Antihypertensive therapy and the concept of total cardiovascular protection

AntihypertensiveTherapy and the Concept of Total CardiovascularProtection DEAN

T.

MASON,

MD,

MING C.

CHAN,

MD,

and

GARRETT

LEE,

MD

ering the ubiquity of essential hypertension, a modified stepped-care regimen advocating initial drug therapy with a p blocker and addition of low-dose thiazide diuretic when necessary constitutes a judicious approach for widespread application. Although there are 8 orally active /!I blockers currently approved in the U.S. for clinical use in systemic hypertension, only acebutoloi possesses ail of the saiutary pharmacologic properties of cardiaselectivity, intrinsic sympathomimetic activity and hydrophiiicity, thereby making this compound an effective and safe B-blocking agent for first-order management of a broad segment of the hypertensive population. (Am J Cardioi 1987;80:2gE-32E)

Drug-induced reduction of elevated blood pressure decreases cardiovascular mortality and morbidity in patients with moderate and severe hypertension. Furthermore, antihypertensive drug studies in mild hypertensive subjects (diastolic blood pressure 90 to 104 mm Hg) have shown protection against stroke, left ventricular hypertrophy, congestive heart failure and progression of renal damage, as well as improved patient longevity. The Hypertension Detection and Follow-up Program trial, recently carried out in the U.S., documented reduced coronary artery disease events (fatal and nonfatal) in special drug-treated patients with mild hypertension. From the standpoint of practical management and consid-

A

ntihypertensive drug efficacy (decreased cardiovascular mortality and morbidity) was initially demonstrated in a prospective and controlled manner by the landmark Veterans Administration Cooperative Study of 1967 (in which severe hypertension was defined as diastolic blood pressure 2115 mm Hg)l and 1970 (in which moderate hypertension was defined as diastolic blood pressure between 105 and 114 mm Hg, and mild hypertension as 90 to 104 mm Hg).2,3Most significantly, these salutary findings were extended to the general hypertensive population throughout the U.S. by the 1979 multicenter, randomized, collaborative Hypertension Detection and Follow-up Program (HDFP).4 At 5-year follow-up (Table I], HDFP revealed a 17% decrease in total mortality for patients receiving systematic rigorous stepped care (SC] antihypertensive drug therapy (diuretic, antiadrenergics and vasodilator as necessary) compared with those having usual referred care (RC]; the corresponding decrease in total cardiovascular mortality [especially stroke and also myocardial infarction] was 19%

.5,6

ClinicalBenefitsof Treating Mild Hypertension

noteworthy was the greater beneficial effect of SC in the 68% of stratum 1 patients with neither end-organ [heart, brain and kidneys] damage nor taking antihypertensive agents at study entry (Table II); the 5-year mortality rate was reduced by 29% compared with RC, indicating that treatment of so-called mild hypertension should be instituted early before end-organ damage occurs. These observations are strongly supported by the 1980 Australian Therapeutic Trial in Mild Hypertension (Table III), which, at 4 years of follow-up of randomized patients without preexisting cardiovascular disease, showed a 69% decrease in cardiovascular mortality in the antihypertensive drug treatment group (thiazide, /3blocker and vasodilator sequentially as required] compared with the placebo control group.8

Cardioprotectionin CoronaryArtery Disease There is now convincing evidence that long-term ,& blockade therapy given prophylactically to survivors of acute myocardial infarction diminishes the subsequent incidence of sudden death and reinfarctiong In ‘5, From The Western Heart Institute, St. Mary’s Hospital and Medical Center, San Francisco, California. Address for reprints: Dean T. Mason, MD, The Western Heart Institute, St. Mary’s Hospital and Medical Center, 450 Stanyan Street, San Francisco, California 94117.

