Effects of Combination Therapy on the Heart

Effects of combination therapy on the heart

FH Messerli and L Michalewicz Department of Internal Medicine, Section on Hypertensive Diseases, Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA, USA

The presence of left ventricular hypertrophy (LVH) usu- avoided. In hypertensive patients with congestive heart ally indicates that hypertension is moderately severe failure, amlodipine should be added to triple therapy and that combination therapy will be required to control with an ACE inhibitor, whereas in the post myocardial blood pressure (BP). Unfortunately, most studies on the ischemia patient, verapamil may exert some additional reduction of LVH have been done with monotherapy. beneficial effects with regard to reinfarction rates. Our knowledge of combination therapy in the treatment Of note, given that two drugs when used separately of hypertensive heart disease is to a great extent extra- are beneficial in a disorder does not necessarily mean polation from monotherapy. Angiotensin-converting that their combination is equally or even more ben- enzyme (ACE) inhibitors in combination with calcium eficial. Thus, combination therapy should primarily be antagonists ought to be particularly efficacious in used for lowering arterial pressure and only secondarily reducing LVH. Drug classes that either stimulate the to possibly improve concomitant pathophysiologic con- renin angiotensin system or the sympathetic nervous ditions associated with hypertensive heart disease. system are less likely to reduce LVH and should be

Keywords: ACE inhibitors; calcium blockers; LVH

Introduction dial infarction, congestive heart failure, sudden death and other cardiovascular events increases six- The most common manifestation of hypertensive to eight-fold with the occurrence of LVH.2–5 Once heart disease is left ventricular hypertrophy (LVH) LVH is present by electrocardiographic and echocar- (Figure 1), arbitrarily deﬁned as an increase in left diographic criteria, hypertension is usually moder- ventricular mass exceeding certain established cri- 1 ately severe and blood pressure (BP) rarely will be teria. LVH cannot simply be considered as a com- controlled by monotherapy. Thus, in the patient pensatory mechanism. The Framingham Heart with LVH, two or more drugs are often used to Study has documented that the risk of acute myocar- achieve normotension. Unfortunately, most studies regarding target organ damage in hypertension were carried out by focusing on the effects of monotherapy. These extrapolations, however provocative and suggestive clinically, may not always prove to be beneﬁcial in terms of morbidity and mortality.

