Role of ACE Inhibitors in Hypertension Complicated by Vascular Disease S 37

Br Heart Jf (Supplement) 1994; 72: 33-37 S 33

Role of ACE inhibitors in hypertension Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from complicated by vascular disease

Gordon T McInnes

Hypertension is an important risk factor for Locally produced angiotensin II may exert a vascular disease. Therefore, it is not surprising significant effect on vascular tone directly by that many patients with hypertension have contracting smooth muscle and indirectly by widespread atherosclerotic disease. Treatment releasing catecholamines from surrounding with conventional antihypertensive drugs can nerve endings. Direct clinical evidence be problematic in such patients. In this article suggests that tissue actions may influence I consider the use of angiotensin converting regional blood flow. Thus, enalapril, at a dose enzyme (ACE) inhibitors in managing hyper- which did not induce significant humoral or tension complicated by vascular disease, pay- systemic haemodynamic effects, reduced left ing particular attention to cerebrovascular ventricular inotropic state and increased disease and peripheral vascular disease affect- coronary blood flow when infused into the ing the legs. Coronary artery disease and coronary bed and increased forearm blood atherosclerotic renovascular disease are flow when infused into the forearm.' considered only briefly. Vascular angiotensin II may be a major ACE inhibitors reduce blood pressure in pathological factor in the development of hypertensive patients by decreasing peripheral atherosclerosis (figure), mediating the pro- resistance with little effect on cardiac output liferation of arterial smooth muscle cells by or heart rate. The lack of reflex tachycardia is many mechanisms, including a direct effect on likely to be due to downward resetting of growth factor production and reciprocal sup- baroceptor reflexes, though ACE inhibitor pression of arterial bradykinin concentrations. induced venodilatation or modification of The effects of ACE inhibition on pro- parasympathetic activity may contribute. The gression of atherosclerosis has been reviewed increase in arterial compliance due to ACE recently by Sharpe.2 Early studies showed no inhibition can influence regional haemo- beneficial effect on aortic atherosclerosis in dynamics, with redistribution of blood flow rabbits fed cholesterol, but in more recent in favour of vital organs. ACE inhibitors work captopril was effective in Watenabe rabbits, increase blood flow and decrease vascular which have an inherited tendency to secondary resistance in the regions supplied by the renal, hyperlipidaemia, without affecting serum carotid, and brachial arteries both in healthy cholesterol concentration; total aortic surface subjects and in patients with hypertension. involvement and the cellularity of athero- http://heart.bmj.com/ Unlike some other antihypertensive agents, sclerotic lesions were reduced. In cynomolgus such as P blockers, ACE inhibitors do not monkeys fed cholesterol, low and high doses interfere with the normal haemodynamic of captopril reduced atherosclerotic lesions in responses to stress or exercise while blood carotid arteries by 80% and 95% respectively; pressure reduction is maintained. As a conse- coronary arteries were almost free of athero- quence of these haemodynamic properties, sclerosis after ACE inhibition. Continuous or ACE inhibitors might be particularly suitable treatment with cilazapril captopril prevented on September 30, 2021 by guest. Protected copyright. for the treatment of hypertension complicated neointimal proliferation after carotid endo- by atherosclerosis. thelial denudation injury by balloon catheter- The beneficial haemodynamic effects of isation; this was not primarily due to blood ACE inhibitors in hypertension are mediated pressure reduction as verapamil was ineffec- primarily by inhibition of ACE and the conse- tive. Similar findings have been reported with quent withdrawal of the vasoconstricting action lisinopril and perindopril in various animal of endogenous angiotensin II. Since ACE can models of atherosclerosis. These actions are also affect bradykinin degradation, some of the likely to be due to blockade of angiotensin II vascular actions of some ACE inhibitors might since the same effect has been seen with an be mediated by changes in concentrations of AT1 receptor antagonist.3 Preservation of vasoactive kinins and prostanoids. Although the effects of captopril may depend partly on Hypertension Vascular injury University with other ACE Department of such mechanisms, studies Medicine and inhibitors have failed to show changes in Therapeutics, prostaglandin metabolism. Induction of vascular ACE Gardiner Institute, Animal studies suggest that tissue ACE and Western Infirmary, Glasgow angiotensin II (particularly in the vasculature) G T McInnes may be more important than plasma concen- Increase in local angiotensin 11 Correspondence to: trations in determining the haemodynamic Dr G T McInnes, inhibitors. It is unclear whether University Department of effects of ACE Medicine and Therapeutics, the local effects of ACE inhibitors are entirely Vascular remodelling Gardiner Institute, to inhibition of local II or II as a in the Westem Infirmary, due angiotensin Vascular angiotensin pathological factor Glasgow G1 1 6NT. interference with other peptide systems. development of atherosclerosis. S 34 McInnes

