A view From Europe John Wikstrand, MD, PhD
llw pharmacologk approach to coronary protection, defined here as the prevention or delay of sudden death and myocardial infarction (without negatively affecting noncardiac mortality), Is critkally dkcussed. The value of pharmacokgkalty treathg mild hypertension and mild hypercholesterolemia is questioned, and the need for welldedghed, randomized clinical trials with definitive endpoints to determine a drugs cardlo= protective capability is emphasized. Based on such studies, R is concluded that some (but perhaps not all) @receptor antagonists as well as aspirin have been shown to protect against sudden cardiac death. Trials of thiazide diuretks, calcium antagonfsts, and angktensin-converthqj enzyme inhlbttors have not shown a reduction in sudden cardiac death, despite hating individual benefRswRhrespecttootheraspectsofcardiovascular disease. The demonstration that some p Mockers are cardioprotective is discussed in terms of the pathophyskkgy of sudden cardiac death, and dtfferences In the pharmacokinetk proflles of hidividual agents. (Am J Cardiol1992;70:33 I-39 I)
oronary protection can be defined as the prevention or delay of sudden cardiac death and myocardial infarction (MI), without negatively affecting noncardiovascular mortality. The aggressive pharmacologic approach to coronary protection as practiced in the United States contrasts with the more conservative approach taken in Europe’-e.g., the aggressive approach to treating hypercholesterolemia taken in the United States, despite little evidence supporting a role for drug therapy in mild hypercholesterolemia.1-3 More extensive study and perhaps new drugs are necessary to demonstrate a reduction in risk with cholesterol-lowering agents in patients with mild hypercholesterolemia, because present data may indicate a negative effect on noncardiovascular mortality with cholesterol-lowering drugs.2j3 Another problem is also the lack of methods able to measure cholesterol accurately. With current techniques, a single sample can vary by 30% over a 2-week period.4 Further, the cost of controlling hypercholesterolemia is an important consideration. Cholesterol-lowering drugs are expensive, and the costeffectiveness of reducing cholesterol on a broad scale is an important issue in the United States and in Europe.
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CORONARY PR0TECTIW.S. AGGRESSIVENESS AND EUROPEAN RESERVATIONS
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Hospital, Gothenburg University, Sweden. Address for reprints: John Wikstrand, MD, PhD, Wallenberg Laboratory, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.
In common with their more conservative view toward the treatment of mild hypercholesterolemia, European experts in the hypertensive field have expressed disagreements with the position of experts in the United States on the use of antihypertensive drugs in patients with mild hypertension.’ For example, the British view toward the treatment of mild hypertension was highlighted in a report of the British Hypertension Society Working Party.5 The criteria in this document are considerably more cautious than those advocated in the fourth Joint National Committee report from the United States.6 The impression is that U.S. colleagues sometimes are too aggressive with regard to drug treatment of mild hypertension as well as of mild hypercholesterolemia. On what evidence, then, A SYMPOSIUM:
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TABLE I Coronary Protection-Present Evidence From Secondary or Primary Preventive Studies
should medical professionals base treatment decisions and make the best choice among treatment alternatives? This is not an easy question to answer, but the aim of this article is to comment briefly on this issue and to summarize the data available, especially with regard to antihypertensive treatment. More comprehensive reviews are presented elsewhere.7,8 lMPORlANCE OF RANDOMIZED CLINICAL TRIMS AND TOTAL MORTMllY
Preventive measuresare sometimesbased solely on the identification and treatment of so-called risk factors. The risk-factor approach to coronary protection is, however, associated with several problems, since the experience from randomized clinical trials illustrates that affecting a coronary risk factor in a favorable way does not necessarily correspond to reduction in risk for coronary events or total mortality. Examples of this are the effect of antihypertensive thiazide diuretic therapy on coronary artery disease (CAD) in middle-aged men7-9 and the effect of cholesterol-lowering drugs on noncardiovascular mortality.2,3 Thus, an intervention may be effective in affecting a risk factor but may be harmful in other respects. This may be exemplified further with results from the International Nifedipine Trial on Atherosclerotic Therapy in which active pharmacologic treatment (nifedipine) reduced the risk for new coronary lesions but significantly increased the risk for total mortality and sudden death, and with the results from the Cardiac Arrhythmia Suppression Trial in which antiarrhythmic drugs (encainide or flecainide) gave an impressive decrease in complex arrhythmias but increased total mortality because of an increase in sudden death.‘@-12Thus, simply identifying and treating a risk factor is not satisfactory. The clinical trial, however, is a key research activity with the potential to improve the quality of health care by careful comparison of alternative treatments.13In these trials, total mortality should be considered, as well as cause-specificfatal events in addition to any surrogate endpoints, whenever possible.12 An important aspect of evaluating coronary protection in randomized clinical trials is the variability of effect observed even within a drug 34 1
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c1ass.7,8J4J5 Drugs with similar pharmacologic profiles, such as different calcium antagonists, may have very different actions14J5;the same may be true for l3 blockers as we11.7,8J6Consequently, findings of a study evaluating one agent from a class of compounds cannot be extrapolated to the entire class. To date, preventive effects have been adequately demonstrated in clinical trials for several interventions (Table I). Data indicate that dietary changes in patients with definite hypercholesterolemia reduce the risk of CAD.17 Although there is a paucity of data from clinical trials on smoking cessation, data from observational studies indicate a positive effect of smoking cessation, in both primary and secondary prevention of CAD.18 Compliance with a change in life-style, such as dietary modification or smoking cessation, is more difficult to ensure, however, than is compliance with drug therapy. Some p blockers have been demonstrated to be effective for both primary and secondary prevention of sudden death and MI (Figure 1).7,8J9The role of aspirin in secondary prevention is important, although its role in primary prevention has not been well-defined.20,21Evidence to date does not support the use of aspirin on a broad scale for primary prevention, at least not in low risk patients, IMPORTANCE OF SUDDEN CARDIAC DEATH
