Prevention of myocardial infarction

Prevention of Myocardial Infarction Michael H. Alderman,

Despite substantial progress in cardiov+cular disea+e prevention, stroke ahd myocardlal infarction remain the leading causes of death throughout the industr&lized workl. Tre&nent of high blood pressure, while contributing importantly to this progress, remains inefficient and less than optimally effective, particularly in regard to coronary artery disease events. Therapeu& Intervention in the renin-amensin system offers promise of progress on both these fronts. Renldlum profIles have been shown to permR pmostk stratification of otherwise indkthqguishabIe hypertensive patients. Indeed, low renin subjects, wRhout other cardkwascular risk factors, have a particularly favorable prognosis. Now, the pharmacologic ability to mute the pathotofi effects of amensin II also offers the genuine possibilRy that the cardioprotecthre value of antihypertensive therapy may be significantly improved. (Am J Cardiol1992;70:2lD-26D)

MD

T

here have been spectacular reductions in the incidence of cardiovascular diseases in the past quarter century. In the United States, interventions based on the risk factor hypothesis have been largely responsible for a 57% decrease in the incidence stroke and a 47% decline in heart attack mortality.’ Nevertheless, stroke and heart attack account for 40-50% of all deaths in developed countries and remain the leading causes of death. EFFICIENCY OF ANTlHYPERTENSlVE

EFFICACY OF ANTIHYPERTENSWE

From the Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, New York. Presented, in part, at the Satellite Symposium Organized by Roussel-Uclaf at the 14th Scientific Meeting of the International Society of Hypertension, Madrid, June 13,1992. Address for reprints: Michael H. Alderman, Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461.

CARE

Current antihypertensive management strategies result in treatment of many patients who are at vanishingly small risk of cardiovascular disease. This reflects the tremendous prognostic heterogeneity that characterizes patients classified primarily by level of blood pressure.2 It is possible, however, by assessment of risk factors and identification of preclinical end organ disease, as defined in the long-term Framingham study,2 to stratify patients at the same level of systemic blood pressure into subgroups with vastly different expectations of subsequent disease events. Despite this capability, current antihypertensive treatment strategies largely ignore these clinical subtleties and generally apply interventions based on blood pressure levels alone. The result is that very many patients are treated, with measurable benefit being received by only a minority. CARE

MacMahon et al3 and Collins et a1,4 in an elegant analysis of the published observational studies of the natural history of hypertension and of the published clinical trials of antihypertensive therapy, have provided a means both to predict the potential results of treatment and to assess the actual benefit achieved. By combining several large population-based studies and correcting for inaccuracies introduced by variation in blood pressure measures, they were able to describe a linear relation between the magnitude of the blood pressure elevation and the likelihood of subsequent cardiovascular events. Meta-analysis of 14 unconfounded clinical trials also provided remarkably A SYMPOSIUM: HYPERTENSION AND ACE INHIBITORS

21D

consistent results. Specifically, in observational studies, a 7.5 mm Hg increase in diastolic blood pressure was related to a 40% increase in incidence of stroke and a 28% increase in heart attacks. In actual clinical trials, a 5-6 mm Hg decrease in diastolic pressure was associated with about a 40% decline in stroke events, but only about a 14% decline in heart attacks. This 50% deficit between the observed and expected decrease in heart attacks cannot readily be explained by existing knowledge. Several possible causes have been identified to explain the disappointing results in regard to coronary events. Diuretics have been used in all the clinical trials. Because they adversely affect lipid and glucose metabolism and electrolyte levels, it has been hypothesized that these alterations have muted the benefit of a lower blood pressure? Beta blockers, which were used extensively in older trials, also distort lipid and glucose metabolism? In addition to the effects of a particular kind of drug, treatment itself has been implicated as carrying the potential for harm. It has been found, in a series of retrospective analyses of clinical trials as well as through examination of cohort studies,7p8 that an increased incidence of myocardial infarction (MI) occurs in those patients whose blood pressure response to therapy was greatest or whose diastolic pressures fell to < 80 mm Hg.738Although considerable controversy continues to surround this repeatedly demonstrated “J-shaped” phenomenon, it seems prudent to moderate blood pressure reduction, particularly among patients with evidence of preexisting coronary artery disease. The great challenge to modern antihypertensive practice, then, is to improve both the efficacy and efficiency of antihypertensive care. Treatment needs to reach those most likely to have heart attacks and

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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 70

strokes and to be more successful in reducing the heart attack rate of those who are treated. THE RENINANGIOTENSIN SYSTEM AND CORONARY ARTERY DISEASE

