ace inhibitors compared with thiazide diuretics as first-step antihypertensive therapy

5
Cardiovascular Drugs and Therapy 3:815-819 1989 Kluwer Academic Publishers. Printed in the U.S.A. ACEINHIBITORS COMPARED WITH THIAZIDE DIURETICS AS FIRST-STEP ANTIHYPERTENSIVE THERAPY SUMMARY. While ACE inhibitors are considerably more expensive than thiazide diuretics, they are slightly more effective antihypertensive agents in white patients and have fewer side effects. They can be regarded as suitable first-line therapy in diabetic hypertensives. It is prob- able that as new drugs in this class are marketed, the price differential will lessen and they will be regarded as acceptable and useful first-line drugs in an increasingly large number of patients. KEY WORDS. hypertension, cost of treatment, thiazide diuretics, ACE inhibitors There is an expanding view that ACE inhibitors merit serious consideration as first-line agents, com- peting with diuretics and beta blockers, in the tradi- tional stepped-care approach. With increased under- standing of pathophysiologic mechanisms in hypertension, a concept of the optimal antihyperten- sire agent is emerging when comparing drugs cur- rently available. Accordingly, comparison of ACE inhibitors and diuretics as potential first-step agents must focus not only on the financial cost of these agents, but also on their relative efficacy, the in- cidence of side effects affecting compliance and the quality of life, metabolic and physiologic effects, duration of action, interaction or synergy with other agents, and the morbidity and mortality associated with long-term use. Discussion of the cost/benefit ratio of thiazides or ACE inhibitors must be set in the context of the overall cost effectiveness of treating mild hyper- tension. The results of large therapeutic trials in mild hypertension reported over the past decade are widely regarded as disappointing. The much-quoted summary statistic that one must treat several hun- dred patients for a year to prevent a single stroke has led us to question the value of drug therapy to the individual patient with mild hypertension. It is difficult, however, to extrapolate fl'om these studies to an individual patient attending a hypertension clinic. If one considers, for instance, the MRC trial, partici- pants in this study were distinctly "well-to-do," blood pressure in the placebo group averaged 90 mmHg I.J. Perry, D.G. Beevers University Department of Medicine, Dudley Road Hospital, Birmingham, UK after 1 year of therapy, the prevalence of cigarette smoking was low, and very few cases had intercurrent cardiovascular or noncardiovascular disease. The study patients were at a distinctly low risk, and the duration of follow-up (5.5 years) was short in terms of the natural history of vascular disease. Despite these limitations, the MRC trial did achieve a 40~ reduc- tion in stroke. Beta blocker- and thiazide-induced side effects contributed significantly to the cost side of the MRC cost/benefit equation. With regard to the prevention of coronary artery disease, a meta analy- sis from the clinical trials published to date I1) suggests an 8c~ reduction (95~ CI, -21c~ to + 6c~1 in mortality from the treatment of mild-to-moderate hypertension, an effect of potentially major impor- tance at the population level. Accordingly, the num- ber of patients commencing antihypertensive therapy is likely to increase, and the choice of the optimal first-step agent will remain under review. Financial Cost Thiazide diuretics are among the lease expensive antihypertensive agents and are approximately 20 times less expensive than captopril, the first commer- cially available ACE inhibitor. It would seem that, in the mass treatment of millions of patients with mild hypertension, expensive drugs such as ACE in- hibitors are difficult to justify. This is a powerful argument and has been used to promote thiazides in preference to other classes of drugs. All new antihy- pertensive agents, however, are expensive when first introduced. Inevitably, if they are successful, similar drugs are produced by rival companies. This competi- tion, combined with increased usage, generally leads Address for correspondence and reprint requests: Dr. D.G. Beevers, University Department of Medicine, Dudley Road Hospital, Bir- mingham B18 7QH, UK. 815

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Page 1: Ace inhibitors compared with thiazide diuretics as first-step antihypertensive therapy

Cardiovascular Drugs and The rapy 3 : 8 1 5 - 8 1 9 1989 �9 Kluwer Academic Publishers. Printed in the U.S.A.