The high mortality rate from CAD in hypertensive subjects can be reduced substantially only if the risk of sudden coronary deaths can be reduced.22y23 Therefore, preventive measures should aim at reducing the risk for sudden death, especially in patients with increased risk. There are 3 important triggering or precipitating factors for ventricular fibrillation and sudden death: ischemia, high sympathetic tone, and low vagal tone. 16a24-29 Increasing vagal tone is protective because it increases electrical stability of the heart. During psychosocial stress, the defense reaction is activated and leads to an increase in sympathetic tone and a decrease in vagal tone. This will decrease the electrical stability of the heart and thus increase the risk of ventricular fibrillation and sudden death.16,24-32 The risk of ventricular fibrillation and sudden death may possibly be decreased by reducing ischemia and sympathetic tone and increasing vagal tone. This might be achieved by simultaneously blocking cardiac p1 receptors and also brain p1 receptors that control cardiac vagal tone and
DECEMBER 21. 1992
electrical stability of the heart. From a theoretical standpoint, one might speculate that relatively lipophilic B blockers that easily pass the bloodbrain barrier would more readily confer this than hydrophilic B blockers that only pass the bloodbrain barrier to a minor degree.16g3G32 Results from animal experiments Evidence that some B blockers reduce the risk of ventricular fibrillation and sudden death in animals subjected to acute myocardial ischemia is now accumulating.30-34The results from animal experiments are of considerable interest and clinical relevance, since they seem to corroborate some observations made in randomized clinical trials. One early study used a dog model in which animals were pretreated with different doses of atenolol.“” Two other studies used a pig model and demonstrated that the combination of psychosocial stress caused by restraint in an unfamiliar environment when associated with acute coronary occlusion is very prone to cause ventricular fibrillation.30,31Dellsperger and colleagues34 used dogs in another study in which hypertension leading to left ventricular hypertrophy was induced by unilateral nephrectomy followed by artial occlusion of the remaining renal artery. w blad and colleagues32 have advanced our understanding further by a more detailed assessment of cardiac vagal control in a rabbit model in which the autonomic disturbance was provoked by chloralose anesthesia. All 5 studies indicate that B1blockade makes an important contribution to a decrease in the risk of ventricular fibrillation and sudden death. The data published by Skinner,30 and Parker and coworkerq31 and Ablad and coworkers32 also indicate an Cumulative No. of Deaths 50
important role for pi receptors located in the brain. The reasons for the reported variations of the antifibrillatory effectiveness of different l3blockers are not fully understood35 but may involve differences in a combination of factors, such as degree of myocardial ischemia and the prevailing sympathetic and vagal activation of the heart as related to dose and the duration of exposure to the given l3 blocker. COMMENTS ON RYPERCENSION IN THE EIDERLY Several large-scale, randomized, double-blind, placebo-controlled studies have been published on the effect of antihypertensive treatment in the elderly,3M0 and several of these trials have been recently published, the briefly summarized results of which follow. The European Working Party on High Blood Pressure in the Elderly (EWPHE) and the Systolic Hypertension in the Elderly Program (SHEP) studies both compared placebo with thiazide diuretic treatment as baseline therapy. Neither of these studies showed a significant effect on total mortality (EWPHE: -9% and SHEP - 13%, differences not significant) or sudden death. A common misconception is that the EWPHE study showed a significant reduction in coronary events. In the EWPHE study, however, a positive effect of the active treatment was demonstrated mainly on pressure-related complications such as heart failure and stroke. Further, data from the intention-to-treat analysis are only available for fatal events, and cause-specific data for coronary mortality have not yet been published from this analysis.
1 Diuretics
FIGURE l. Une graph showl~~$ cumulatlvenumbersforsudden cardhvasculardaathsInthe2 randomlzath groups in the Metc~~rdol A-Is PreventlonlnHypertendves(MAPHY) study.Thepvalue4rehrstothe dtfferencaInrlskbetweenthe2 rambmkatlon gruups during the entlre study perled. (Reptinted wRhpermbshfromAmIHypertens. l9
(n=1625)
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2
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blocker. No significant reduction in the pooled incidence of fatal and nonfatal coronary eventswas recorded (relative risk, 0.87; 95% confidence interDiuretic Placebo val 0.49-1.56). Time* (n = 2,365) (n = 2,371) The British Medical Research Council study in < 1 hour 23 23 older adults compared placebo, thiazide diuretic ~24 hours 44 47 treatment, and atenolol. In the diuretic group *After onset of symptoms. Adapted from JAMA.3* favorable data were seen both for stroke and coronary events, although total mortality and sudThe results from the SHEP study, in addition to den death were unaffected by treatment. An unexan effect on stroke of a low-dose diuretic, also pected result was a more favorable outcome for showed a significant reduction in the pooled inci- total mortality and coronary events with diuretics dence of fatal and nonfatal coronary events. An compared with atenolol. Thus, these data on the analysis of sudden cardiac death in the SHEP comparison of diuretics and atenolol seem to study, however, showed that 67% of coronary corroborate the results of the atenolol arm of the deaths were sudden, without any difference be- Heart Attack Primary Prevention in Hypertension tween the 2 treatment groups (Table II). For Tria1.‘Js41To elucidate the reasons why atenolol statistical reasons, it is evidently very difficult to did not reduce total mortality, sudden death, or show a significant effect on total or coronary other coronary events in any of the 3 trials permortality if the treatment does not reduce the risk formed will require further study. of sudden death.22 The study published by Coope and Warrender3’ compared placebo with atenolol as first-line treat- COMMENTS ON ACE INHlBrrOBB AND ment in elderly hypertensive patients. The results CALCIUM ANTAGONISTS During the last several years, an astonishing showed a significant reduction of active treatment in stroke, but incidence of coronary events and increase in the use of angiotensin-converting entotal mortality was unaffected by treatment (rela- zyme (ACE) inhibitors and calcium antagonists has tive risk for coronary events was 1.03, and for total been seen both in patients with hypertension and in patients after MI. It is interesting, therefore, to mortality, 0.97). The Swedish Trial in Old Patients with Hyper- evaluate critically what data from randomized tension study, in which several different B blockers clinical trials show for these agents. Clinical trials were part of the first-line treatment, showed a have not yet produced long-term prognostic data statistically significant effect on total mortality on the effects of ACE inhibitors, calcium antago(-43%, p = 0.0079; 95% confidence interval 0.37- nists, or (Y blockers on cardiovascular complica0.87) and concomitantly a favorable trend on tions and sudden death in hypertensive patients.6 sudden death.3gBecause of its relatively small size Long-term prognostic studies with ACE inhibitors (approximately 200 patients on each B blocker), in hypertensive patients are urgently needed. One results were not published separately