A fruitful avenue of inquiry, based on investigation of human blood pressure control mechanisms, has shown that malfunction of the renin-angiotensin system may help to explain both the clinical heterogeneity of hypertensive patients and the apparent failure of current antihypertensive treatment to realize its full potential. Over the past: half century, the sodium-renin-angiotensin-aldosterone axis has proved to be a powerful instrument for the analysis of blood pressure control? Analysis of this system has also provided a framework for the selection of antihypertensive therapy. This servocontrol feedback mechanism integrates plasma volume and vasoconstriction in the expression of systemic blood pressure. Renin stimulates the conversion of angiotensinogen to angiotensin II (Figure l), which is the most powerful vasoconstrictive agent known. Renin also contributes to volume expansion, indirectly by stimulating aldosterone secretion and directly by increasing renal tubular sodium resorption. An increasing arterial pressure then provides the signal to suppress renin secretion. These specific biochemical actions have provided convenient sites to guide pharmacologic interventions that can lower pressure by altering physiology. More recently, however, it has become clear that the renin-angiotensin system, particularly through expression of angiotensin II, can also produce vascular damage. In both experimental animalslO and in human investigations,11 it has been possible to demonstrate that angiotensin II stimulates vascular smooth muscle mitogenesis and cellular hypertrophy. The net result of these effects on the vascular wall can be to impede blood flow and produce hypoxic target organ damage. Some 20 years ago, Brunner et all2 postulated the clinical relevance of these physiologic relationships. In a retrospective analysis of 240 hypertensive subjects, they found that the sodium-to-renin relation provided a convenient means to stratify patients into subgroups with different levels of cardiovascular risk. A prospective study has now confirmed this hypothesis.13 Plasma renin activity and urinary sodium excretion of 1,717 mild and moderately hypertensive subjects were determined before the initiation of antihypertensive therapy. Over a follow-up period of 8 years, blood pressure control was maintained by application of a modi-

OCTOBER29,1992

fied stepped-care regimen by therapists blinded to the renin profile status. Some 58 cardiovascular morbid and mortal events were observed during follow-up, including 27 MIS and 12 strokes. The renin/sodium profile was used to stratify patients into high (12%), normal (56%) and low (32%) renin status. In this study, younger white men were most likely to have high, and older black women were most likely to have low, renin levels. Some minor pretreatment differences in blood pressure existed between groups, but throughout follow-up, blood pressure control was good and equivalent in the 3 groups. No differences were found in prior cardiovascular disease, lipid or glucose metabolism, or left ventricular hypertrophy (LVH) between groups. Drug use was similar in the 3 groups, with diuretic use, initially most common, increasingly replaced by calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and cxblockers. Throughout, B blockers were used by about 25% of patients. The principal finding of the study was that patients with a high sodium/renin profile were at greatest risk of MI (Table I). Multivariate analysis confirmed the significance of an elevated renin profile as an independent predictor of MI. In fact, among these patients, in addition to renin profile status, only cholesterol, LVH, gender, and cigarette smoking were independently associated with the risk of MI. No measure of blood pressure in these successfully treated hypertensive patients remained in the multivariate analysis model as predictive of MI. Bivariate analysis revealed that, in general, the renin profile-to-MI relation persisted regardless of gender, age, the presence or absence of hypercholesterolemia, smoking, or fasting blood sugar level (Figures 2 and 3). However, in certain situations, that was not the case. In particular, the renin profile-to-MI relation, most dramatically displayed in whites, did not appear among blacks. However, since MI was relatively rare in blacks treated in this study, the paucity of events affected the statistical power to test this relation.14 It should also be noted that the renin/sodium profile was not associated with stroke, although, again, the number of such events was small. Finally, when patients were stratified according to the presence or absence of other risk factors (Figure 4), the renin profile remained a powerful discriminator of risk. An earlier retrospective analysis of 1,999 persons drawn from a general population indicated that no relation existed between plasma renin and cardiovascular disease.15Many important method-

TABLE I Unadjusted and Adjusted Incidence of Myocardial Infarction Per 1,000 Person-Years, According to Renin Profile* Renin Profile Variable No. events Follow-up (personyears) Unadjusted incidence Adjusted incidence

High 7

539.3 13.0 14.7

Normal 15

2,851X

i Low

Rate Ratiot

5

1,519.8

5.3

3.3

3.9

5.6

2.8

5.3 (3.4-8.3)

(1.2-12.3)

‘The Incidence was adjusted for dlstribubonal differences in age, sex, and race with the entire study population used as the standard. tThe rate ratio 1s that between the high-profile and low-profile groups. Values m parentheses are 95% confidence intervals.