ACE INHIBITORS COMPARED WITH THIAZIDE DIURETICS AS FIRST-STEP ANTIHYPERTENSIVE THERAPY

SUMMARY. W h i l e ACE i n h i b i t o r s are c o n s i d e r a b l y m o r e e x p e n s i v e t h a n t h i a z i d e d i u r e t i c s , t h e y are s l i g h t l y m o r e e f f e c t i v e a n t i h y p e r t e n s i v e a g e n t s in w h i t e p a t i e n t s a n d h a v e f e w e r s i d e e f fec ts . T h e y can be r e g a r d e d as s u i t a b l e f i r s t - l ine t h e r a p y in d i a b e t i c h y p e r t e n s i v e s . It is prob- ab le tha t as n e w d r u g s in th i s c l a s s are m a r k e t e d , th e p r i c e d i f f e r e n t i a l w i l l l e s s e n a n d t h e y wi l l be r e g a r d e d as a c c e p t a b l e a n d u s e f u l f i r s t - l ine d r u g s in an i n c r e a s i n g l y l a r g e n u m b e r of p a t i e n t s .

KEY WORDS. h y p e r t e n s i o n , cos t of t r e a t m e n t , t h i a z i d e d i u r e t i c s , ACE i n h i b i t o r s

There is an expanding view that ACE inhibitors meri t serious consideration as first-line agents, com- pet ing with diuretics and beta blockers, in the tradi- tional stepped-care approach. With increased under- s tanding of pathophysiologic mechanisms in hypertension, a concept of the optimal ant ihyperten- sire agent is emerging when comparing drugs cur- rent ly available. Accordingly, comparison of ACE inhibitors and diuretics as potential first-step agents mus t focus not only on the financial cost of these agents, but also on their relative efficacy, the in- cidence of side effects affecting compliance and the quality of life, metabolic and physiologic effects, durat ion of action, interaction or synergy with other agents, and the morbidity and mortal i ty associated with long-term use.

Discussion of the cost/benefit ratio of thiazides or ACE inhibitors must be set in the context of the overall cost effectiveness of t rea t ing mild hyper- tension. The resul ts of large therapeut ic trials in mild hypertension reported over the past decade are widely regarded as disappointing. The much-quoted s u m m a r y statist ic that one must t rea t several hun- dred pat ients for a year to prevent a single stroke has led us to question the value of drug therapy to the individual pat ient with mild hypertension. It is difficult, however, to extrapolate fl'om these studies to an individual pa t ient a t tending a hypertension clinic. I f one considers, for instance, the MRC trial, partici- pan ts in this s tudy were distinctly "well-to-do," blood pressure in the placebo group averaged 90 m m H g

I.J. Perry, D.G. Beevers University Department of Medicine, Dudley Road Hospital, Birmingham, UK

after 1 year of therapy, the prevalence of cigarette smoking was low, and very few cases had intercurrent cardiovascular or noncardiovascular disease. The study pat ients were at a distinctly low risk, and the duration of follow-up (5.5 years) was short in te rms of the natura l history of vascular disease. Despite these limitations, the MRC trial did achieve a 40~ reduc- tion in stroke. Beta blocker- and thiazide-induced side effects contributed significantly to the cost side of the MRC cost/benefit equation. With regard to the prevention of coronary ar tery disease, a meta analy- sis from the clinical trials published to date I1) suggests an 8c~ reduction (95~ CI, -21c~ to + 6c~1 in mortal i ty from the t r ea tment of mild-to-moderate hypertension, an effect of potential ly major impor- tance at the population level. Accordingly, the num- ber of pat ients commencing ant ihyper tensive therapy is likely to increase, and the choice of the optimal first-step agent will remain under review.

Financial Cost

Thiazide diuretics are among the lease expensive ant ihyper tensive agents and are approximate ly 20 t imes less expensive than captopril, the first commer- cially available ACE inhibitor. It would seem that, in the mass t r ea tmen t of millions of pat ients with mild hypertension, expensive drugs such as ACE in- hibitors are difficult to justify. This is a powerful a rgument and has been used to promote thiazides in preference to other classes of drugs. All new antihy- pertensive agents, however, are expensive when first introduced. Inevitably, if they are successful, s imilar drugs are produced by rival companies. This competi- tion, combined with increased usage, generally leads

Address for correspondence and reprint requests: Dr. D.G. Beevers, University Department of Medicine, Dudley Road Hospital, Bir- mingham B18 7QH, UK.

815

Page 2: Ace inhibitors compared with thiazide diuretics as first-step antihypertensive therapy

816 Perry and Beevers

to a fall in price. If financial cost alone were used to just in ' the choice of antihypertensive therapy, then there would be little prospect of innovation or ira- provement in the pharmacology of hypertension.