for each B such study is underway.42 Several placebo-controlled studies with enalapril havebeen published on patients with moderate30to-severe congestive heart failure: the Cooperative b North Scandinavian Enalapril Survival Study .t: ii (CONSENSUS I), 43and the Studies of Left Ventric20= ular Dysfunction (SOLVD).44 In both trials the P benefit of treatment was evident in deaths from t Placebo progressive heart failure but there was no effect on 8 sudden deaths (Figure 2). In the SOLVD trial the t P benefit was conferred on those with very low ejection fractions ( < 30%). In another study enalapril was compared with hydralazine-isosorbide 30 36 42 48 0 6 12 18 24 dinitrate in patients also with chronic congestive Month heart failure.45The study did not include a placebo FmllRE2. EfkJctofenabprllonnlortalltypresumedtobe group. Since hydralazine may increase the risk of duetoanawhythda(suddendeath)IntheStudlesofLef& sudden death, results on this endpoint are difficult Veubtrkular Dysfuncth (SOLVD). ns = dlffwuwa not slgto judge from this study. n&ant. (Reprhted wtth permlsslon from N En@ I Med.M) TABLE II Sudden Death in the 2 Randomized Groups in the Systolic Hypertension in the Elderly Program (SHEP) Study
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The results from the first secondary preventive TABLE III Pooled Results from Post-Myocardial infarction placebo-controlled study with an ACE inhibitor Patients with Calcium Antagonists of the Dihydropyridine Type (enalapril) in patients with MI have recently been Calcium presented.46The study was performed in 103 ScanAntagonists Placebo % Difference Endpoint (n = 4,731) (n = 4,733) dinavian centers with 3,044 patients randomized to Reinfarction 124 111 +11 enalapril and 3,046 to placebo. Intravenous enalaTotal mortality 365 330 +4 prilat (the active metabolite of enalapril) was given Adapted from Am J Cardiol.52 during the acute phase of an MI followed by 6 months of double-blind oral treatment (20 mg daily). During this follow-up, 598 patients died. are rather flat and therefore the strategy of combinThe study was stopped prematurely, mainly be- ing drugs rather than increasing the doses seemsto cause of a negative trend in patients randomized to be an advantage for blood pressure control and for quality of life, and possibly for coronary protection. the ACE inhibitor. There was an equal number of deaths in the 2 The same considerations must be taken into acgroups during the first 5 days after randomization, count in combining drugs as when choosing the but thereafter the curves started to diverge and the initial drug, i.e., what impact the combination will results showed a nonsignificant slightly higher rela- have on total mortality and on the risk of coronary tive risk with enalapril compared with placebo events occurring, and what effect it will have on (relative risk 1.10; 95% confidence interval 0.93- quality of life. Present data indicate improved 1.30;p = 0.28). The results from this study contrast quality of life with ACE inhibitors and different with the beneficial effect shown on total mortality cardioselective l3 blockers.53Nonselective l3 blockand sudden death with a l.3blocker using a very ers such as propranolol, however, do not seem to Further studies similar study design (intravenous followed by long- be as well tolerated (Figure 3).54955 are needed to define the way in which different term oral treatment in patients with MI).47 Although animal data indicate that ACE inhibition drugs and drug combinations affect both the under(captopril) may have an antiatherogenic effect,48 lying atherosclerotic disease and mechanisms that results regarding sudden death from randomized may influence precipitating factors for ventricular fibrillation and sudden death, aswell as life satisfacclinical trials have not been encouraging. Animal data indicate that calcium antagonists tion and quality of life. also may have an antiatherogenic effect, especially with regard to the development of new lesions.49 CONCWSION Coronary protection can be defined as the Calcium antagonists have also been extensively studied in post-MI patients. A recent review con- prevention or delay of sudden cardiac death and cluded that the results were disappointing, since MI without negatively affecting noncardiovascular pooled data actually showed a trend toward in- mortality. The aggressivepharmacologic approach creased mortality with the calcium antagonists to coronary protection pursued in the United compared with placebo (Table III).5o There is some evidence, however, that the effect of verapaACE Cardiomil in post-MI patients might differ from that of calcium antagonists of the dihydropyridine type,51,52 although there are no data to indicate that verapamil significantly affects total mortality or sudden death. The available, large-scale, randomized secondary preventive trials with ACE inhibitors and calcium antagonists indicate that results with regard to sudden death have been disappointing. COMRINATION TREATMENT AND OTHER ISSUES
A large number of patients with mild-tomoderate hypertension are not well-controlled on a low-to-moderate dose of a single drug. The dose-response curves for antihypertensive drugs
I FlGURE3.ChnngeslnglolAscores oftheufesatwactlonQuestllInnalnatmatherapy-to ltudlna.ACE=aW --Wi!enqrmelnhbC tors;Cap=captopd;Enal=emlapdl;Cadosel= ca~e(~:Non-sel=nW mwHmdd).(~~~pennhrlon~ I Hum MJq#eam.r A SYMPOSIUM:
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States contrasts with the more conservative approach taken in Europe. In common with their more conservative view toward the treatment of mild hypercholesterolemia, European experts in the hypertensive field have expressed disagreements with the position of experts in the United States on the use of antihypertensive drugs in patients with mild hypertension. On what evidence, then, should we base our treatment decisions and make the best choice among treatment alternatives? The clinical trial is a key research activity with the potential to improve the quality of health care by careful comparison of alternative treatments. Present data indicate an important role for some l3 blockers in secondary prevention after MI and also for primary prevention in men with mild-to-moderate hypertension. Data available from post-MI patients also indicate a very important clinical role for B blockade in patients with diabetes, a group with a high risk of sudden death.7>8,56 Other data from the post-MI situation indicate a similar benefit in Blacks and Caucasians, and in both males and females.57J8 Adding aspirin to B blockade will further reduce the risk for coronary events in patients after an MI.*l Evidence to date, however, does not support the use of aspirin on a broad scale for primary prevention, at least not in low risk patients. In addition to the choice of drug used, risk reduction is probably also dependent on improved detection and the effective management of concomitant risk factors for CAD, especially smoking cessation. Clinical trials to date have not yet produced long-term primary prevention data on the effects of ACE inhibitors, calcium antagonists, or (Yblockers on cardiovascular complications and sudden death in hypertensive patients. Large-scale secondary preventive studies presently available on ACE inhibitors and calcium antagonists indicate that the results with regard to sudden death have been disappointing, although results on the prevention of death from progressive heart failure are important.
