Diureticsz Cornerstone of Antihypertensive therapy

Norman M. Kaplan, MD

Diuretics have been used less often for the treat- of death. Moreover, resistance to antihypertensive ment of hypertension over the past few years for a therapy is most commonly caused by inadequate variety of reasons. However, their use will almost diuretic therapy. Therefore, I believe diuretics will certainty go back up for many reasons, including continue to be a cornerstone of antihypertensive the recent publication of trials with appropriately thempy in the future. low doses of diuretics that have shown excellent (AmJCardiol1996;77:3B4B) protection against the major cardiovascular causes

D iuretics for the United

were the most popular drugs used treatment of hypertension in the States for 230 years, from soon

after their introduction in 1957l until 1993 when they were surpassed by calcium antagonists (Figure 1). I will first review the reasons for the phenom- enal sustained record of diuretic use, then attempt to explain why their use fell over the past few years, and end with a prediction that a resurgence will occur in their use so that they will remain, as they have long been, the cornerstone of antihyperten- sive therapy.

RISE OF DIURETIC THERAPY The modern era of antihypertensive therapy

began in the 1950s with the introduction of orally effective, reasonably well-tolerated agents, includ- ing reserpine, hydralazine, and, soon thereafter, methyldopa and guanethidine.2 When these drugs were given alone, pseudoresistance (sometimes erroneously referred to as tachyphylaxis) was often observed, with the initial fall in blood pressure largely ablated. The problem was soon recognized to arise from reactive renal sodium retention with expansion of plasma volume that blunted the antihypertensive efficacy of the adrenergic inhibi- tor or direct vasodilator3 (Figure 2). The pseudore- sistance was easily shown to be overcome by addition of a diuretic.4

Since diuretics, when used alone, had been shown to have equal antihypertensive efficacy to the other drugs then available, clinical practice rather quickly embraced their use as the first choice rather than the second, to be added only if

From the Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.

Address for reprints: Norman M. Kaplan, M.D., Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 752355 8899.

other agents became ineffectual. They soon be- came the cornerstone of therapy, serving as the initial agent in virtually every large controlled clinical trial from the initial Veterans Administra- tion Cooperative Study published in 19675 through the trials in the elderly published in the early 199Os.6

Since diuretics and, to a lesser extent, P-block- ers have been the only classes of drugs used in the multiple trials done over the past 30 years that have conclusively documented the value of antihyperten- sive therapy on cardiovascular morbidity and mor- tality, they were given preference as the initial choice of monotherapy in the 1993 report of the Fifth Joint National Committee (JNC-V).7

THE FALL FROM FAVOR Despite these positive overall effects, diuretic-

based therapy did not provide the full degree of protection against coronary mortality as predicted by epidemiologic estimates.8 Although many pos- sible reasons were offered for this shortfall, the multiple adverse biochemical and hormonal changes induced by the relatively high doses of diuretics used in the pre-1985 trials was one of the most commonly proposed.9

The evidence that these high doses of thiazides- equivalent to as much as 200 mg down to 50 mg of hydrochlorothiazide a day-caused such biochemi- cal and hormonal perturbations was unequivocal. These included hypokalemia, hyperuricemia, hyper- glycemia, decreased insulin sensitivity, and rises in serum cholesterol (except with the non-thiazide indapamide).

Although the pathologic consequences of these changes were debated, many practitioners became increasingly uneasy about using diuretics and be- gan to turn to the steady stream of new agents being introduced, which serendipitously did not

A SYMPOSIUM: DIURETICS, HYPERTENSION, AND LVH 38

70 Diuretics

6o -\

40

t

-f- Beta blockers

L-

3oc All others

L,

r ’ 1966

I I 1987 1966 1989 1990 1991 1992 1993 1994

require a diuretic to be given with them to avoid reactive sodium retention.

These new choices included l3 blockers and angiotensin-converting enzyme inhibitors, which partially block the renin-angiotensin-aldosterone (RAA) mechanism that is partly responsible for the reactive sodium retention. With a suppressed RAA mechanism and less sodium retention, they usually maintain their antihypertensive efficacy without a diuretic. The other major addition were the calcium antagonists, which have a slight but definite natriuretic action of their own,,1° so they, too, might not need a diuretic to preserve their efficacy.

Not only were these agents more capable of standing on their own, but they were heavily promoted and widely advocated as “state-of-the- art” antihypertensive therapy. In the 10 or so years since their introduction, they have been shown to provide relief from many of the concomitant condi- tions that frequently accompany hypertension, such as angina, congestive heart failure, and nephropa- thy-so practitioners were given more and more reasons to switch away from diuretics.

NON-OIUQE T/C ANTIHYPERTENSIVE

AGENTS

+, (

i 1 RENAL SODlUM RETENTION - INCREASE FLUID #LUME

1 t ALDOSTERONE

1 f RENIN SECRETION

t VASOOIL A TORS

FIGURE 2. Manner by which nondiuretic antihypertensive agents moy lose their effectiveness by reactive renal sodium retention.

FIGURE 1. Numbets of prescrip- tions written for antihyperlensive dtugs, in millions, in the United States during 19861992 (Na- tional Prescription Audi, Ambler, Pennsylvania: MS, 1994).

