Service de Néphrologie, Médecine Interne, CHU d'Amiens, France
Correspondence and offprint requests to: Albert Fournier, Service de Néphrologie, Médecine Interne, CHU d'Amiens, Hôpital Sud, Av René Laënnec-Salouel, F-80054 Amiens Cedex, France.
Introduction
Angiotensin-converting enzyme inhibitors (ACEI) are widely prescribed. In the US their prescription rate for hypertension places them third, behind calcium antagonists and diuretics but in front of beta blockers [1]. This success, in spite of the cough problem, is due to aggressive marketing based around putative cardioprotective and nephroprotective effects. The cardioprotective effect has been demonstrated by the reduction of overall cardiac morbidity and mortality in patients with congestive heart failure or post-infarction left ventricular dysfunction [2]. The nephroprotective effect is claimed for diabetic [3] and non-diabetic [4] renal patients on the basis of greater reduction of proteinuria and greater delay in the progression to end-stage renal failure when compared to conventional treatment, although blood-pressure-independent protection has not been convincingly shown [4]. Primary cardiovascular protection in hypertensive patients had, however, not been specifically tested. Therefore the results of the Captopril Prevention Project (CAPPP) [5], the first large trial evaluating ACEI for primary prevention in hypertensive patients, were eagerly awaited. Now the results are out. An intense discussion of the results and how they might influence our daily practice, seems warranted indeed.
Results of CAPPP
A total of 10985 patients with a diastolic pressures 100 mmHg were randomly assigned to either captopril or diuretics and beta blockers. In the intention to treat analysis, the overall cardiovascular morbidity and mortality, as well as the rate of myocardial infarction and of congestive heart failure, were similar. However, the relative risk of fatal and non-fatal strokes was higher with captopril (189 vs 148; RR=1.25 (1.011.55) P=0.04). This difference was even more marked in the on treatment analysis (1.43 (1.21.82) P=0.004). As a post-hoc hypothesis, the de novo occurrence of diabetes was lower with captopril (RR=0.86 (0.740.99) P=0.04). In the subgroup of 572 patients with diabetes mellitus at baseline, the overall cardiovascular event incidence was significantly decreased with captopril, as well as the number of myocardial infarctions. The incidence of strokes was the same in this subgroup analysis.
On the one hand, these results are reassuring; captopril was no better or worse than diuretics and beta blockers. In the subgroup of diabetic patients, captopril may have the advantage. On the other hand, these results are disquieting since they show a significant increase of stroke risk with captopril. Before considering the practical consequences of such a disturbing finding, the reliability of the observation and a possible explanation should be discussed.
How reliable are the results of CAPPP?
CAPPP was conducted with the PROBE methodology; however, the randomization assignment was not centralized. This fact may explain some differences between the two groups after randomization. The reported relative risks were adjusted for some dissimilarities in baseline characteristics (age, gender, diabetes, systolic BP, and previous antihypertensive treatment). Some subjects received captopril only once a day, which does not fit the drug's pharmacokinetic profile. The role of this potential confounder has been dismissed since the relative risk was the same in the patients receiving the drug once or twice daily. However, the confounding effect of a higher systolic BP maintained for the 6 years follow-up in the captopril group is less amenable to statistically adjusting the relative risks. These factors make the overall interpretation of both the positive and negative aspects of the data more difficult.
Nevertheless, considering the fact that the increase in stroke was 43% with captopril and taking into account the estimate of MacMahon et al. [6] that such an increase would require a DBP elevation of 7.5 mmHg, this disquieting finding cannot be ignored. The HOT study [7] results would underscore that view. A five-step aggressive treatment starting with felodipine and followed by either ACE inhibitor or beta blocker in a second and fourth step and by diuretics only in the last step, compared three levels of DBP: 85.2, 83.2 and 81.1 mmHg. There was no significant stroke reduction when the two groups with the lowest and highest BP were compared (RR=0.95). Indeed, a difference of 4 mmHg should have decreased stroke by 27%, according to MacMahon et al. [6]. The lower DBP was obtained in the HOT study by the more frequent use of ACE inhibitors (45 vs 35%), rather than that of felodipine (79 vs 77%) or of diuretics (24 and 19%), or beta blockers (32 vs 25%). Thus, one is left with the disconcerting hypothesis that stronger angiotensin II synthesis inhibition could possibly provide lower stroke protection. The next step should be an examination of this hypothesis and a consideration of the available data.