Of considerable importance, 72% of the HDFP population constituted mild hypertensive subjects (stratum l] in whom total mortality was 20% lower in the SC compared with the RC group.’ Particularly 29E

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the 1981 Beta Blocker Heart Attack Trial, after nearly 3 years of follow-up for patients randomized (5 to 21 days postinfarction) to propranolol versus placebo (Table IV], total mortality was reduced by 26% [coronary disease mortality by 27% and sudden death by 289’0].~OJ~ Similar to this trial, additional randomized studies have shown the beneficial effects of other /3 blockers in reducing mortality after acute myocardial infarction. In the acute myocardial infarction trial of

Table I Hypertension Detection Year Findings in 10,940 Adults

and Follow-Up

Program: Flve-

Diastolic blood pressure: 72% 90-104 mm Hg. 18% 105-I 10% 1115mmHg Stepped care (SC) vs referred care (RC) SC: diuretic + antiadrenergic + hydralazine -I guanethidine 17% 4 total mortality (8.4 SC vs 7.7% RC) 19% 1 cardiovascular mortality (195 vs 240 patients) 45% i stroke mortality (29 vs 52 patients) 26 % 1 AMI mortality (5 1 vs 69 patients)

14 mm Hg and

AMI = acute myocardial infarction. From references 4 through 6.

TABLE II Hypertension Mild Hypertension

Detection

and Follow-Up

7,825 (72%) of 10,940 adults randomized to stepped care (SC) vs referred care (RC) for 5 years 20% 1 total mortality (5.9 SC vs 7.4% RC) 45% 4 stroke mortality (17 vs 31 patients) 20% 1 coronary mortality (86 vs 107 patients)

From references

6 and 7.

TABLE Ill Australian National Blood Pressure Study: Four-Year Findings in 3,427 Adults Diastolic blood pressure: 95-109 mm Hg Thiazide + antiadrenergic i- hydralazine stepped care (SC) vs placebo 53% 1 total mortality (9 SC vs 19 placebo patients) 69% 4 cardiovascular mortality (4 vs 13 patients) (stroke, coronary disease and aortic aneurysm) 24% $ cardiovascular morbidity (82 vs 108 patients) (stroke and retinopathy) From reference

TABLE IV Follow-Up

8.

Beta-Blocker

Heart Attack Trial: 25 Months’ Average

3,837 AMI survivors randomized 5 to 21 days postinfarction 180-240 mg/day propranolol (serum >20 ngldl) vs placebo 26% 4 total mortality (7.2 fl blockade vs 9.8% placebo patients) 27% 1 coronary mortality (6.2 vs 8.5% patients) 28% 1 sudden death (3.3 vs 4.6% patients) From references 10 and 11. AMI = acute myocardial infarction.

1981 carried out in Sweden, metoprolol therapy for 3 months reduced total mortality by 36% compared with placebo.12 The 1981 Norwegian postinfarction timolol study demonstrated that 17 months (average] of treatment decreased total mortality by 36%, sudden death by 45% and reinfarction rate by 29% compared with placebo.13 It is generally acknowledged that such long-term cardioprotection for myocardial infarction survivors afforded by B-blocking agents is a class action (blockade of /3 adrenoreceptors],sJ4 and the antiarrhythmic mechanism appears to be mediated by special antifibrillatory activity (increased ventricular fibrillation threshold) perhaps principally via the antiischemic property of @ blockade. l5 These important findings concerning the role of p blockers in the secondary prevention of coronary disease have opened a new era in preventive cardiology, which may extend to cardioprotection in coronary artery disease before myocardial infarction. Since hypertension is a cardinal risk factor for coronary disease as well as the principal precursor of stroke, l6 these observations are particularly germane to the use of @blockers in the initial treatment of hypertension.