Table 1 Possible endothelial function with ACE inhibitors has with decreased sympathetic drive and increased mechanisms of effect of been shown in the aortic segments of rabbits compliance of large vessels. The vasodilating Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from ACE inhibitors on atherosclerosis on a long term atherogenic diet,2 possibly action of ACE inhibitors on peripheral vessels through accumulation of bradykinin, which might lead to improved blood flow to the Mechanism enhances release of endothelial derived limbs. Ancillary actions such as inhibition of Reduction in blood pressure relaxing factor and production of cyclic AMP platelet aggregation and thromboxane A2 Reduction in arterial Thus or release after captopril may be particularly permeability and (cAMP). ACE inhibitors may prevent lipoprotein entry retard the development of atherosclerosis. advantageous since hyperaggregability of Inhibition of growth factors: Table 1 lists potential mechanisms. Angiotensin II platelets may contribute to the atherogenic Platelet derived growth process and to formation of mural thrombi factor Fibroblast growth factor and platelet emboli. Epidermal growth factor Peripheral vascular disease In healthy subjects ACE inhibitors have Transforming growth Intermittent is the flow to the factor a claudication primary been reported to increase blood Free radical scavenging symptom of chronic occlusive peripheral arms and legs. Blood flow to skeletal muscle (SH group) and on antioxidant for low density vascular disease of the legs. Like hypertension, and skin is augmented because of an action lipoprotein cholesterol its prevalence increases with age. Its pattern is large arteries and arterioles and because of Anti-inflammatory effects similar to that of angina but it occurs 10 years improved compliance.6 By contrast, other later; 3-20% of subjects over 65 years are studies have indicated no change in limb affected.4 Atheroma is a generalised disease, blood flow with captopril in hypertensive and intermittent claudication might be subjects.7 Peripheral vasodilatation is offset by expected to coexist with coronary artery lowered perfusion pressure and flow is disease and cerebrovascular disease. About unaltered; the normal response to exercise is 50% of sufferers have evidence of myocardial maintained. These effects may not be ischaemia; a smaller proportion have cerebro- accompanied by clear clinical advantages. vascular disease. About 15% have myocardial Herrick et al found no difference between infarction and 5% a stroke within five years. enalapril and atenolol in exercise duration, Only two approaches have been shown to be subjective dyspnoea, or tiredness in hyper- of benefit in improving symptoms: stopping tensive patients.' smoking and regular exercise. Angioplasty or Anecdotal reports suggest that the symp- reconstructive surgery offers good relief of toms of peripheral vascular disease seen with symptoms if there is continuous serious 3 blockers may improve dramatically by handicap for at least one year despite con- switching to treatment with an ACE inhibitor. servative measures; pain at rest; or gangrene. Properly conducted studies of ACE inhibitors Medical treatment of coexistent hypertension, in hypertensive patients with peripheral hyperlipidaemia, and diabetes mellitus may be vascular disease are difficult to find. Uncon- required, but there is no evidence that this trolled observations in 20 patients treated with leads to symptomatic improvement. captopril 50 mg daily for eight weeks indicated The optimal choice of treatment for hyper- improvement in ankle/arm pressure index at

