easily work in hypertensive patients without previous complications. ACEI may even prove to be deleterious at this stage of arterial disease since in the case of arterial occlusion the recruitment of collateral circulation is delayed because of lack of angiotensin II, as shown by the experiments of Fernandez et al. [8] in the gerbil model of brain ischaemia due to acute unilateral carotid ligation. In this model, infusion of angiotensin II decreased mortality and increased ipsilateral cerebral blood flow (CBF) recovery, whereas pre-infusion of enalaprilat increased the mortality.
The deleterious effect of ACEI pre-administration in this model is furthermore reminiscent of the prevention by ACEI or by saralazin, a non-specific blocker of angiotensin II receptors, of the compensatory increase of cerebral blood flow induced by hypoxia in the rabbit [9]. This latter experiment is associated with no increase of angiotensin II plasma concentration and therefore shows the ability of the brain to fight against neuronal anoxia by stimulating either the endogenous synthesis of angiotensin II or the expression of angiotensin receptors responsible for vasodilatation. The role of non-AT1-receptor stimulation in this vasodilatation has been documented by pre-administration of angiotensin II receptor type I-specific antagonist (AT1RA) before carotid ligation of the gerbil, since this manoeuvre does not increase mortality (Mazouz and Achard, personal communication) or even decrease it, as does the administration of PD 123 319, an AT2 ligand with agonist properties [8]. Whereas the beneficial AT1RA effect is blunted by co-administration of ACEI, this is not the case with the AT2 ligand, suggesting that AT2 receptor stimulation mediates the more rapid recruitment of collateral circulation. Indeed, in contrast to ACEI, which inhibit angiotensin II synthesis, AT1RA stimulate angiotensin II synthesis by blunting the AT1R-mediated inhibition of renin secretion, and therefore leads to the stimulation of the non-opposed AT2 receptors. Other experimental data suggest that AT1RA may improve neurological outcome in case of brain ischaemia by inducing increased neuronal resistance to ischaemia independently of CBF recovery either directly or by stimulation of AT2 receptors [10].
Since AT1RA have been shown experimentally to have the same anti-atherothrombotic effect as ACEI [11] we propose to perform a large trial for primary stroke prevention, comparing ACEI and AT1RA in hypertensive patients whose hypertension cannot be optimally controlled by low-dose diuretics. Such a trial would aim to prove that AT1RA are superior to ACEI via the above discussed additional rescue mechanisms, namely collateral circulation recruitment and neuronal resistance to ischaemia, in case of cerebral artery occlusion.
References
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Luft F. STOPPING at the CAPPP of good HOPE. Nephrol Dial Transplant2000; 15: 451–452
[Free Full Text] - Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet2000; 355: 253–259[Web of Science][Medline]
- Hansson L, Zanchetti A, Carruthers G et al. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. Lancet1998; 351: 1755–1762[Web of Science][Medline]
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ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA2000; 283: 1967–1975
[Abstract/Free Full Text] - MRC Working Party. MRC trial of treatment of mild hypertension. Principal results. Br Med J1985; 291: 97–104 (meta-analysis BMJ1988; 296: 1565–1570)
- Klungel OH, Heckbert SR, Longstreth WT Jr et al. Antihypertensive drug therapies and the risk of ischemic stroke. Circulation2000; 101: 720 (abstract)
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Ardaillou R, Michel J. The relative roles of circulating and tissue renin angiotensin systems. Nephrol Dial Transplant1999; 14: 283–286
[Free Full Text] - Fernandez L, Caride V, Strömberg C, Näveri L, Wicke J. Angiotensin AT2 receptor stimulation increases survival in gerbils with abrupt unilateral carotid ligation. J Cardiovasc Pharmacol1994; 24: 937–940[Web of Science][Medline]
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Maktabi M, Todd M, Stachovi G. Angiotensin II contributes to cerebral vasodilation during hypoxia in the rabbit. Stroke1995; 26: 1871–1876
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Dai WJ, Funk A, Herdegen T, Unger T, Culman J. Blockade of central angiotensin AT1 receptors improves neurological outcome and reduces expression of AP-1 transcription factors after focal brain ischemia in rats. Stroke1999; 30: 2391–2399
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Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM. Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation2000; 101: 1586–1593
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