Explanation for the brain ischaemia protective effect of angiotensin II
Perhaps the answer lies in actions of angiotensin II (Ang II). Ang II promotes angiogenesis and independently of this effect might be important in rapidly recruiting pre-existing collateral circulation in cases of acute ischaemia. Nelissen-Vrancken et al. [8] showed that hypotensive doses of ACEI decrease the capillary/fibre ratio of the aerobic soleus muscle in rats with a ligated iliac artery. Fernandez et al. [9] first published convincing evidence in the rat with aortic ligation between the two renal arteries that Ang II plays an important role, independent of its BP-lowering effect, in protecting against acute muscular ischaemia of its hindlimbs by stimulating rapid use of pre-existing collateral circulation. Then they used the model of unilateral carotid ligation in the gerbil to show the protective effect of Ang II against acute ischaemia. The gerbil has an incomplete circle of Willis, which makes the poor animal particularly stroke-prone upon complete carotid ligation. Massive ipsilateral brain ischaemia occurs with a mortality rate of 50% at 48 h when the ligation is made under saline infusion but of only 15% when the ligation is performed under Ang II infusion [10]. On the contrary, the mortality rate after incomplete carotid ligation increased from 15% under saline infusion to 50% when it was performed after enalaprilat infusion [11]. In a study involving 300 gerbils, the investigators showed that losartan improved survival, while saline or ACEI enalaprilat did not [12]. To test the hypothesis that Ang II might be offering some protection by occupying AT2 receptors, the investigators administered the AT2 ligand, PD-123319. This compound also improved survival in the gerbils [12]. Coadministration of enalaprilat removed the protection, suggesting that the removal of Ang II was counterproductive in terms of protecting from stroke [12]. The protective role of Ang II appears therefore to be linked to the stimulation of its non-AT1 receptors. A recent work by Kramar et al. [13] provided evidence that AT4 receptor stimulation could also be involved since the increase of cerebral blow during hypertensive perfusion of Ang II was cancelled by the AT4 receptor antagonist, Divalinal-ang IV, but not by the AT2 receptor antagonist, PD 123177.
How might these experimental works help explain the more efficient protective effect from myocardial events of ACEI compared to diuretics and beta blockers in diabetes? Obviously they cannot. We propose, therefore, the following explanatory hypothesis. According to Safar and London [14], ACEI improve the distensibility of large vessels more than beta blockers and diuretics. In that way, they decrease aortic impedance, myocardial wall stress, and cardiac oxygen consumption. This effect is particularly beneficial to the heart and can be considered a compensation for the presumed decrease in capillary density and the lower speed of collateral circulation recruitment in case of progressive coronary stenosis. Such a compensating mechanism does not work, however, for brain protection. The brain might actually benefit more from the increased Ang II production stimulated by diuretics, provided BP is decreased, and still more so when AT1 receptors are blocked, since non-AT1 receptor stimulation increases cerebral blood flow.
Proposal to evaluate AT1 receptor blockade for the prevention of strokes
The above arguments should encourage a trial of AT1 receptor blockade as a stroke prophylaxis. This issue is not being addressed in currently ongoing trials involving other organ systems, such as LIFE and VALUE for cardiac protection and like RENAAL and IDNT for renal protection [15]. These trials do not directly address the question of AT1-receptor blocker efficacy in stroke prevention and will not observe the 700 strokes necessary to show the 20% risk reduction with a power of 80% according to the estimation of by MacMahon [16]. In the US, age-adjusted incidence of strokes has actually increased since 1994 [17]. The poor quality of BP control in the identified hypertensive patients (25%) has not changed. However, the number of antihypertensive drug prescriptions is increasing in favour of ACE inhibitors and dihydropyridine calcium antagonists at the expense of diuretics and ß-blockers [1]. A large clinical trial comparing AT1 receptor blockers to ACEI in the prevention of stroke seems therefore particularly timely, all the more because such considerations should probably also be applied to neutral endopeptidase inhibitors, since they also decrease Ang II synthesis.
Practical consequences for antihypertensive drug prescriptions
Until the results of the STOP2 and the ALLHAT trials become available in 1999 and 2002 [15] and either confirm or dismiss the results of CAPPP, clinicians cannot ignore the finding that the risk of stroke may be increased by ACEI compared to diuretics and beta blockers. Cutler concurred in that view in his accompanying editorial to CAPPP [18]. He stated, `at present, for most hypertensive patients who require therapy (including patients with type 2 diabetes), drugs other than diuretics or beta blockers should be selected infrequently'. This recommendation was also made by the JNC 6th report [19] but is quite at odds with those of WHO and International Society of Hypertension [20]. These latter learned panels of experts prefer to wait for the results of STOP2 and ALLHAT trials [20] to admit that brain protection with ACEI might be worse than with diuretics, beta blockers, and dihydropyridine calcium antagonists. They also do not recommend in diabetics to prefer ACE inhibitors to dihydropyridines as this has been suggested by the ABCD trial [21], but not invalidated by the post hoc analysis of the Syst-Eur trial [22]. They put forward the view that treatment options among the six main classes of drugs (diuretics, beta blockers, ACEI, calcium antagonists, alpha1 blockers, and AT1 antagonists) should be based solely on individual patient characteristics for special indications or contraindications, and on their blood pressure-lowering power. In that regard they insist on the necessity of multiple therapy to achieve the optimal target BP, which is definitively below 140/90 as demonstrated by the HOT study [7].
The meta-analysis of Stason et al. [23] showing that adjusted risk of cardiovascular events is significantly greater when long-acting nifedipine is used in monotherapy rather than in combination suggests, however, that liberal advice for dihydropyridines as first-choice drug without concomitant sympathetic inhibiting drugs may not be optimal. The same remark may be made concerning the use of ACE inhibitor as first-choice drug in patients at increased risk of stroke. Therefore, as proposed by Levy [24], their systematic combined use, especially with diuretics, may be presently recommended, as long as the comparative trial of ACE inhibitor with AT1 receptor antagonist has not definitively proven the superiority of the latter.
In conclusion, for the present time clinicians must search their conscience, when they face each individual patient and arrive at a decision. First do no injury, primum non nocere, should always be a primary consideration when faced with uncertainty.
References