tension complicated by peripheral vascular rest and after exercise, in absolute pain free http://heart.bmj.com/ disease is limited by the unwanted effects on interval, and in reduction in blood pressure.9 peripheral vascular resistance and regional Libretti and Catalano also compared captopril haemodynamics of many of the most effective at the same dose with chlorthalidone 25 mg drugs currently available. Antihypertensive daily in 20 hypertensive patients with Fontaine drugs should not lower blood flow to the legs stage Ila and Ilb peripheral vascular disease.'0 as symptoms of peripheral vascular disease Only captopril reduced blood pressure may be exaggerated. In peripheral vascular significantly, increased ankle/arm arterial

disease arterioles in the leg may already be pressure index at rest and on exercise, and on September 30, 2021 by guest. Protected copyright. dilated maximally because of local production increased relative and absolute pain free of muscle metabolites. Atheromatous blood intervals on exercise. This study had several vessels may also be so sclerotic that they are shortcomings: only subjects previously shown unable to dilate further, and use of a vaso- to be "responders" to captopril were included; dilator may divert or "steal" blood flow away the treatments do not seem to have been from the worst affected areas. Thus generalised allocated at random and were open labelled; vasodilatation does not improve intermittent the groups were not well matched at outset; claudication and may even make it worse. By and the drugs were not compared directly. contrast, 3 blockers reduce blood flow during Inspection of the data suggests no significant exercise perhaps because of diminished blood differences between captopril and chlorthali- pressure, reduced cardiac output, or blockade done for any of the variables. of 32 receptors in the vessels supplying Roberts et al conducted one of the few working muscles. No change in claudication adequate studies on this subject." In a was seen with atenolol, which does not randomised, placebo controlled, crossover antagonise P2 receptors, but patients could not trial they compared captopril 25 mg twice walk as far when the cardioselective , blocker daily, atenolol 100 mg once daily, labetalol was combined with nifedipine.5 This tends 200 mg twice daily, and pindolol 10 mg twice to support the notion that drugs with vaso- daily for one month in 23 patients with mild dilating properties may direct blood flow to to moderate hypertension and chronic stable unaffected vascular beds. intermittent claudication. Peripheral arterial Patients with hypertension and peripheral disease was confirmed by clinical observation vascular disease might be expected to respond (including pedobrachial systolic pressure ratio well to ACE inhibitors, which are associated <0.9) and aortofemoral angiography. Three Role ofACE inhibitors in hypertension complicated by vascular disease S 35