REASONS WHY DIURETICS WILL PERSIST

As seen in Figure 1, these various forces have reduced the overall use of diuretics even as the total antihypertensive market has grown. However, a number of counterforces have come into play that will surely work to slow or reverse the decline in diuretic use and likely preserve their place as the cornerstone of therapy. These counterforces in- clude: 1. The increasing recognition that lower doses of

diuretics, equivalent to 12.5 mg of hydrochloro- thiazide, usually provide most if not all of the antihypertensive efficacy but less, if any, of the biochemical and hormonal perturbations of larger doses.11-14 Similar results have been shown for lower doses of indapamide.15 When used in combination with other agents, even less di- uretic, 6.25 mg of hydrochlorothiazide, is clearly effective and usually all that is needed. Again, this was demonstrated some time ago16J7 but reaffirmed even more conclusively recently.18

2. These low doses of diuretic have now been used in 3 large clinical trials, all involving elderly hypertensive patients, and shown to provide even better protection against all of the cardio- vascular endpoints, including coronary disease, that were seen in the prior studies on middle- aged hypertensive patients given larger doses of diuretic@ (Table I).

3. Perhaps as one of the mechanisms for such cardioprotection, diuretics have been shown to reduce left ventricular hypertrophy (LVH).19~20 Doubts about this have likely caused some to use other agents thought to have greater ability to regress LVH.

4. Recognition that inadequate diuretic therapy is the most common reason for true resistance to antihypertensive therapy.*l In a series of 91

48 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 77 FEBRUARY 22, 1996

TABLE I Effects of Therapy in Elderly Hypertensive Patients

Swedish Trial Systolic in Old Medical Hypertension

Patients- Research in the Elderly Hyperienslon Council Program

Mean BP at entry (mm Hg) 195/102 185/91 I70/77 Stroke* 0.53t 0.75t 0.67t Coronary artery disease* 0.87$ 0.81 0.73t Congestive heart failure* 0.49t 0.45t All cardiovascular disease* 0.60t 0.83t 0.68t

‘Events per 1000 patient-years (treated versus placebo)/ r&me rtsk +Stotlsticaily slgnlficant. $Myocordiol lnfarctlon, sudden deaths reduced from 13 to 4.

patients, the addition of a diuretic was the most commonly effective action to overcome the resis- tance to multiple other drugs. Resistance is usually accompanied by an expanded fluid vol- ume, reflecting the interaction of excessive sodium intake, loss of renal excretory capacity by progressive nephrosclerosis, and the re- active sodium retention previously described (Figure 2).

5. The need to moderate the costs of health care has forced many practitioners to reconsider the use of less expensive, older drugs rather than more expensive newer ones.

6. The recommendations of JNC-V and most of the other expert committee reports from other countries22 that diuretics be given either prefer- ence to or equal footing with other classes of drugs.

For all of these reasons, I believe diuretics will once again take their rightful place as a corner- stone in the treatment of hypertension. This will surely involve lower doses of thiazides and indap- amide for most patients but, in approximate doses, diuretics will overcome.

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5. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAVA 19fz202:1w1034. 6. MacMahon S, Rodgers A. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hyperten- sties. Clin Exp Hypertens 1993;15:967-978. 7. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Fifth Report of the Joint National Committee on D&c- tion, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154183. 8. MacMahon S, Peto R, Cutler .I, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective obsewational studies corrected for the regression dilution bias. Lancet 19!%335: 765-774. 9. Kaplan NM. Treatment of hypertension: rationale and goals. In: Kaplan NM, ed. Clinical Hypertension, 6th ed. Baltimore: Williams & Wiis, 1994:145- 170. 10. Krisha GG, Riley LJ Jr, Deuter G, Kapoor SC, Narins RG. Natriuretic effect of calcium-channel blockes in hqpertensives. Am J Kidney Dis 1991118: 56572. 11. McVeigh G, Galloway D, Johnson D. The case for low dose diuretics in hypertension: comparison of low and conventional doses of cyclopenthiazide. Br Med J 1988;297:95-98. 12. Carlsen JE, Ktiber L, Tarp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical ef- fects. Br Med J 1990,300:97.%978. 13. Johnston GD, Wilson R, McDermott BJ, McVeigh GE, Duffin D, Logan J. Low-dose cyclopenthiazide in the treatment of hypertension: a one-year community-based study Q JMed 1991;78:135-143. 14. Harper R, Ennis CN, Sheridan B, Atkinson AB, Johnston GD, Bell PM. Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. Br Med J 1994;309:22@30. 15. Hall WD, Weber MA, Ferdinand K, Flamenbaum W, Marbury T, Jain AK, Weidler D, Weiss R, Herron J, Codispoti J, Stokes A, McNally C. Lower dose diuretic therapy in the treatment of patients with mild to moderate hypertension. J Hum Hypetens 199%8:571-575. 16. And&, L, Weiner, L, Svensson, & Hansson, L. Enalapril with either a “very low” or “low” dose of hydrochlorothiazide is equally effective in essential hypertension. A double-blind trial in 100 hypertensive patients. J Hyperen.&n 1983;l(suppl 2):384386. 17. MacGregor GM, Banks RA, Markandu ND, Bayliss J, Roulston J. Lack of effect of beta-blocker on flat dose response to thiazide in hypertension: efficacy of low dose thiazide combined with beta-blocker. Br Med J 1983;286:1535-1538. 18. Frishman WH, Bryzinski BS, Coulson LR, DeQuattro VL, Vlachakis ND, Mroaek WJ, Dukart G, Goldberg JD, Alemaychu D, Kouty K. A multifacto- rial trial design to assess combination therapy in hypertension. Arch Intern Med 1994;154:146-1468. 19. Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Lewis CE, Liebson PR. Treatment of mild hypertension study. Final results. JAu4 1993;270:71>724. 20. Senior R, Imbs J-L, Bory M, Amabile G, Denis B, Zannad F, De Luca N, Marchegiano R, Lahiri A, Raftery EB, Guez D, Chic M. Indapamide reduces hypertensive left ventricular hypertrophy: an international multicenter study. J Cardiovasc Phannacol 1993;22(suppl6):S1MllO. 21. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med 1991;151:178&1792. 22. &ales JD. Guidelines on guidelines. J Hypofens 1993;11:89%903.

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