5. Report of the British Hypertension Society working party. Treating mild hypertension.Agreement from the large trials. Br Med J 1989;298:694698. 6. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med 1988,148:10231038. 7. Wiitrand J, Berglund G, Tuomilehto J. P-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence.Circulation 1991;84(supplVI):VI93-VI-100. 8. Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden death. Review of present evidence.Eur Heari .I. 1992:13(SupplD):lll120. 9. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. fmg Cardiovasc Dk 1986, 29(suppl 1):9%118. l0. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jest S, Decker JW. Retardation of angiographic progression of coronary artery disease by nifedipine. Lancet 1990,335:1109. Li. The Cardiac Arrhythmia SuppressionTrial (CAST) Investigators.Preliminary report: effect of encainide and Aecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N En@ J Med 1989;321:406412. l2. Wikstrand J, Wiiund 0. Frontiers in cardiovascularscience:Quantitative measurementsof atherosclerotic manifestations in man. Artuimch Thumb 1992;12:114?119. 19. Miettinen OS. The need for randomization in the study of intended effects.StatMed 1983;2:267-271. l4. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina:An overview. Br Med J 1989;299:1187-1192. lS. Yusuf S, Held P, Furber C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies.AmJCardid 1991;67:129> 1297. l& Eckberg DL. Badrenergic blockade may prolong life in post-infarction patients in part by increasingvagal cardiac inhibition. Med Hptheses 1984,15: 421432. 17. Hjennamt 1, Holme I, Leren P. Oslo Study Diet and Antismoking Trial: results after 102months.Am J Med 1986;8O(suppl2A):7-11. 18. Gottlieb DS. Cardiovascular benefits of smoking cessation.Heart Diwue and stroke 1992;1:17LL175.
is. Olsson G, Tuomilehto J, Berghmd G, Ehnfeldt D, Wamold I, Barber H, Eliasson K, Jastrup B, Karatzas N, Leer J, Marchetta F, RagnatssonJ, RobitailIe NM, VaIkova L, Wesseling H, Wiistrand J for the MAPHY Study Group. Primary prevention of sudden cardiovascular death in hypertensive patients: Mortality results from the MAPHY study.Am J Hymens 1991;4:151158. 20. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirii, both, or neither among 17 187 cases of suspectedacute myocardial infarction: ISISZ. Lancet 1988$:34%360. 21. Wallentin LC and the Research Group on Instability in Coronary Artery Disease in SoutheastSweden.Aspirin (75 mgiday) after an episodeof unstable coronary artery disease:long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization.JACC 19y1;18: 1587-1593. 22.Cupples LA, Gagnon DR, Kannel WB. Long- and short-term risk of suddencoronary death. Circul&n 1992;85(SupplI):l-11-l-18. 23. Iown B. Suddencardiac death: The major challengeconfronting contemporary cardiology.Am .I Cardiol1979;43:313-328. 24. Bigger JT Jr, KIeiger RE, Fleiss JL, Rolnitzky LM, Steinman RC, Miller JP, and the Multicenter Postinfarction Research Group. Componentsof heart rate variability measured during healing of acute myocardial infarction. Am J Car&l 1988;61:2Q8215. 25. Bilhnan GE, Hoskins RS. Tie-series analysis of heart rate variability during submaximalexercise. Evidence for reduced cardiac vagal tone in aniREFERENCES l. Kaplan NM. Critical comments on recent literature. The cholesterol cam- mals susceptibleto ventricular fibrillation. Circulation 1989;80:146157. paign: American aggressiveness and British reservations..4m J H@ns 1989;2: 26. Malik M, Farrell T, Camm AJ. Circadian rhythm of heart rate variability after acute myocardial infarction and its influence on the prognostic value of 941-942. 2. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentra- heart rate variability. Am J Cnm?o11990,66:1@4%1054. tions and mortality: a quantitative review of primary prevention trials. Br Med J 27.Hayano J, Yamada A, Mukai S, Sakakibara Y, Yamada M, Ohte N, Hastimoto T, Fujinami T, Takata K Severity of coronary atherosclerosiscorre1990;301:30%314. 3. Oliver MF. Might treatment of hypercholesterolaemiaincrease non-cardiac lates with the respiratory component of heart rate variability. Am Heart J 1991;121:107~1079. mortality? Lancer 1991;i:152%1531. 28. Farrell TG, Paul V, Cripps TR, Malik M, Bennet ED, Ward D, Camm 4. Lang CA, Ransohoff DF. Can diagnosticmarker studiesprovide evidenceof efficacy for colon cancer screening? A methodologic assessment.C[in Res AJ. Baroreflex sensitivity and ekctrophysiologicaI correlates in patients after acute myocardial infarction. Circulntin 1991;83:945-952. 1989;37:318A.
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29. Vanoli E, De Ferrari GM, Stramba-Badiale M, HulI SS Jr, Foreman RD, Schwartz PJ. Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res IY91;68:1471-1481. 30. Skinner JE. Regulation of cardiac vulnerability by the cerebral defense system. JAm Co11Cardiol1985;5:88E94B. 3L Parker GW, Michael LH, Hartley CJ, Skinner JE, Entman JE. Central P-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs. Circ Res 1990;66:25%270. 32. Ablad B, Bjur(i T, BjGrkman J-A, Edstriim T, Olsson G. Role of central nervous p-adrencceptors in the prevention of ventricular fibrillation through augmentation of cardiacvagal tone. JAm Co11Cardiol1991;17,2:165A. 33. Menken U, Wiegand V, Bucher P, Meesmann W. Prophylaxis of ventricular fibrillation after acute experimental coronary occlusion by chronic P-adrenoceptor blockade with atenolol. Cardiovasc Res 197%13:586594. 34. Dellsperger KC, Martins JB, Clothier JL, Marcus ML. Incidence of sudden cardiac death associated with coronary artery occlusion in dogs with hypertension and left ventricular hypertrophy is reduced by chronic P-adrenergic blockade. Circulation 1990;82:94-950. 35. Muller CA, Opie LH, Peisach M, Pineda CA, Hamm CW, Thandroyen FT. Critical role of dose in protection by propranolol against ventricular fibrillation in a pig model of acute myccardial &hernia. J Cardiovmc Phanmcol 1989;13:192-197, 36. Amery A, BirkenhPger W, Brixko P, Bulpitt C, Clement D, Deruyttere M, DeSchaepdryver A, Dollery C, Fagard R, Forette F, Forte J, Hamdy R, Henry JF, Joossens JV, Leonetti G, Lund-Johansen P, O’Malley K, Petrie J, Strasser T, Tuomilehto J, Williams B Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancer 198S;i;134%1354. 37. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J 1986,293:1145-1151. 38. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA IY91;265:3255-3264. 39. Dahl6f B, Lindholm LH, Hansson L, SchentCn B, Ekbom T, Wester P-O. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:128-1285. 40. Medical Research Council Working Party. Medical Research Council trial of treatment of hypertension in older adults: Principal results. Br Med J 1992;304405412. 41 MAPHY and the two arms of HAPPHY. (Letter.) JAM4 1989;262:32723274. 42. The CAPPP group. The captopril prevention project: A prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension. J Hypemu 1990;8:985-9%. 43. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Sulvival Study (CONSENSUS). N En& J Med 1987;316:1429-1435, 44. The SOLVD Investigators. Effect of enalapril on sunival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med IYY1;325:2Y.%302.
45. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman B, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. NE@ J Med 1991;325:30%310. 46. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H, on behalf of the CONSENSUS II Study Group. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Sutival Study 11 (CONSENSUS II). N En@ J Med lY92;327:678+X 47. Hjalmarson ,&, Herlitz J, Holmberg S, RydCn L, Swedberg K, Vedin A, Waagztein F, Waldenstram A, Waldenstriim J, Wedel H, Wiihelmsen L, Wilhelmsson C The Gijteborg Metoprolol Trial: effects on mortality and morbidity in acute myocardial infarction. Circulation 1983;67(suppl 1):12&132. 48. Chobanian AV, Haudenschild CC, Nickerson C, Drago R. Antiatherogenie effect of captopril in the Watanabe heritable hyperlipidemic rabbit. H~rtmion 19’x); 15:327-33 I, 49. Jackson CL, Bush RC, Bowyer DE. Mechanism of antiatherogenic action of calcium antagonists. Atherosclerosis 1989;80:17-26. 50. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina: an overview. Br Med J 1989;299:1187-1192. 51 The Danish Study Group on Verapamil in Myocardial Infarction. Effect of verapamil on mortality and major events after acute myocardial infarction (The Danish VerapamiI Infarction Trial II-DAVIT II). Am J Cardiol 1990;66:77% 785. 52. Yusuf S, Held P, Furber C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies. Am J Cardbl 1991;67:12YS1297. 53. Dahlijf C. Well-being (quality of life) in connection with hypertensive treatment. Clin Cardi 1991;14:97-103. IX. Steiner SS, Friedhoff AJ, Wilson BL, Wecker JR, Santo JP. Antihypertensive therapy and quality of life: A comparison of atenolol, captopril, enalapril and propranolol. J Hum H~mm 1990,4:217-225. 55. Dime”% E, Kerr D, Macdonald TA. P-adrenoceptor blockade and CNSrelated subjective symptoms: a randomized, double-blind, placebcontrolled comparison of metoprolol CR/ZOK atenolol and propranolol LA in healthy subjects. J Clin Phamcol 1990,30(suppl):S10~S107. 56. Kjekshus J, Gilpin E, Cali G, Blackey AR, Henning H, Ross J Jr. Diabetic patients and P-blockers after acute myocardial infarction. Eur Heart J 199O;ll: 43-50. 57. Hapood W. Coronary heart disease mortality/morbidity and risk in blacks. I: Clinical manifestations and diagnostic criteria: the experience with the p Blocker Heart Attack Trial. Am Heart J 1984;108:787-793. 58. Olsson G, Wiistrand J, Warnold I, Manger Cats V, McBoyle D, Herlitz J, Hjalmarson I$ Sonnenblick EH . Metoprolol induced reduction in postinfarction mortality: Pooled results from five double-blind randomized trials. Eur Heart J IY92;13:28-32.
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llw pharmacologk approach to coronary protection, defined here as the prevention or delay of sudden death and myocardial infarction (without negatively affecting noncardiac mortality), Is critkally dkcussed. The value of pharmacokgkalty treathg mild hypertension and mild hypercholesterolemia is questioned, and the need for welldedghed, randomized clinical trials with definitive endpoints to determine a drugs cardlo= protective capability is emphasized. Based on such studies, R is concluded that some (but perhaps not all) @receptor antagonists as well as aspirin have been shown to protect against sudden cardiac death. Trials of thiazide diuretks, calcium antagonfsts, and angktensin-converthqj enzyme inhlbttors have not shown a reduction in sudden cardiac death, despite hating individual benefRswRhrespecttootheraspectsofcardiovascular disease. The demonstration that some p Mockers are cardioprotective is discussed in terms of the pathophyskkgy of sudden cardiac death, and dtfferences In the pharmacokinetk proflles of hidividual agents. (Am J Cardiol1992;70:33 I-39 I)
oronary protection can be defined as the prevention or delay of sudden cardiac death and myocardial infarction (MI), without negatively affecting noncardiovascular mortality. The aggressive pharmacologic approach to coronary protection as practiced in the United States contrasts with the more conservative approach taken in Europe’-e.g., the aggressive approach to treating hypercholesterolemia taken in the United States, despite little evidence supporting a role for drug therapy in mild hypercholesterolemia.1-3 More extensive study and perhaps new drugs are necessary to demonstrate a reduction in risk with cholesterol-lowering agents in patients with mild hypercholesterolemia, because present data may indicate a negative effect on noncardiovascular mortality with cholesterol-lowering drugs.2j3 Another problem is also the lack of methods able to measure cholesterol accurately. With current techniques, a single sample can vary by 30% over a 2-week period.4 Further, the cost of controlling hypercholesterolemia is an important consideration. Cholesterol-lowering drugs are expensive, and the costeffectiveness of reducing cholesterol on a broad scale is an important issue in the United States and in Europe.
C
CORONARY PR0TECTIW.S. AGGRESSIVENESS AND EUROPEAN RESERVATIONS
From the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Hospital, Gothenburg University, Sweden. Address for reprints: John Wikstrand, MD, PhD, Wallenberg Laboratory, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.