patients were withdrawn from the study mechanism mediated by variations in the

because of other cardiovascular events (two calibre of cerebral arterioles and small arteries, Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from with non-fatal myocardial infarctions and one which respond to increases in perfusion with transient ischaemic attacks), reflecting pressure by constriction and to decreases in the high morbidity of this condition. All treat- perfusion pressure by dilatation. Below a ments were equally effective in reducing blood certain perfusion pressure, autoregulatory pressure, and there were no differences between vasodilatation is inadequate; flow decreases treatments in resting blood flow measured by with the risk of ischaemia. With acute occlusion plethysmography. Postexercise calf increases in blood pressure beyond a certain blood flow was reduced by labetalol and level, autoregulatory vasoconstriction is over- pindolol, and all a blockers improved the ridden, with consequent increase in cerebral recovery in calf blood flow after exercise, blood flow. Thus, there is an upper and which was reduced by captopril. Labetalol and lower limit of autoregulation. Atheromatous pindolol reduced pain free walking distance; narrowing of intracranial arteries, either within atenolol reduced total walking distance. or outside the cranium, may limit auto- Captopril did not alter either walking distance. regulation in response to a fall in perfusion Increases in the frequency and severity of pressure, and, at regional level, fixed symptoms of intermittent claudication were obstruction (due to vascular disease) in the seen only with labetalol and pindolol. There larger intracranial vessels may lead to local were no correlations between calf blood flow ischaemia when blood pressure falls.'3 indices and walking distances. This study In chronic hypertension the absolute value indicates that captopril has advantages over of cerebral blood flow is the same as that in [ blockers, regardless of their ancillary normal subjects, but autoregulation of cerebral properties. The lack of effect on resting calf blood flow is adapted to higher pressure. The blood flow suggests little (or no) direct or lower limit of autoregulation is shifted to the compensatory action on vessels distal to the right on the blood pressure axis in proportion arterial obstruction, probably because of medial to the severity of hypertension. '4 This atrophy in the arterial wall. The preservation increases the risk of ischaemic effects as blood of limb flow with captopril strongly supports pressure falls. The shift is probably due to an action of this drug in maintaining the structural changes in hypertensive resistance collateral circulation. vessels, which are narrowed and have ACE inhibitors may be appropriate anti- thickened walls and thus have a restricted hypertensive agents in peripheral vascular capacity for vasodilatation. A shift in the upper disease, particularly if this is associated with limit probably explains tolerance to very high good collateral flow. The incidence of blood pressures, which would precipitate coexisting renal artery stenosis in such patients hypertensive crises in normal subjects. How- is, however, high, with consequent risk of ever, the shift towards higher pressure of the acute renal failure induced by ACE inhibition upper limit of autoregulation may be less (see later). A prospective study of renal obvious than the shift in the lower limit, such arteriography in 100 patients referred for that the autoregulatory plateau may be shorter http://heart.bmj.com/ investigation of peripheral vascular disease in some patients with hypertension than in found that many patients had bilateral renal normal subjects. Resting cerebral blood flow is artery stenosis; seven had a single functioning nearer the threshold for cerebral ischaemia, kidney.'2 Peripheral vascular disease is the particularly in elderly patients. best clinical marker of anatomical renal artery Antihypertensive treatment protects against stenosis. Normal renal function has been cerebrovascular events. In most cases the assumed to preclude renal artery stenosis, benefit is much greater than the risk of but as most patients in this study had ischaemia from lowering blood pressure. on September 30, 2021 by guest. Protected copyright. normal serum creatinine concentrations this Although the autoregulatory curve is shifted is clearly not the case. In patients with upwards, there is still a considerable reserve peripheral vascular disease ACE inhibitors between resting pressure and the lower limit of should be used with caution. Consideration autoregulation and between resting pressure should be given to coexistent renal artery and the even lower pressure at which clinical stenosis. symptoms of brain hypoperfusion are seen. The cerebral circulation might also readapt during long term treatment, with consequent Cerebrovascular disease shift of the lower end of the cerebral blood Hypertension and other risk factors for flow autoregulation curve towards normal. In atheroma such as smoking, diabetes, and animals the shift in the lower limit is hyperlipidaemia predispose to cerebrovascular completely reversed by antihypertensive treat- disease. If hypertension is long standing, the ment. This finding may be relevant in treating risk of development of stenosis in extracranial young or middle aged patients who have and intracranial segments of major arteries had hypertension for a short time. Whether supplying the brain is increased.'3 As a result, more longstanding hypertensive adaptation of cerebral blood flow is reduced; the decline is cerebral circulation with degenerative changes particularly well documented in elderly in cerebral vessels could be reversed by anti- people. hypertensive treatment is unknown, although Cerebral blood flow is usually auto- at least partial reversal would be expected. regulated.'4 It is kept constant during wide Reversal of the shift in the upper limit of changes in perfusion pressure by an intrinsic autoregulation has not been shown. S 36 McInnes