ologic differences between that earlier study and the current prospective study make comparison difficult. Nevertheless, in that report >95% of patients were normotensive. The possibility certainly exists that plasma renin and the renin profile may have prognostic value primarily in hypertensive patients. In other words, variations in plasma renin among normotensive patients may reflect appropriate physiologic response to maintain blood pressure and flow. In contrast, among hypertensive patients, where renin levels would be expected to be set at or near 0, any substantial elevation can be pathologic. l6 In this regard, it is of note that when our patients were stratified by level of diastolic pressure, elevated renin levels were most predictive of hypertensive events among those with the highest pressures. In fact, among patients with diastolic pressures <95 mm Hg, high renin subjects were not at significantly greater risk than normal or low renin subjects. This, at first glance, would suggest that the 2 studies may be compatible. However, the small number of events observed among the hypertensive patients (n = 6) with pressures <95 mm Hg precludes drawing a definitive conclusion. Of particular note is the finding that in patients with no other risk factors who also had a low renin/sodium profile, not a single MI infarction occurred over 8 years of follow-up. Overall, 240 subjects, or 14% of the total, fell into this seemingly protected subgroup. Because of the strong inverse relation of sodium ingestion and plasma renin levels (Figure 5), the renin profile was designed to take sodium intake into account. In an attempt to determine whether sodium intake might have an additional, independent impact on the occurrence of MI, we determined the incidence of myocardial infarction in patients stratified both by the renin profile and by whether their sodium intake was above or below the median for the group (126 mmo1/24 hours). The analysis was limited to men, in whom 82% of A SYMPOSIUM: HYPERTENSION AND ACE INHIBITORS

23D

MIS occurred. It can be seen that in both sodium intake strata, the renin profile is a powerful predictor of subsequent events (Figure 6). In addition, within each renin profile category (high, normal, and low), those consuming a lower sodium diet were at greater risk of subsequent events. This occurred despite the fact that there were no significant differences among the 6 subgroups in age, race, presence of LVH, cigarette smoking, or pre- or in-treatment blood pressure. As expected,

241)

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stratification by sodium intake revealed that, for example, high renin subjects consuming less salt had a slightly higher absolute plasma renin activity (7.47 vs 5.24 ng/mL/hour) than those consuming more sodium. This analysis is ongoing, but the available data confirm the well-recognized relation between sodium intake and plasma renin activity and suggest that, at the very least, a low sodium intake, which elevates plasma renin, may not be beneficial for treated hvDertensive aatients.

OCTOBER 29, 1992

Clearly, appreciation of the renin-angiotensin system has now passed beyond merely being perceived as a participant in the mechanisms for blood pressure control. Instead, a more profound understanding of the full biologic significance of the renin-angiotensin system suggests that treatment regimens can be more rationally designed to improve both the efficiency and the efficacy of antihypertensive therapy. l6 First the available data suggest that those hypertensi;e patients who have no evidence of preclinical end-organ disease, have a favorable risk factor profile, and are in the low renin profile category are at exceedingly low risk of subsequent cardiovascular disease events. Since these observations have been made in a cohort of successfully treated hypertensive patients, a prospective clinical trial is still needed to test the hypothesis that such patients may do as well with as without drug therapy. A positive finding in such an -~-I.

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experiment would make it possible for a sizable fraction (perhaps 15%) of mild-to-moderate individual hypertensive patients to avoid the cost, inconvenience, and possible harm of drug therapy, while producing substantial savings for society as a whole. At the same time, elevated renin levels in the presence of elevated systemic blood pressure prospectively identifies that subgroup of hypertensive patients who can be expected to experience an increased incidence of MI, enabling them to receive special attention and, it is hoped, more appropriately tailored and effective therapy. The clinical data, combined with substantial animal and some human experimental evidence of end-organ damage associated with elevated angiotensin II levels, strongly support the view that the reninto-MI relation is causal? Although no clinical trial has tested the hypothesis that inhibition of the renin system with an ACE inhibitor would enhance the cardiovascular protection produced by tradi-

I2.5

4

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FIGURE 5. Urinary sodhm (UNa), potassium (UK), and plasma renin (PM) in unhated hypWmsh mm.