In the context of health-service resource allocation, however, the current cost must influence the current prescribing practice. An illustrative example is the South of Ireland, where the use of 50 mg daily of captopril as opposed to 2.5-5 mg daily of bendro- fluazide as initial therapy in the majority of mild hypertensives would consume around 2.55} of the annual health expenditure. 1Resource allocation of this magnitude is difficult to justify.

Efficacy

A large number of studies comparing ACE inhibitors with thiazide diuretics and thiazide-ACE combina- tions have been reported [2-18l ITable 1). These studies vaw considerably in their size and quality. A number of observations, however, may be made. It is clear that the combination of a thiazide diuretic and an ACE inhibitor is superior to either agent used alone. This synergy is predictable from the mode of action of the drugs and will not be considered fur ther beyond noting that the adverse metabolic effects of thiazides appear to be partially a t tenuated by ACE inhibition. In the majority of studies involving Cau- casian patients, ACE inhibitors achieved slightly gn-eater reductions in blood pressure (BP) and/or achieved normalization of BP in a greater proportion of patients. The difference obsmwed in individual studies has tended to be small and not statistically significant. By contrast, thiazides are clearly of superior efficacy in black patients.

Turning to individual studies, that of Helgeland et al. [21 is of part icular relevance with regard to the assessment of first-line ant ihypertensive agents, as it was performed in a general practice setting. En- alapril 20-40 mg, atenolol 50-100 mg, and hydro- chlorothiazide 25-50 mg were compared in a double- blind parallel study involving 486 patients. Enalapril and hydrochlorothiazide were remarkably similar in this study. In a s tudy from this depar tment , Zezulka et al. [10] compared enalapril 10-40 mg with bendrofluazide 2.5-10 mg in a hospital-based double- blind study involving 40 patients. Enalapri l produced a clinically and statistically greater reduction of systolic and diastolic supine BP than did bend- rofluazide. Both drugs were well tolerated, although there were adverse effects on serum potassium, blood glucose, and uric acid levels associated with thiazide therapy.

Side effects of diuretics

Coupled with the possible advantages of ACE in- hibitors over thiazide diuretics in terms of efficacy, at least in Caucasian patients, there is also the impor- tant question of side effects. In general, modern antihypertensive drugs do not have major side effects of the sort that were a problem with ganglion- blocking and centrally acting drugs. However, many patients develop more subtle side effects, which are not necessarily detected unless special efforts are made. In the long-term t rea tment of mild hyper- tension, subtle side effects that impair the patient's quality of life are unacceptable. Of interest in this context is the landmark study of Croog et al. [19] on the effects of ant ihypertensive therapy on the quality of life. Captopril was clearly superior to ei ther methyldopa or propranolol in this regard (not an unexpected finding), but the addition of a thiazide diuretic had negative effects on the quality of life in all three t rea tment groups.

A range of clinical and metabolic side effects associated with thiazide therapy have been well documented over three decades of use. The long-term use of thiazides is associated with an increased incidence of hyperuricemia and gout, glucose in- tolerance and clinical diabetes mellitus, and male impotence [20]. In addition, they cause depletion of serum and total body potassium, sodium, and mag- nesium, and elevation of plasma total cholesterol with a fall in HDL cholesterol [21]. The electrolyte problems have been linked with ventr icular ectopy and a possible increased incidence of sudden death associated with thiazide therapy. The apparent fai- lure of ant ihypertensive therapy to substantial ly reduce the incidence of myocardial infarction has been at t r ibuted at least partially to thiazide-induced metabolic effects [21]. Understandably, the epide- miologic and clinical significance of these alterations is disputed [22]. There is no doubt that both clinical and metabolic side effects are substantial ly reduced by the use of low-dose thiazide regimes, without loss of ant ihypertensive efficacy [23]. Fur thermore , minor degrees of potassium/magnesium depletion may not be of clinical relevance in pat ients free of ischaemic hear t disease. Alterations in plasma cholesterol tend to resolve with long-term use [22]. Clinicians are familiar with the side effects of thiazides and may justifiably argue that these agents, as used, for instance, in the European Working Par ty Study of Hypertension in the Elderly 124J, have been shown to both reduce morbidity and to be safe and well tolerated. This a rgument remains valid in the context

Page 3: Ace inhibitors compared with thiazide diuretics as first-step antihypertensive therapy