Evidence in humans is sparse. Observations pressure with ACE inhibitors is well recog-

during long term treatment of patients with nised in these circumstances. Symptomatic Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from hypertension suggests similar changes in auto- hypotension is no more common in elderly regulation, at least in some. 14 Groups at subjects than in the overall population treated particular risk of cerebral ischaemia include with ACE inhibitors."' The cautious use of those with malignant hypertension during the most antihypertensive agents in elderly people, early phase of treatment, those with acute however, does not compromise cerebral blood stroke with high blood pressure, and elderly flow. 1' people with hypertension. Although elderly In addition to the above properties, ACE people are at particular risk of stroke, they inhibitors may have an advantage in inhibiting often complain of increased dizziness after thrombosis and the atherosclerotic process treatment, and occasional strokes follow over- in patients with cerebral atherosclerotic disease. zealous treatment. Elderly people cannot be Platelet angiotensin concentration is increased expected to show noticeable readaption of after cerebral infarction, and at least some ACE hypertensive vascular changes, and treatment inhibitors reduce platelet angiotensin II in this should probably be conservative. context. Recent animal studies support a pos- Numerous studies in experimental models sible beneficial effect of ACE inhibitors on the of hypertension have shown that treatment cerebral vasculature in hypertensive patients. with ACE inhibitors normalises blood pressure ACE inhibitors may protect cerebral vessels by and restores autoregulation of cerebral blood a number of mechanisms (table 2). flow. Thus cerebral blood flow is maintained at normal levels despite a measurable decrease in perfusion pressure, although there remains Coronary artery disease doubt about distribution of blood flow within Coronary artery disease is the most common different brain areas. ACE inhibitors seem vascular complication of mild to moderate to influence cerebral blood flow uniquely hypertension. Plaques in coronary vessels are since both lower and upper limits are shifted particularly likely to be symptomatic since the to lower pressure. These changes improve myocardium in hypertension has an increased tolerance to acute hypotension and, if con- oxygen demand because of hypertrophy and firmed in humans, might explain why ACE increased afterload. Some antihypertensive inhibitors are seldom associated with drugs such as 1 blockers and calcium orthostatic hypotension. As yet, studies of long antagonists have well recognised antianginal term treatment are awaited. properties, but the reflex tachycardia and non- After ACE inhibition in healthy human specific coronary vasodilatation caused by volunteers the diameter of and flow in carotid arterial vasodilatators such as hydralazine may arteries increase in a dose-dependent precipitate or worsen angina. manner. ' Despite reduction in blood A series of controlled studies has failed to pressure, ACE inhibitors do not significantly show a difference between ACE inhibitors and affect cerebral blood flow.'6 The mechanism placebo.'9-2' More recently, a comparison of of action of ACE inhibitors on cerebral blood placebo and captopril in patients with heart http://heart.bmj.com/ flow may include inhibition of local angio- failure and angina suggested that the ACE tensin II at the luminal membrane of cerebral inhibitor may exacerbate the symptoms of arteries, which leads to dilatation of the angina and increase nitrate consumption; arteries and large cerebral resistance vessels, exercise performance was reduced and thus with compensatory constriction of smaller increased mobility could not account for the cerebral arteries; this explains a shift mainly of deterioration in symptoms.22 This topic is