FIGURE 8. Renhl pmfk, uMary sdum (Wa), and myocardial Infamtion (MI) among hypwbdve mm. A SYMPOSIUM: HYPERTENSION AND ACE INHWTQRS

ZtiD

tional diuretic and p blocker therapy, available evidence offers encouragement. In particular, Dahlof et all7 have shown that vascular changes associated with hypertension are more completely reversed when patients are treated with converting enzyme inhibitors than with diuretics, despite the fat; that blood pressure reduction was fairl; similar in the 2 groups. These findings suggest the possibility that blood pressure control coupled with suppression of the renin-angiotensin system may close the gap between what is expected and what can be achieved by blood pressure reduction. Moreover, the existence of pharmacologic means to lower pressure by inhibiting angiotensin II generation offers the prospect that blood pressure reduction achieved in this way may yield cardiovascular protection even beyond that ascribable to the blood pressure change itself. Finally, there is the possibility that normotensive patients with elevated renin levels may be at greater risk of cardiovascular events than their low renin confreres. Although no evidence exists to support this hypothesis, since more than half of all heart attacks occur among normotensive persons, the availability of a precise biologic marker to identify and perhaps suggest an effective intervention would be of enormous public health value. CONCUJSION Application of our knowledge of the reninangiotensin system is central to understanding and treating hypertensive disease. Available knowledge already makes it clear that the ability to quantitate the activity levels of the renin system accurately now provides the means to unravel the prognostic heterogeneity of hypertension and to describe blood pressure control mechanisms as the basis for rational therapeutic intervention. In addition, there is the possibility that manipulation of the reninangiotensin system may dramatically improve the capacity of antihypertensive therapy to prevent

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coronary artery disease in millions of hypertensive patients. REFERENCES

1. National Center for Health Statistics.Births, Marriages, Divorces and Deaths for 1990.Hyattsville, MD: Public Health Service;~0139,no. 12. 2. Kannel b, McGee DI, Gordon T. A genkral cardiovascular risk profile. The FraminghamStudy.Am J Cardiol 1976;38:46-51. 3. MacMahon S, Peto R, Cutler J, Collins R, Soriie R, Neaton J, Abbott J, Godwin J, Dyer A, Star&r J. Blood pressure, stroke and coronary heart disease,I: prolonged differenes in bid pressure: prospective observational studiescorrected for the regression dilution bias.Lancet 1990;335:76774. 4. Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO. I&d pressure,stroke and-coronary heart disease, t1: short-term reductions in blood pressure: oveniew of randomized drug trials in their epidemiologicalcontext. Lancet 1990;335:827-838. 5. PolIare T, Lithe11H, Berne C. A comparisonof the effects of hydrochlorothiazide and captoprl on glucoseand lipid metabolismin patients with hypertension.N En@ J Med 1989;321:868-873. 6. Medical Research Council Working Party. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension.Lancer 198 1;ii:539-

W.

7. Alderman MH, Ooi WI+ Madhavan S, Cohen H. Treatment-induced blood pressure reduction and the risk of myocardial infarction. JM 1989;262:92&

924.

8. Famett L, MuIrow CD, Linn WD, Lucey CR, Tuley MR. The J-curve phenomenonand the treatment of hypertension.JAMA 1991;265:489-495. 9, Laragh RI, SealeyJE. The renin-an~otens~al~~erone systemin hypefiensive disorders: a key to two forms of arteriolar vasoconstriction and a possible clue to risk of vascular injury (heart attack and stroke) and prognosis. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology,diagnosis,and management.New York: Raven Press,1990:132%1348. u). Gavras H, Brown JJ, Lever AF, Macadam RF, Robertson JIS. Acute renal failure, tubular necrosis, and myocardial infarction induced in the rabbit by intravenous angiotensinI. Lmcet 1971;ii:19-22. iz GrifIin S, Brown WCB, MacPherson F, McGrath JC, W&n VG, Korsgaard N, Mulvany MJ, Lever AF. Angiotensin II causesvaScularhypertrophy in part by a non-pressormechanism.Hjrperfension1991;17:6=35. l2. Brunner HR, Laragh JH, Baer L, Newton MA, Goodwin FT, K&off LR, Bard RH, Buhler FR. Essential hypertension:renin and aldosterone, heart attack and stroke. N EngiJ Med 1972;2%:441449. l3. Alderman MH, Madhavan S, Qoi WI+ Cohen H, Sealey JE, Laragh JH. Association of the renin-sadiumprofile with the risk of myocardial infarction in patients with hypertension.N Engl J Med 1991;32411098-l104. 14. Ooi WL, Budner NS, Cohen H, Madhavan S, Alderman MH. Impact of race on treatment response and cardiovascular disease among hypertensives. Hypetiemtin

1989;14:227-234.

l6. Meade ?W, Imeson JD, Gordon D, Peart WS. The epidemiology of plasmarenin. Clin Sci 1983;64:273-280. l5. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, SommarsSC, Laragh JH. On the renal basis for essentialhypertension: nephron heterogeneity with disoordantrenin secretionand sodiumexcretion causinga hypertensivevasoconstriction-volume.J H*m 1988;6:763-777. 17. Dahlof B, Herlitz H, Aurell M, Hansson L. Reversal of cardiovascular structural changeswhen treating essentialhypertension.The importance of the renin-angiotensin-aldosteronesystem.(In press.)

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