ACE Inhibitors Compared with Thiazides 817

Table I. Summao, of studies comparing ACE inhibitors, thiazide diuretics and ACE / thiazide combination

Sitting BP Patients Efficacy of Study No. of Dosage (~ reduction) responding ACE inhibitor I Ref. ] patients (mg/day) sys t/diast (c/~ 1 vs. thiazide Comments

Helgeland EN 20-40 11/11 1986 [21 436 Aten 50-100 7/14 Similar

HCTZ 25-50 9/11 Weinberger Cap 75 4/6 42c/~ 1982 [31 207 HCTZ 45 10/9 65~ Less

Cap + HCTZ 15/15 84~ Weinberger Cap 100 9/10 52c/~ 1983 14] 415 HCTZ 50 9/11 71~ Less (Study BI Cap + HCTZ 13/17 77~ Merril Lis 20 -/4 1987 15 ] 207 HCTZ 6.25-25 -/6 Similar

Lis + HCTZ -/14 Pool Lis 20-80 11/13 82c/~ 1987 16] 394 HCTZ 12.5-50 9/8 67r Greater

Lis + HCTZ 17/14 84r;} Vidt EN 20-40 15/11 22cr 1984 17] 455 HCTZ 50-100 20/13 42c/; Less

EN + HCTZ 33,/21 80~ Muiesam Placebo 6~ 1987 18] 152 Cap 50 60r Greater

HCTZ 25 29~ Cap + HCTZ 83r

Shapiro EN 10-20 11/9 42c/~ 1987 [9J 174 HCTZ 12.5-25 11/9 43c~ Similar

EN + HCTZ 13/12 82r

Zezulka 52 EN 10-20 15/16 Greater 1987 110] BFZ 2.5-10 8/9 Frishman EN 10-20 12/9 28c/~ 1987 I 111 37 HCTZ 25-50 10/8 46~/~ Less

EN + HCTZ 13/15 100~ Bauer & Jones EN 20-40 15/20 1984 [121 39 HCTZ 50-100 13/13 Greater

EN + HCTZ 20/21 Freier EN 20-40 7/14 1984 [13] 29 HCTZ 50-100 16/15 Less

EN + HCTZ 29/27 Vlasses EN 40 -/3 1983 1141 14 HCTZ 50 -/4 Simimlar

EN + HCTZ -/16 Woo Cap 12.5-75 15/15 75c/~ Similar 19871151 Dyazide i-ii 17/15 Kayanaks Placebo 6/9 48C} 1987{161 211 Cap 50 11/14 73c/~ Similar

HCTZ 25 10/12 75~ Cap + HCTZ 15/18 88c/~

Kochar Lis 20-80 17/14 80g 1987 117J 24 HCTZ 12.5-50 30q Greater

Lis + HCTZ 19/17 100~ Gums EN 10-20 42C~ 1987 1181 37 HCTZ 12.5-25 53c/~ Less

EN + HCTZ

Higher c/~ of clinical and metabolic side effects on thiazides

9c4 patients black; better response to HCTZ in black patients Better response to HCTZ in black patients Elderly patients; fewer clinical and metabolic side effects on captopril than placebo Patients > 65 yr systolic BP fall for isolated systolic hypertension; EN similar to HCTZ 94~,; EN group white; 86r BFZ group white Middle age; 8 black patients

28 patients were black

Elderly Chinese patients; crossover study

Once daily regimens

No significant reduction on HCTZ?

Age > 65; combined t reatment most effective in patients who received HCTZ first

Aten = atenolol; EN = enalapril; Cap = captopril; Lis = lisinopril; HCTZ = hydrochlorothiazide; BFZ = bendrofluazide.

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818 Perry and Beevers

of retaining thiazides in the therapeut ic a rmamen- tar ium.

Side Effects of Ace Inhibitor's

Discussion of the relative meri ts of thiazides com- pared with ACE inhibitors must inevitably focus at tent ion on thiazide-induced side effects, but ACE inhibitors are not entirely devoid of adverse effects. However, if used with appropriate care serious clinical adverse effects are rare. Problems with ACE inhibitor use have tended to occur in pat ients receiving high-dose therapy, in association with diuretic-induced p lasma volume depletion, in indi- viduals with under lying renal impairment , renal a r te ry stenosis, collagen vascular disease, or a com- bination of these factors. In pat ients with renal art- ery stenosis, part icularly if bilateral (or involving a solitary kidney), efferent glomerular ar teriolar tone, and hence glomerular perfusion, distal to the stenosis may be critically dependent on angiotensin II levels [25]. Rash and dysgeusia are not uncom- mon, part icularly in pat ients receiving captopril. Cough may occur in 15~ or more of pat ients as a class side effect.