Combination therapy: general principles Because of multiple mechanisms that are involved in the pathogenesis of essential hypertension, a sin- gle drug class may not address all of them; in fact, monotherapy sufficiently controls BP in only 50– 60% instances.6 Efficacy of a drug is often lowered due to the stimulation of compensatory mechanisms. Combination therapy allows the use of lower doses of each antihypertensive agent; therefore, excess stimulation may be avoided, and, con- ceivably, the second component of combination may counteract this stimulation. It is not yet clear Figure 1 Determinants and cardiac sequelae of LVH. (Used with whether combining two different antihypertensive permission from Messerli FH, Soria F. Hypertension, left ven- agents results in an additive, sub-additive or supra- tricular hypertrophy, ventricular ectopy, and sudden death. Am 7,8 J Med 1992; 93 (Suppl 2A): 21–26S). additive effect on arterial pressure. We recently showed at most an additive effect of antihypertensive therapy regardless of which combination of 9 Correspondence: Dr FH Messerli, Ochsner Clinic, 1514 Jefferson drug classes was used. The use of lower doses of Highway, New Orleans, LA 70121, USA antihypertensive agents reduces the risk of dose- Effects of combination therapy on the heart FH Messerli and L Michalewicz 30 related adverse reactions. Moreover, the use of one its BP lowering effects alone. Whether angiotensin agent may counteract the deleterious effects of the receptor inhibitors, either in monotherapy or in other. It has been reported that adjunctive angioten- combination, are as efficient as ACE inhibitors in sin-converting enzyme (ACE) inhibitor therapy has reducing LVH remains undocumented at the present attenuated diuretic-associated hypokalemia, hyper- time. Most of the other commonly used combi- glycemia, hyperuricemia and hypercholesterolem- nations, such as diuretics plus beta-blockers, ACE ia.10 inhibitors plus beta-blockers, as well as beta-block- Combination therapy is an attractive choice, ers plus dihydropyridine calcium antagonists, are especially in the presence of concomitant patho- prone to reduce LVH in parallel with the fall in physiologic conditions associated with hyperten- arterial pressure. sion. Is there any drug combination that should be avoided in patients with LVH? Drug classes that Left ventricular hypertrophy either stimulate the renin angiotensin system or the sympathetic nervous system, or both, are less likely Of all antihypertensive drugs, ACE inhibitors are to reduce LVH than drug classes that do not stimu- probably the most effective in reducing LVH.5,11,12 late these systems. The combination of an arteriolar Recently, Schmieder et al13 performed a meta-analy- vasodilator, such as hydralazine or minoxidil, with sis that only considered randomized studies com- a diuretic should, therefore, probably not be used in paring the effects of two or more therapies by an asymptomatic patient with LVH. Such a combi- assessing LVH and structure with blindly read echo- nation may also synergistically elicit hypokalemia cardiograms. Out of more than 400 applications, which could aggravate or trigger ventricular arrhyth- only 39 clinical trials fulfilled these criteria. Similar mias. to previous meta-analyses, the decrease in left ventricular mass was greater with active drug treatment than with placebo, and was directly related to the pretreatment left ventricular mass, control of pres- Systolic dysfunction – congestive heart sure and duration of treatment. When the analysis failure was adjusted for the study duration, ACE inhibitors were most efficient in reducing LVH followed by As hypertensive cardiovascular disease progresses, calcium channel blockers, the diuretics and the beta the hypertrophied heart is no longer able to compen- blockers.13 Indeed, some reports suggest that ACE sate for an ever-increasing afterload. The left inhibitors may lower BP more than one would chamber becomes dilated, and a decrease in ejection expect from their unloading properties alone. The fraction and cardiac output can be observed.20 Con- ability of ACE inhibitors at a dose that does not gestive heart failure is known to be a common com- lower BP to produce regression in LVH supports the plication of untreated longstanding hypertension.21 hypothesis that the local cardiac angiotensin system Clearly, therefore, in the patient with systolic dys- is a significant determinant of heart structure and function, drugs that exert negative inotropic effects, function.14,15 As a class, calcium antagonists seem such as some calcium antagonists and beta-blockers, slightly less potent in reducing LVH than the ACE should be used with restraint. It must be remem- inhibitors with heart rate lowering agents possibly bered, however, that low doses of beta-blockers have having a greater effect than the dihydropyridines. A been shown to be beneficial, particularly in patients lesser effect is assigned to the beta-blockers, the suffering from congestive heart failure as a result of postsynaptic alpha-blockers and the diuretics. Of dilated cardiomyopathy. Similarly, it has recently note, however, recent findings in 690 men from the been documented that the new compound carvedi- VA cooperative study showed hydrochlorothiazide lol improves morbidity and mortality in patients to be more efficacious than atenolol, captopril, dilti- with congestive heart failure.22 azem, prazosin or clonidine in reducing LVH.16 It ACE inhibitors remain a cornerstone in the man- must be emphasized, however, that with a few agement of congestive heart failure and have been exceptions17–19 there are no prospective, ran- clearly shown to be of benefit early as well as late domized, controlled trials comparing the effects of in the evolution of the disease. The standard therapy various antihypertensive drugs on left ventricular of congestive heart failure consists therefore of a mass. Also, there is uncertainty as to what a drug- diuretic, digitalis, and an ACE inhibitor. Two of induced reduction of LVH exactly means in terms these drug classes are also commonly used to treat of morbidity and mortality. hypertension. In the PRAISE study,23 patients with There are no conclusive data that a reduction in congestive heart failure from dilated cardiomyopa- LVH would confer a benefit that exceeded the one thy benefited from the addition of amlodipine. A conferred by the reduction in arterial pressure per reasonable combination to be used in such patients se. These drawbacks notwithstanding, it can be who are concomitantly suffering from hypertension extrapolated that the combination of an ACE inhibi- would, therefore, be a diuretic, digitalis, an ACE tor with a calcium blocker ought to be particularly inhibitor, and either amlodipine or perhaps carvedi- efficacious with regard to a reduction of LVH (Table lol. Unlike amlodipine, which had no effect in 1). Because both of these drug classes have the patients with congestive heart failure caused by potential to interfere with pathogenesis of LVH at a ischemic cardiomyopathy, carvedilol had equal similar level, one can argue that this combination benefits in patients with both dilated cardiomyopa- will reduce LVH more than one would expect from thy and ischemic cardiomyopathy. Effects of combination therapy on the heart FH Messerli and L Michalewicz 31 Table 1 Possible synergism resulting from a combination of a calcium antagonist and an ACE inhibitor

DHP-Calcium HRL-Calcium ACE antagonist antagonist inhibitor

Kidneys ↑ Renal blood flow yes yes yes ↑ Efferent vasodilation little little yes ↑ Afferent vasodilation yes yes yes ↓ Microproteinuria little yes yes ‘Renoprotection’ unknown possible yes Vascular Tree ↓ Endothelin mediated yes yes no vasoconstriction ↑ Nitric oxide release no no yes ↑ Arterial compliance yes yes yes ↓ Vascular hypertrophy yes yes yes ↓ Atherogenesis yes yes yes Heart ↓ Left ventricular hypertrophy yes yes yes ↑ Left ventricular filling yes yes no ↑ Contractility, unloading some no yes ↑ Coronary flow yes yes some Secondary ‘cardioprotection’ no some yes

ACE = angiotensin-converting enzyme; DHP = dihydropyridine; HRL = heart-rate-lowering; ↑ = increase; ↓ = decrease.