the lower limit of autoregulation of cerebral explored further in this supplement by on September 30, 2021 by guest. Protected copyright. blood flow towards lower blood pressures." Davies.23 Changes in carotid artery haemodynamics Beneficial effects on coronary events have after ACE inhibition in hypertensive patients also been shown in studies of long term are similar to those seen in normal subjects.'7 outcome in patients with heart failure,24 Table 2 Possible Clinical studies of short and long term suggesting that ACE inhibitors may have mechanisms ofprotective ACE inhibition show total and regional secondary protective effects in human effect ofACE inhibitors on cerebral blood flow is unchanged even coronary artery disease. A series of large out- cerebral vessels in hypertension though blood pressure is reduced.7 '7 There- come trials are currently under way to test this fore autoregulation seems to be intact, but no hypothesis, the most important of which is the Mechanism consistent effect on the lower limit of auto- quinapril ischaemic event trial (QUIET). The Normalisation of cerebral regulation has been shown. QUIET study has several substudies, which vascular reserve Decrease in vascular Patients presenting with acute stroke are will investigate various aspects of coronary hypertrophy particularly prone to develop further ischaemia vessel structure and function, as well as Increase in external diameter Normalisation of: during acute antihypertensive treatment since produce cost-benefit analyses. Endothelial function autoregulatory capacity is lost in the partially In conclusion, ACE inhibitors may be useful Vascular mechanisms in treatment of with Antiatherosclerotic effect: ischaemic areas of brain surrounding the the hypertensive patients Decrease in proliferation infarcted area. ACE inhibitors do not change coronary artery disease. It is premature to of smooth muscle cells* acute consider these as an alternative treat- Prevention of endothelial ischaemic regional cerebral blood flow in drugs infiltration of stroke. '7 ment for coronary heart disease. Published macrophages*t Elderly patients and those with severe work is heavily weighted by poor quality *Characteristic steps of early atheroma have rigid vessels, which make them studies. Properly conducted, randomised, phase of atherosclerosis. sensitive to hypotension. The double blind clinical trials are required to tLater form "foam cells," in particularly which cholesterol accumulates. development of stroke after reduction in blood settle the issue. Role of ACE inhibitors in hypertension complicated by vascular disease S 37

Renal vascular disease 3 Dzau VJ. Vascular renin-angiotensin system and vascular J protection. Cardiovasc Phannacol 1993;22(suppl 5): Br Heart J: first published as 10.1136/hrt.72.3_Suppl.S33 on 1 September 1994. Downloaded from Renovascular hypertension probably accurs in S1-9. no more than 2-5% of hypertensive patients 4 Bevan EG, Waller PC, Ramsay LE. Pharmacological approaches to the treatment of intermittent claudication. but is a frequent cause of drug resistant hyper- Drugs and Aging 1992;2:125-36. tension. Such patients often have widespread 5 Solomon SA, Ramsay LE, Yeo WW, Pamell L, Morris-Jones W. ,-Blockade and intermittent vascular disease, of which renal vascular claudication: placebo controlled comparison of atenolol atheroma is only one component. Further and nifedipine and their combinations. BMJ 1991; in 303:1100-4. consideration is given to this topic this 6 Banas JS. Effects of inhibitors of angiotensin converting supplement by Fluck and Raine.25 enzyme on regional hemodynamics. Anm Jf Cardiol 1992;69:40-5c. 7 James IM, Dickenson EJ, Burgoyne W, et al. Treatment of hypertension with captopril: preservation of regional blood flow and reduced platelet aggregation. J Humn Conclusions Hypertens 1988;2:21-5. Theoretical considerations support a role for 8 Herrick AL, Waller PC, Berkin KE, et al. Comparison of enalapril and atenolol in mild to moderate hypertension. ACE inhibitors in hypertension complicated Amn JfMed 1989;86:421-6. by vascular disease, particularly in the 9 Catalano M, Libretti A. Captopril for the treatment of patients with hypertension and peripheral vascular management of cerebrovascular disease, where disease. Angiology 1985;36:293-6. ACE inhibitors seem capable of preserving 10 Libretti A, Catalano M. Captopril in the treatment of hypertension associated with claudication. Postgrad autoregulation of flow. Few patients, however, MedJ7 1986;62(suppl 1):34-7. are at risk of cerebral underperfusion, and 11 Roberts DH, Tsao Y, McLoughlin GA, Breckenridge A. Placebo-controlled comparison of captopril, atenolol, most antihypertensive drugs are well tolerated labetalol, and pindolol in hypertension complicated by if used sensibly. ACE inhibitors do not seem intermittent claudication. Lancet 1987;ii:650-3. 12 Choudhri AH, Cleland JGF, Rowlands PC, Tran TL, to worsen symptoms in most hypertensive McCarty M, Al-Kutoubi MAO. Unsuspected renal patients with angina, but their antianginal artery stenosis in peripheral vascular disease. BMJ 1 1990;301:1197-8. effect is modest at best. Blockers or calcium 13 Rajagopalan B, Ledingham JGG. Cerebral blood flow and antagonists are more effective options in the impact of blood pressure reduction. Current Opinion ACE in Cardiology 1988;3(suppl 1):S31-41. patients with symptoms. Although 14 Strandgaard S. Cerebral blood flow in hypertension. Acta inhibitors are widely advocated as anti- Med Scand Suppl 1983;678:11-25. in with 15 Belz GG, Kirch W, Kleinbloesem CH. Angiotensin- hypertensive agents patients peripheral converting enzyme inhibitors. Relationship between vascular disease, there is a high risk of pharmacodynamics and pharmacokinetics. Clin Pharma- cokinet 1988;15:295-318. unsuspected renal artery disease in such 16 Brogden RN, Todd PA, Sorkin EM. Captopril. An update patients and renal function, as for patients of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart with known renal artery stenosis, must be failure. Drugs 1988;36:540-600. monitored carefully. 17 Waldemar G, Paulson OB. Angiotensin converting enzyme inhibition and cerebral circulation-a review. Br Jf Clin ACE inhibitors have the potential to cause Pharmacol 1989;28(suppl 2): 177-82S. regression of atherosclerosis or even prevent it. 18 Jenkins AC, Knill JR, Dreslinski GR. Captopril in the treatment of elderly hypertensive patients. Arch Intern If preliminary findings in animals are Med 1985;145:2029-31. confirmed in humans the application of ACE 19 Gibbs S, Crean PA, Mockus L, Wright C, Sutton GC, inhibitors in with Fox KM. The variable effects of angiotensin-converting hypertensive patients enzyme inhibition on myocardial ischaemia in chronic vascular disease will be greatly widened. Such stable Br HeartJ