The major advantage of ACE inhibitors over thia- zide therapy is undoubtedly the lack of adverse effects on vascular risk factors. The fact tha t long-term studies have yet to confirm the clinical relevance of this observation cannot realistically be used as an a rgumen t against ACE therapy. A significant portion of hyper tensives have hypercholesterolemia and glu- cose intolerance, and it is clearly illogical to use thiazide therapy in these patients. ACE inhibitors may be specifically indicated for hypertension asso- ciated with diabetes mellitus. Several groups have now demonst ra ted that ACE inhibition reduces mi- croproteinuria in hypertensive diabetics and may re ta rd the progression towards diabetic nephropa thy 126}. If the benefits are confirmed, ACE inhibitors will unquest ionably be optimal first-line therapy in dia- betic hypertensives.

Thiazides are associated with hyperur icemia in up to 60~ of cases [201. Whether hyperur icemia is in fact an independent risk factor of coronary vas- cular disease or a confounding variable is un- certain. I t is associated with high alcohol intake, obesity, hypercholesterolemia, and hypertension. I t is clear, however, tha t the ideal ant ihyper tens ive drug should not cause hyperuricemia, and again this problem is not described in association with ACE inhibitor therapy.

Mode of Action

The long-term hypotensive effects of thiazides derive principally from poorly understood vasodilator effects associated with volume depletion. This effect we suspect will increasingly be regarded as a primitive approach to lowering blood pressure. In contrast, ACE inhibitors have an at t ract ive hemodynamic profile. They do not reduce p lasma volume or reduce cardiac output in hypertensive patients, and they are associated with increased renal perfusion. Coronary and cerebral blood flow is likewise protected despite significant reductions in arterial pressure. Despite their vasodilator properties, ACE inhibitors are not associated with sodium retention or sympathet ic nervous system activation. While thiazides are ob- viously saluretic, they are associated with activation of both the renin-angiotension system and the sympa- thetic nervous system. Activation of these counter- regulatory mechanisms is obviously undesirable, par- ticularly in the context of potass ium depletion. Accordingly, ACE inhibitors in their hemodynamic profile approximate more closely the ideal anti- hypertensive agent to which we alluded earlier than thiazide diuretics.

For tunate ly both thiazides and ACE inhibitors achieve adequate blood pressure control over 24 hours following a single dose (captopril not excepted, despite its short half-life), and significant drug inter- actions are uncommon. An additional requi rement of a first-step ant ihyper tens ive drug is tha t it should interact favorably with other ant ihyper tens ive agents. Both thiazides and ACE inhibitors are syn- ergistic with the majori ty of other ant ihyper tens ive agents.

We conclude tha t ACE inhibitors are modestly more effective than thiazides in white hypertensives, and they have fewer clinical and metabolic side effects. In selected pat ients they are already optimal an t ihyper tens ive agents, and with increas inguse and competit ion between pharmaceut ica l companies they will become cheaper. Thiazides used in a low dosage, however, are useful agents in many patients. A wide choice of an t ihyper tens ive agents remains desirable.

References

1. McMahon SW, Cutler JA, Furberg CD, et al. The effects of drug treatment for hypertension on mobility and mortality from cardiovascular disease: A review of randomised controlled trials. Prog Cardiovasc Dis 1986; (Suppl 1} 24:99-118.

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ACE Inhibitors Compared with Thiazides 819

2. Helgeland A, Strommen R, Hagelund C, et al. Enalapril, atenolol and hydrochlorothiazide in mild to moderate hypertension. Lancet 1986; 1:872-875.

3. Weinberger MH. Comparison of captopril and hydro- chlorothiazide alone and in combination in mild to mod- erate essential hypertension. Br J Clin Pharmacol 1982; 14:127S-131S.

4. Weinberger MH. Influence of an angiotensin converting enzyme inhibitor on diuretic-induced metabolic effects in hypertension. Hypertension 1983; (Suppl III) 00:132-138.

5. Merrill DD, Byymy RL, Carr A, et aL LisinoprilfHCTZ in essential hypertension (abstract). Clin Pharmacol Ther 1987; 41:227.