Advantagesof Beta Blockers in HypertensiveTherapy

Program and

5,322 (68%) of the 7,825 mild hypertensives on entry without long-standing diastolic blood pressure and/or end-organ damage 29% 1 total mortality (4.0 SC vs 5.6% RC) 50% 4 stroke incidence (0.8 vs 1.6%)

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t

The group of agents constituting the P-blocking drugs are therapeutically equivalent to propranolol in satisfactorily lowering elevated blood pressure.l’ Thus the antihypertensive effect of the /3blockers is a class action (/3-adrenoreceptor blockade), the mechanism of which seems to be largely inhibition of renin secretion with ultimate decrease in peripheral vascular resistance.ls From the standpoint of practical management and considering the ubiquity of essential hypertension, a modified stepped-care regimen [Table V] advocating an initial trial with a /3blocker or a thiazide-type diuretic appears a prudent approach for widespread application?g Renin profiling is reserved for drug-resistant patients and when indicated for exclusion of certain types of secondary hypertension. In general, the goal of antihypertensive therapy is to maintain diastolic blood pressure <90 mm Hg without drug-related side effects.20Initial management of mild hypertension is nonpharmacologic (weight reduction if obese and moderate sodium restriction] with the safest effective first drug administered a ,&blocking agent (especially in patients <60 years of age and those with coronary artery disease) in the absence of chronic obstructive pulmonary disease, bradycardia or congestive heart failure. 21If diastolic blood pressure control is not achieved, a small dose of thiazide diuretic is added. Substitution with an angiotensin-converting enzyme inhibitor or a calcium antagonist is an alternative step-2 therapy. The final step is the judicious addition of hydralazine, prazosin, methyldopa, clonidine, reserpine, minoxidil or guanethidine in the approximately 10% of hypertensive patients who prove unsatisfactorily responsive to the fundamental P blocker plus diuretic regimen.22 After control of hypertension is secured, serial subtraction and dose reduc-

Sep?ember 38, !987

tion should be attempted to establish the long-term regimen that requires the minimum number of drugs in their lowest effective dosage.

PharmacologicProfile of Beta-BlockingAgents Eight orally active fl blockers have been approved by the Federal Drug Administration in the U.S. for clinical use in systemic hypertension: propranolol, metoprolol, nadolol, atenolol, timolol, pindolol, labetalol and acebutolol.17 Although the therapeutic response to all of these agents is similar, differences in the pharmacodynamic and pharmacokinetic properties of these drugs are clinically important (Table VI). These compounds are classified according to the relative presence or absence of &-receptor selectivity (cardioselectivity), intrinsic sympathomimetic activity, membrane stabilizing activity, a-adrenergic blocking activity and lipid solubility. Cardioselectivity (& receptors unopposed) confers the advantage of being safer for patients with chronic obstructive pulmonary disease and peripheral vascular disease. Intrinsic sympathomimetic activity defines partial P-receptor agonism and thereby attenuates reductions of heart rate and cardiac output; ,8blockers without intrinsic sympathomimetic activity have a deleterious effect on serum lipid profiles. Membrane stabilizing activity refers to direct quinidine-like effect on the cardiac action potential, an antiarrhythmic property believed little operational at clinically meaningful doses. Lipophilicity signifies greater hepatic metabolism, relatively short plasma half-life (variable bioavailability) and increased brain uptake (predilection for untoward central nervous system side effects]. Hydrophilic agents are more slowly eliminated [greater renal excretion); therefore, they possess longer duration of action and have more consistent bioavailability. Individually, propranolol and timolol are noncardioselective, lack intrinsic sympathomimetic activity and are lipophilic. While atenolol and nadolol are both hydrophilic, the former lacks intrinsic sympathomimetic activity and the latter lacks both intrinsic sympathomimetic activity and cardioselectivity. Metoprolol is cardioselective but lacks intrinsic sympathomimetic activity, pindolol has intrinsic sympathomimetic activity but lacks cardioselectivity; both agents are relatively lipophilic. Acebutolol possesses all of the salutary pharmacologic properties of cardioselectivity, intrinsic sympathomimetic activity, membrane stabilizing activity and hydrophilicity.23 This agent has been shown to be effective in several multicenter randomized clinical trials for hypertension, and is effective orally on a once-daily basis .24These important properties make acebutolol a particularly useful [effective and safe) pblocking agent for first-order management of a broad segment of the hypertensive population.