In common with their more conservative view toward the treatment of mild hypercholesterolemia, European experts in the hypertensive field have expressed disagreements with the position of experts in the United States on the use of antihypertensive drugs in patients with mild hypertension.’ For example, the British view toward the treatment of mild hypertension was highlighted in a report of the British Hypertension Society Working Party.5 The criteria in this document are considerably more cautious than those advocated in the fourth Joint National Committee report from the United States.6 The impression is that U.S. colleagues sometimes are too aggressive with regard to drug treatment of mild hypertension as well as of mild hypercholesterolemia. On what evidence, then, A SYMPOSIUM:
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TABLE I Coronary Protection-Present Evidence From Secondary or Primary Preventive Studies
should medical professionals base treatment decisions and make the best choice among treatment alternatives? This is not an easy question to answer, but the aim of this article is to comment briefly on this issue and to summarize the data available, especially with regard to antihypertensive treatment. More comprehensive reviews are presented elsewhere.7,8 lMPORlANCE OF RANDOMIZED CLINICAL TRIMS AND TOTAL MORTMllY
Preventive measuresare sometimesbased solely on the identification and treatment of so-called risk factors. The risk-factor approach to coronary protection is, however, associated with several problems, since the experience from randomized clinical trials illustrates that affecting a coronary risk factor in a favorable way does not necessarily correspond to reduction in risk for coronary events or total mortality. Examples of this are the effect of antihypertensive thiazide diuretic therapy on coronary artery disease (CAD) in middle-aged men7-9 and the effect of cholesterol-lowering drugs on noncardiovascular mortality.2,3 Thus, an intervention may be effective in affecting a risk factor but may be harmful in other respects. This may be exemplified further with results from the International Nifedipine Trial on Atherosclerotic Therapy in which active pharmacologic treatment (nifedipine) reduced the risk for new coronary lesions but significantly increased the risk for total mortality and sudden death, and with the results from the Cardiac Arrhythmia Suppression Trial in which antiarrhythmic drugs (encainide or flecainide) gave an impressive decrease in complex arrhythmias but increased total mortality because of an increase in sudden death.‘@-12Thus, simply identifying and treating a risk factor is not satisfactory. The clinical trial, however, is a key research activity with the potential to improve the quality of health care by careful comparison of alternative treatments.13In these trials, total mortality should be considered, as well as cause-specificfatal events in addition to any surrogate endpoints, whenever possible.12 An important aspect of evaluating coronary protection in randomized clinical trials is the variability of effect observed even within a drug 34 1
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c1ass.7,8J4J5 Drugs with similar pharmacologic profiles, such as different calcium antagonists, may have very different actions14J5;the same may be true for l3 blockers as we11.7,8J6Consequently, findings of a study evaluating one agent from a class of compounds cannot be extrapolated to the entire class. To date, preventive effects have been adequately demonstrated in clinical trials for several interventions (Table I). Data indicate that dietary changes in patients with definite hypercholesterolemia reduce the risk of CAD.17 Although there is a paucity of data from clinical trials on smoking cessation, data from observational studies indicate a positive effect of smoking cessation, in both primary and secondary prevention of CAD.18 Compliance with a change in life-style, such as dietary modification or smoking cessation, is more difficult to ensure, however, than is compliance with drug therapy. Some p blockers have been demonstrated to be effective for both primary and secondary prevention of sudden death and MI (Figure 1).7,8J9The role of aspirin in secondary prevention is important, although its role in primary prevention has not been well-defined.20,21Evidence to date does not support the use of aspirin on a broad scale for primary prevention, at least not in low risk patients, IMPORTANCE OF SUDDEN CARDIAC DEATH
The high mortality rate from CAD in hypertensive subjects can be reduced substantially only if the risk of sudden coronary deaths can be reduced.22y23 Therefore, preventive measures should aim at reducing the risk for sudden death, especially in patients with increased risk. There are 3 important triggering or precipitating factors for ventricular fibrillation and sudden death: ischemia, high sympathetic tone, and low vagal tone. 16a24-29 Increasing vagal tone is protective because it increases electrical stability of the heart. During psychosocial stress, the defense reaction is activated and leads to an increase in sympathetic tone and a decrease in vagal tone. This will decrease the electrical stability of the heart and thus increase the risk of ventricular fibrillation and sudden death.16,24-32 The risk of ventricular fibrillation and sudden death may possibly be decreased by reducing ischemia and sympathetic tone and increasing vagal tone. This might be achieved by simultaneously blocking cardiac p1 receptors and also brain p1 receptors that control cardiac vagal tone and
DECEMBER 21. 1992
electrical stability of the heart. From a theoretical standpoint, one might speculate that relatively lipophilic B blockers that easily pass the bloodbrain barrier would more readily confer this than hydrophilic B blockers that only pass the bloodbrain barrier to a minor degree.16g3G32 Results from animal experiments Evidence that some B blockers reduce the risk of ventricular fibrillation and sudden death in animals subjected to acute myocardial ischemia is now accumulating.30-34The results from animal experiments are of considerable interest and clinical relevance, since they seem to corroborate some observations made in randomized clinical trials. One early study used a dog model in which animals were pretreated with different doses of atenolol.“” Two other studies used a pig model and demonstrated that the combination of psychosocial stress caused by restraint in an unfamiliar environment when associated with acute coronary occlusion is very prone to cause ventricular fibrillation.30,31Dellsperger and colleagues34 used dogs in another study in which hypertension leading to left ventricular hypertrophy was induced by unilateral nephrectomy followed by artial occlusion of the remaining renal artery. w blad and colleagues32 have advanced our understanding further by a more detailed assessment of cardiac vagal control in a rabbit model in which the autonomic disturbance was provoked by chloralose anesthesia. All 5 studies indicate that B1blockade makes an important contribution to a decrease in the risk of ventricular fibrillation and sudden death. The data published by Skinner,30 and Parker and coworkerq31 and Ablad and coworkers32 also indicate an Cumulative No. of Deaths 50
important role for pi receptors located in the brain. The reasons for the reported variations of the antifibrillatory effectiveness of different l3blockers are not fully understood35 but may involve differences in a combination of factors, such as degree of myocardial ischemia and the prevailing sympathetic and vagal activation of the heart as related to dose and the duration of exposure to the given l3 blocker. COMMENTS ON RYPERCENSION IN THE EIDERLY Several large-scale, randomized, double-blind, placebo-controlled studies have been published on the effect of antihypertensive treatment in the elderly,3M0 and several of these trials have been recently published, the briefly summarized results of which follow. The European Working Party on High Blood Pressure in the Elderly (EWPHE) and the Systolic Hypertension in the Elderly Program (SHEP) studies both compared placebo with thiazide diuretic treatment as baseline therapy. Neither of these studies showed a significant effect on total mortality (EWPHE: -9% and SHEP - 13%, differences not significant) or sudden death. A common misconception is that the EWPHE study showed a significant reduction in coronary events. In the EWPHE study, however, a positive effect of the active treatment was demonstrated mainly on pressure-related complications such as heart failure and stroke. Further, data from the intention-to-treat analysis are only available for fatal events, and cause-specific data for coronary mortality have not yet been published from this analysis.