6. Pool JL, Gennari J, Goldstein R, et al. Controlled multi- centre study of antihypertensive effects of l isinopril, hydro- chlorothiazide, and lisinopril plus hydrochlorothiazide in the treatment of 394 patients with mild to moderate essential hypertension. J Cardiovasc Pharmacol 1987; 9 (Suppl 3):$36-$42.

7. Vidt DG. A controlled multiclinic study to compare the antihypertensive effects of MK-421 hydrochlorothiazide, and MK-421 combined with hydrochlorothiazide in pa- tients with mild to moderate essential hypertension. J Hypertens 1984; 2 (Suppl 2):81---88.

8. Muiesan G, Agabiti-Rosei E, Buoninconti R, Carotti A, Corea L, et al. Antihypertensive efficacy and tolerability of captopril in the elderly; comparison with hydrochlorothia- zide and placebo in a multi-centre double-blind study. J Hypertens 1987; 5 (Suppl 5):$599--$602.

9. Shapiro DA, Liss CL, Walker JF, et al. Enalapril and hydrochlorothiazide as antihypertensive agents in the elderly. J Cardiovasc Pharmacol 1987; 00 (Suppl 7):S160- S162.

10. Zezulka AV, Gill JS, Dews I, et al. Comparison of enalapril and bendrofluazide for treatment of systemic hypertension. Am J Cardiol 1987; 59:630-633.

11. Frishman WH, Goldberger J, Sherman D. Enalapril, hydro- chlorothiazide, and combination therapy in patients with moderate hypertension. J Clin Hypertens 1987; 3:520-527.

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13. Freier PA, Wollam GL, Hall WD, et al. Blood pressure, plasma volume, and catecholamine levels during enalapril therapy in blacks with hypertension. CIin Pharmacol Ther 1984; 36:731-787.

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ative antihypertensive effects of enalapril maleate and hydrochlorothiazide, alone and in combination. J Clin Pharrnacol 1983; 23:227-233.

15. Woo J, Woo KS, To Kin, et al. A single-blind randomised cross-over study of angiotension-converting enzyme in- hibitor and triamterene and hydrochlorothiazide in the treatment of mild to moderate hypertension in the elderly. Arch Intern Med 1987; 147:1386-1389.

16. Kayanakis JG, Baulac L. The comparative study of once- daily administration of captopril 50 rag, hydrochlorothia- zide 25 mg and their combination in mild to moderate hypertension. Br J Clin Pharmacol 1987; 23:89S-92S.

17, Kochar MS, Bolek G, Kalbfieisch JH, et al. A 52 week comparison of lisinopril, hydrochlorothiazide and their combination in hypertension, J Clin Pharmacol 1987; 27:373-377.

18. Gums JG, Lopez MN, Quay GP, Stein GH, McCarley DL. Comparative evaluation of enalapril and hydrochlorothia- zide in elderly patients with mild to moderate hyper- tension. Drug Intell Clin Pharm 1988; 22:680-684.

19. Croog SH, Levine S, Testa MA, Brown B, Bulpitt CJ, Jenkins CD, et al. The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986; 314:1657-1664.

20. Medical Research Council Working Party. MRC trial of mild hypertension: Principal results. Br Med J 1985; 291:97-104.

21. Lasser NL, Grandits G, Caggiula AW, et al. Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am d Med 1984; 76(2A):52-66.

22. Freis ED. The cardiovascular risks of thiazide diuretics. Commentary. Clin Pharmacol Ther 1986; 39'.239-244.

23. Varden S, Mehrotra KG, Mookherjee S, et al. Efficacy and reduced metabolic side-effects of 16 mg of chlorthalidone formulation in the treatment of mild hypertension, JAMA 1987; 252,.484-488.

24. Amery A, Birkenhager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet 1985; 1:1349-1354,

25. Hricik DE, Browning PJ, Kopelman R, et al. Captopril. induced functional renal insufficiency in patients with bilateral renal-artery stenoBes or renal-artery stenosis in a solitary kidney. N Engl J Med 1983; 31]~378-376,

26. ttommel E, Parving H-H, M a t h i ~ e x ~ Ed~bsrg B, Nielsen MD, Giese J. Effect of captopril on, l~idney function in insulin-dependent diabetic patients witl~ nephropathy. Br Med J 1986; 293:467--470.