SymposiumOverview This symposium is initiated by Roberts, who evaluates the central role of systemic hypertension in the precipitation of fatal cardiovascular events. By analysis of the frequency of hypertension and necropsy evidence of cardiomegaly, it is shown that both conditions

THE AMERICAN

TABLE V

JOURNAL

OF CARDIOLOGY

Modified Steplped Care Approach

0. Nonpharmacologic therapy ,weight reduction Imoderate sodium restriction 1. p blocker or thiazide diuretic 2.” p blocker’ plus thiazide diuretic + (peripheral or central antiadrenergic) * [calcium blocker or angiotensin converting Vasodilator Guanethidine * alternative

TABLE VI

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enzyme inhibitor]

step-2 therapy; t substitute antiadrenergic.

Major Properties

Generic Name

Trade Name

Acebutolol Atenolol Labetalol Metoprolol Nadolol Pindolol Propranolol Timolol

Sectral Tenormin Normodyne Lopressor Corgard Visken lnderal Blocarden

+ = present; 0 = absent. ISA = intrinsic sympathomimetic activity.

of p Blockers Cardioselectivity + + 0 + 0 0 0 0

activity;

ISA

MSA

Lipid Solubility

+ 0 0 0 0 + 0 0

+ 0 0 0 0 + + 0

0 0 0 f 0 f + 0

MSA = membrane

stabilizing

are usually present in patients dying with atherothrombotic stroke or with coronary artery disease (sudden death, angina pectoris and acute myocardial infarction], particularly with the complications of infarction of myocardial rupture and left ventricular aneurysm. Most striking is the finding that hypertension appears to be the fundamental underlying risk factor for most instances of aortic dissection and cerebrovascular rupture. In addition, this study reemphasizes that hypertension is operative in the acceleration of atherosclerosis and its lethal consequences. Concerning the contemporary management of hypertension, MacGregor focuses on the increasing use of p blockers as first-line therapy and the appropriate addition of low-dose diuretics to these agents. In investigations of combined treatment with once-daily acebutolol and hydrochlorothiazide, 12.5 mg of the diuretic provided the same decrease in blood pressure as did 50 mg, whereas 400 mg of the /3 blocker had greater antihypertensive effect than 200 mg. Thus, as with a thiazide diuretic used alone, there is a flat dose-response of the diuretic even in the presence of /3blockade. This observation is of considerable clinical importance in guarding against the adverse metabolic properties of high-dose thiazide diuretics. In the examination of the effects of antihypertensive drugs on plasma lipids, Nakamura observed that chlorthalidone increased low density lipoprotein cholesterol, furosemide increased triglyceride and trichlormethiazide, propranolol and methyldopa each raised triglyceride and decreased high density lipoprotein cholesterol. In contrast, no untoward effects on plasma lipids took place with acebutolol, prazosin,

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guanabenz, nifedipine or captopril. In a related study by Miller, P-blocking agents without intrinsic sympathomimetic activity (propranolol, sotalol, metoprolol and atenolol) were found to increase plasma triglyceride concentrations with concomitant decrease in high density lipoprotein cholesterol; whereas /3 blockers with intrinsic sympathomimetic activity (acebutolol, pindolol and oxprenolol], labetolol and prazosin were without such unfavorable influences on plasma lipoprotein concentrations. While the adverse effects of diuretics and p blockers without intrinsic sympathomimetic activity on lipid metabolism tend to be modest, the possibility that such actions may contribute to the process of atherogenesis should be considered in the long-term treatment of patients with hypertension. While noting the current trend toward beginning antihypertensive therapy with p blockers rather than diuretics, Harrison delineates the pharmacologic profile of the spectrum of available /?-adrenergicblocking drugs to permit judicious selection of the most appropriate agent for blood pressure reduction with the least side effects. In this regard, the salutary properties of cardioselectivity, hydrophilic@, intrinsic sympathomimetic activity and membrane stabilizing activity are depicted. Finally, the present report considers the concept of total cardiovascular protection and highlights the broad value of p blockade in the long-term treatment of patients with systemic hypertension.