1 Diuretics
FIGURE l. Une graph showl~~$ cumulatlvenumbersforsudden cardhvasculardaathsInthe2 randomlzath groups in the Metc~~rdol A-Is PreventlonlnHypertendves(MAPHY) study.Thepvalue4rehrstothe dtfferencaInrlskbetweenthe2 rambmkatlon gruups during the entlre study perled. (Reptinted wRhpermbshfromAmIHypertens. l9
(n=1625)
40
30
20
10
0 0
1
2
3
4 5 Follow-up
6
7 Years
a
0
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11
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r
blocker. No significant reduction in the pooled incidence of fatal and nonfatal coronary eventswas recorded (relative risk, 0.87; 95% confidence interDiuretic Placebo val 0.49-1.56). Time* (n = 2,365) (n = 2,371) The British Medical Research Council study in < 1 hour 23 23 older adults compared placebo, thiazide diuretic ~24 hours 44 47 treatment, and atenolol. In the diuretic group *After onset of symptoms. Adapted from JAMA.3* favorable data were seen both for stroke and coronary events, although total mortality and sudThe results from the SHEP study, in addition to den death were unaffected by treatment. An unexan effect on stroke of a low-dose diuretic, also pected result was a more favorable outcome for showed a significant reduction in the pooled inci- total mortality and coronary events with diuretics dence of fatal and nonfatal coronary events. An compared with atenolol. Thus, these data on the analysis of sudden cardiac death in the SHEP comparison of diuretics and atenolol seem to study, however, showed that 67% of coronary corroborate the results of the atenolol arm of the deaths were sudden, without any difference be- Heart Attack Primary Prevention in Hypertension tween the 2 treatment groups (Table II). For Tria1.‘Js41To elucidate the reasons why atenolol statistical reasons, it is evidently very difficult to did not reduce total mortality, sudden death, or show a significant effect on total or coronary other coronary events in any of the 3 trials permortality if the treatment does not reduce the risk formed will require further study. of sudden death.22 The study published by Coope and Warrender3’ compared placebo with atenolol as first-line treat- COMMENTS ON ACE INHlBrrOBB AND ment in elderly hypertensive patients. The results CALCIUM ANTAGONISTS During the last several years, an astonishing showed a significant reduction of active treatment in stroke, but incidence of coronary events and increase in the use of angiotensin-converting entotal mortality was unaffected by treatment (rela- zyme (ACE) inhibitors and calcium antagonists has tive risk for coronary events was 1.03, and for total been seen both in patients with hypertension and in patients after MI. It is interesting, therefore, to mortality, 0.97). The Swedish Trial in Old Patients with Hyper- evaluate critically what data from randomized tension study, in which several different B blockers clinical trials show for these agents. Clinical trials were part of the first-line treatment, showed a have not yet produced long-term prognostic data statistically significant effect on total mortality on the effects of ACE inhibitors, calcium antago(-43%, p = 0.0079; 95% confidence interval 0.37- nists, or (Y blockers on cardiovascular complica0.87) and concomitantly a favorable trend on tions and sudden death in hypertensive patients.6 sudden death.3gBecause of its relatively small size Long-term prognostic studies with ACE inhibitors (approximately 200 patients on each B blocker), in hypertensive patients are urgently needed. One results were not published separately for each B such study is underway.42 Several placebo-controlled studies with enalapril havebeen published on patients with moderate30to-severe congestive heart failure: the Cooperative b North Scandinavian Enalapril Survival Study .t: ii (CONSENSUS I), 43and the Studies of Left Ventric20= ular Dysfunction (SOLVD).44 In both trials the P benefit of treatment was evident in deaths from t Placebo progressive heart failure but there was no effect on 8 sudden deaths (Figure 2). In the SOLVD trial the t P benefit was conferred on those with very low ejection fractions ( < 30%). In another study enalapril was compared with hydralazine-isosorbide 30 36 42 48 0 6 12 18 24 dinitrate in patients also with chronic congestive Month heart failure.45The study did not include a placebo FmllRE2. EfkJctofenabprllonnlortalltypresumedtobe group. Since hydralazine may increase the risk of duetoanawhythda(suddendeath)IntheStudlesofLef& sudden death, results on this endpoint are difficult Veubtrkular Dysfuncth (SOLVD). ns = dlffwuwa not slgto judge from this study. n&ant. (Reprhted wtth permlsslon from N En@ I Med.M) TABLE II Sudden Death in the 2 Randomized Groups in the Systolic Hypertension in the Elderly Program (SHEP) Study
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The results from the first secondary preventive TABLE III Pooled Results from Post-Myocardial infarction placebo-controlled study with an ACE inhibitor Patients with Calcium Antagonists of the Dihydropyridine Type (enalapril) in patients with MI have recently been Calcium presented.46The study was performed in 103 ScanAntagonists Placebo % Difference Endpoint (n = 4,731) (n = 4,733) dinavian centers with 3,044 patients randomized to Reinfarction 124 111 +11 enalapril and 3,046 to placebo. Intravenous enalaTotal mortality 365 330 +4 prilat (the active metabolite of enalapril) was given Adapted from Am J Cardiol.52 during the acute phase of an MI followed by 6 months of double-blind oral treatment (20 mg daily). During this follow-up, 598 patients died. are rather flat and therefore the strategy of combinThe study was stopped prematurely, mainly be- ing drugs rather than increasing the doses seemsto cause of a negative trend in patients randomized to be an advantage for blood pressure control and for quality of life, and possibly for coronary protection. the ACE inhibitor. There was an equal number of deaths in the 2 The same considerations must be taken into acgroups during the first 5 days after randomization, count in combining drugs as when choosing the but thereafter the curves started to diverge and the initial drug, i.e., what impact the combination will results showed a nonsignificant slightly higher rela- have on total mortality and on the risk of coronary tive risk with enalapril compared with placebo events occurring, and what effect it will have on (relative risk 1.10; 95% confidence interval 0.93- quality of life. Present data indicate improved 1.30;p = 0.28). The results from this study contrast quality