angina. 1989;62:112-7. http://heart.bmj.com/ are at risk of vascular 20 Ikram H, Low CJS, Shirlaw T, Webb CM, Richards AM, patients great events, Crozier IG. Anti-anginal, hemodynamic and coronary and even a modest benefit would have an vascular effects of captopril in stable angina pectoris. Am enormous clinical Clinical con- 7 Cardiol 1990;66:164-7. impact. 21 Strozzi C, Cocco G, Portaluffi F, et al. Effects of captopril firmation, or otherwise, awaits the outcome of on the physical work capacity of normotensive patients with stable effort angina pectoris. Cardiology 1987;74: long term trials. In the meantime, there is a 226-8. dearth of good quality evidence to guide 22 Cleland JGF, Henderson E, McLenachan J, Findlay I. decisions. Well controlled clinical trials Dargie HJ. Effect of captopril, an angiotensin clinical converting enzyme inhibitor, in patients with heart

of ACE inhibitors in hypertensive patients failure and angina pectoris. .7 Am Coll Cardiol 1991 ;17: on September 30, 2021 by guest. Protected copyright. with all forms of vascular disease are needed. 733-9. 23 Davies MK. Effects of ACE inhibitors on coronary haemodynamics and angina pectoris. Br Heart _7 1994;72(3) (suppl):S52-6. 1 Salvetti A. Newer ACE inhibitors. A look at the future. 24 SOLVD Investigators. Effect of enalapril on survival in Drugs 1990;40:800-28. patients with reduced ejection fractions and congestive 2 Sharpe N. The effects of ACE inhibition on progression of heart failure. N EnglJ7 Med 199 1;325:293-302. atherosclerosis. J Cardiovasc Pharmacol 1 993;22(suppl 9): 25 Fluck RJ, Raine AEG. ACE inhibitors in non-diabetic renal S9-1 2. disease. Br Heart .7 1994;72(3) (suppl) :S46-51.