References 1. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. I. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. TAMA 1967;202:116-122. 2. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. /AMA 1970;213:1143-1152. 3. Veterans Administration Cooperative Study Group on Antihypertensive Agents. III. Influence of age, diastolic pressure, and prior cardiovascular disease; further analysis of side effects. Circulation 1972;45:991-1004. 4. Hypertension Detection and Follow-up Program Cooperative Group. Fiveyear findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure, including mild

RISK FACTOR

hypertension. JAMA 1979;242:2562-2571. 5. Hypertension Detection and Follow-up Program Cooperative Group. Fiveyear findings of the Hypertension Detection and Follow-up Program. II. Mortality by race-sex and age. TAMA 1979;242:2572-2577. 6. Hypertension Detection and Follow-up Program Cooperative Group. Fiveyear findings of the Hypertension Detection and Follow-up Program. III. Reduction in stroke incidence among persons with high biood pressure. JAMA 1982;247:633-638. 7. Hypertension Detection and Follow-up Program Cooperative Group. The effect of treatment on mortality in “mild” hypertension. Results of the Hypertension Detection and Follow-up Program. N EngI r Med 1982;307:976-980. 6. Report by the Management Committee. The Australian Therapeutic Trial in Mild Hypertension. Lancet 1980;1:1261-1267. 9. Furberg CD, Friedewald WT, Eberlein KA, eds. Proceedings of the workshop on implications of recent beta-blocker trials for post-myocardial infarction patients. Circulation 1983;67:suppl I:l-111. 10. B-Blocker Heart Attack Study Group. The P-Blocker Heart Attack Trial. JAMA 1981;246:2073-2074. 11. &Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results. /AMA 1982;247:1707-1714. 12. Hjalmarson A, Herlitz J, Malek I, Ryden L, Vedin A, Waldenstrom A, Wedel H, Elmfeldt D, Holmberg S, Nyberg G, Swedberg K, Waagstein F, Waldenstrom J, Wilhelmsen L, Wilhelmsson C. Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet 1983;2:823-827. 13. The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-838. 14. Lui HK, Lee G, Dhurandhar R, Hungate EJ, Laddu A, Dietrich P, Mason DT. Reduction of ventricular ectopic beats with oral acebutolol: a doubleblind, randomized crossover study. Am Heart J 1983:105:722-726. 15. Singh BN, Venkatesh N. Prevention of myocardial infarction and of sudden death in survivors of acute myocardial infarction: role of prophylactic ,&adrenoceptor blockade. Am Heart 1 1984;107:189-200. 16. Kannel WB. Some lessons in cardiovascular epidemiology from Framingham. Am J Cardiol 1976;37:269-282. 17. Frishman WH, Teicher M. Beta-adrenergic blockade: an update. Cardiology 1985:72:280-296. 16. Laragh JH. Anti-renin system therapy. A new horizon for understanding and treating hypertension. Am Heart J 1981;101:364-368. 19. The loint National Committee on Detection, Evaluation, and Treatment of High Blbod Pressure. The 1984 report of the Joint National Committee on detection. evaluation. and treatment of hieh blood oressure. Arch Intern Med 1984;144:iO45-1057. 20. Moser M, Black H, Stair D. The dilemma of mild hypertension. Drugs 1986;31:279-287. 21. Kaplan NM. Mild hypertension: when and how to treat. Arch Intern Med 1983;143:255-259. 22. Frohlich ED. Antihypertensive therapy: newer concepts and agents. Cardiology 1985;72:349-365. 23. Frishman WH, Meltzer AH, Pow T. New p-blockers for hypertension. Part 1. Acebutolol. Hosp Ther 1986;46-58. 24. Mason DT. Proceedings of the symposium on improved beta-adrenergic blockade therapy: results of acebutolol trials. Am Heart J 1985;109 (part 2]:1119-1224. 1

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