of life with ACE inhibitors and different with the beneficial effect shown on total mortality cardioselective l3 blockers.53Nonselective l3 blockand sudden death with a l.3blocker using a very ers such as propranolol, however, do not seem to Further studies similar study design (intravenous followed by long- be as well tolerated (Figure 3).54955 are needed to define the way in which different term oral treatment in patients with MI).47 Although animal data indicate that ACE inhibition drugs and drug combinations affect both the under(captopril) may have an antiatherogenic effect,48 lying atherosclerotic disease and mechanisms that results regarding sudden death from randomized may influence precipitating factors for ventricular fibrillation and sudden death, aswell as life satisfacclinical trials have not been encouraging. Animal data indicate that calcium antagonists tion and quality of life. also may have an antiatherogenic effect, especially with regard to the development of new lesions.49 CONCWSION Coronary protection can be defined as the Calcium antagonists have also been extensively studied in post-MI patients. A recent review con- prevention or delay of sudden cardiac death and cluded that the results were disappointing, since MI without negatively affecting noncardiovascular pooled data actually showed a trend toward in- mortality. The aggressivepharmacologic approach creased mortality with the calcium antagonists to coronary protection pursued in the United compared with placebo (Table III).5o There is some evidence, however, that the effect of verapaACE Cardiomil in post-MI patients might differ from that of calcium antagonists of the dihydropyridine type,51,52 although there are no data to indicate that verapamil significantly affects total mortality or sudden death. The available, large-scale, randomized secondary preventive trials with ACE inhibitors and calcium antagonists indicate that results with regard to sudden death have been disappointing. COMRINATION TREATMENT AND OTHER ISSUES
A large number of patients with mild-tomoderate hypertension are not well-controlled on a low-to-moderate dose of a single drug. The dose-response curves for antihypertensive drugs
I FlGURE3.ChnngeslnglolAscores oftheufesatwactlonQuestllInnalnatmatherapy-to ltudlna.ACE=aW --Wi!enqrmelnhbC tors;Cap=captopd;Enal=emlapdl;Cadosel= ca~e(~:Non-sel=nW mwHmdd).(~~~pennhrlon~ I Hum MJq#eam.r A SYMPOSIUM:
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States contrasts with the more conservative approach taken in Europe. In common with their more conservative view toward the treatment of mild hypercholesterolemia, European experts in the hypertensive field have expressed disagreements with the position of experts in the United States on the use of antihypertensive drugs in patients with mild hypertension. On what evidence, then, should we base our treatment decisions and make the best choice among treatment alternatives? The clinical trial is a key research activity with the potential to improve the quality of health care by careful comparison of alternative treatments. Present data indicate an important role for some l3 blockers in secondary prevention after MI and also for primary prevention in men with mild-to-moderate hypertension. Data available from post-MI patients also indicate a very important clinical role for B blockade in patients with diabetes, a group with a high risk of sudden death.7>8,56 Other data from the post-MI situation indicate a similar benefit in Blacks and Caucasians, and in both males and females.57J8 Adding aspirin to B blockade will further reduce the risk for coronary events in patients after an MI.*l Evidence to date, however, does not support the use of aspirin on a broad scale for primary prevention, at least not in low risk patients. In addition to the choice of drug used, risk reduction is probably also dependent on improved detection and the effective management of concomitant risk factors for CAD, especially smoking cessation. Clinical trials to date have not yet produced long-term primary prevention data on the effects of ACE inhibitors, calcium antagonists, or (Yblockers on cardiovascular complications and sudden death in hypertensive patients. Large-scale secondary preventive studies presently available on ACE inhibitors and calcium antagonists indicate that the results with regard to sudden death have been disappointing, although results on the prevention of death from progressive heart failure are important.
5. Report of the British Hypertension Society working party. Treating mild hypertension.Agreement from the large trials. Br Med J 1989;298:694698. 6. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.Arch Intern Med 1988,148:10231038. 7. Wiitrand J, Berglund G, Tuomilehto J. P-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence.Circulation 1991;84(supplVI):VI93-VI-100. 8. Wikstrand J, Kendall M. The role of beta receptor blockade in preventing sudden death. Review of present evidence.Eur Heari .I. 1992:13(SupplD):lll120. 9. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. fmg Cardiovasc Dk 1986, 29(suppl 1):9%118. l0. Lichtlen PR, Hugenholtz PG, Rafflenbeul W, Hecker H, Jest S, Decker JW. Retardation of angiographic progression of coronary artery disease by nifedipine. Lancet 1990,335:1109. Li. The Cardiac Arrhythmia SuppressionTrial (CAST) Investigators.Preliminary report: effect of encainide and Aecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N En@ J Med 1989;321:406412. l2. Wikstrand J, Wiiund 0. Frontiers in cardiovascularscience:Quantitative measurementsof atherosclerotic manifestations in man. Artuimch Thumb 1992;12:114?119. 19. Miettinen OS. The need for randomization in the study of intended effects.StatMed 1983;2:267-271. l4. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarction and unstable angina:An overview. Br Med J 1989;299:1187-1192. lS. Yusuf S, Held P, Furber C. Update of effects of calcium antagonists in myocardial infarction or angina in light of the second Danish Verapamil Infarction Trial (DAVIT-II) and other recent studies.AmJCardid 1991;67:129> 1297. l& Eckberg DL. Badrenergic blockade may prolong life in post-infarction patients in part by increasingvagal cardiac inhibition. Med Hptheses 1984,15: 421432. 17. Hjennamt 1, Holme I, Leren P. Oslo Study Diet and Antismoking Trial: results after 102months.Am J Med 1986;8O(suppl2A):7-11. 18. Gottlieb DS. Cardiovascular benefits of smoking cessation.Heart Diwue and stroke 1992;1:17LL175.
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