Impaired left ventricular filling and to the development of coronary atherosclerosis, hypertrophic obstructive cardiomyopathy exaggerated reactivity of cardiac arterioles, increased hemodynamic burden of the heart and Impairment in left ventricular filling has been docu- increase in left ventricular mass. The two drug mented as an early finding in hypertensive heart dis- classes most commonly used to treat coronary artery ease.24–26 However, most often this impairment is disease are the calcium antagonists and the beta- asymptomatic and does not necessitate specific ther- blockers. It seems logical, therefore, to use a combi- apy. In the occasional patient who is suffering from nation of these two drug classes in hypertensive dyspnea on exertion secondary to impaired filling, patients who are suffering from coronary artery dis- the addition of either a calcium antagonist or a beta- ease and require two or more drugs for lowering of blocker to the current antihypertensive regimen arterial pressure. Indeed, fixed combinations of should be sufficient. When given for a prolonged some dihydropyridine calcium antagonists and beta- period of time, ACE inhibitors have been shown to blockers have been marketed outside the US30,31 but improve left ventricular filling inconsistently.27 In only for hypertension and not for coronary artery contrast to the findings with calcium antagonists disease. By and large, the combination of a heart rate and beta-blockers which also have a direct effect on lowering calcium antagonist (verapamil, diltiazem) the early rapid filling phase, the effect by the ACE with a beta-blocker should be avoided because the inhibitors seems to be solely mediated by their two molecules could exert synergistic negative potential to improve ventricular compliance second- chronotropic and negative inotropic effects. ary to a reduction in left ventricular wall thickness. The most commonly used drugs to treat hypertrophic obstructive cardiomyopathy (HCOM) are the The post MI patient calcium antagonists and the beta-blockers. Both of Multiple studies have shown that beta-blockers these drug classes are commonly used in the treat- reduce the reinfarction rate and mortality after myo- ment of hypertension and, therefore, can be com- cardial infarction (MI).32 Similarly, ACE inhibitors bined in a patient concomitantly suffering from have been shown to be beneficial in that they pre- HCOM and hypertension. Of note, heart rate lower- vent remodeling (and thereby reduce the long-term ing calcium antagonists may have a greater benefit risk of congestive heart failure) and reduce reinfarc- than the dihydropyridines because the former pro- tion rates and even sudden death.33 In contrast to long diastole and allow better left ventricular filling. beta-blockers and ACE inhibitors, the role of cal- HCOM may, therefore, be an indication for the com- cium antagonists in the post MI patient is less well bination of a heart rate lowering calcium antagonist established. In the DAVIT II study, verapamil sig- with a beta-blocker. This combination requires care- nificantly reduced reinfarction rates when treatment ful electrocardiographic monitoring since it may began 1 to 2 weeks after the acute event.34 Similarly, lead to an AV block or unmask sick sinus syndrome. in the MDPIT study, diltiazem was shown to have some benefits in the patient with a non-Q wave 35 Coronary artery disease infarction. The effects of both verapamil and diltiazem were more pronounced in patients with hyper- Myocardial ischemia has been shown to be common tension36 and in patients without congestive heart among hypertensive patients.28,29 This may be due failure. Calcium antagonists are a heterogeneous Effects of combination therapy on the heart FH Messerli and L Michalewicz 32 group and even different galenic formulations of the mechanisms and therapy. Am J Med 1983; 75 (3A): same molecule may have significantly different 1–3. pharmacologic effects. It must be emphasized that 2 Kannel WB, Gordon T, Offutt D. Left ventricular the fact that beta-blockers, heart rate lowering cal- hypertrophy by electrocardiogram. Prevalence, inci- cium antagonists and ACE inhibitors have some dence and mortality in the Framingham Study. Ann benefit in the post MI patient, does by no means Intern Med 1969; 71: 89–105. 3 Devereux RB et al. Left ventricular mass as a predictor imply that their combination is as good or even bet- of development of hypertension. Am J Hypertens 1991; ter than monotherapy. We therefore advise caution 4: 603S–607S. when using this combination for the prevention of 4 Levy D et al. Prognostic implications of echocardio- reinfarction, although it seems reasonable to con- graphically determined left ventricular mass in the sider a low-dose combination of these agents in the Framingham Heart Study. N Engl J Med 1990; 322: patient who concomitantly is suffering from hyper- 1561–1566. ¨ tension and needs combination therapy for BP con- 5 Dahlof B, Pennert K, Hansson L. Reversal of left ven- trol. tricular hypertrophy in hypertensive patients. A meta- analysis of 109 treatment studies. Am J Hypertens 1992; 5: 95–110. Arrhythmias 6 Chalmers J. The place of combination therapy in the treatment of hypertension in 1993. Clin Exp Hypertens Hypertensive patients with LVH have a significantly [A] 1993; 15: 1299–1313. greater prevalence of premature ventricular contrac- 7 Holland OB, Kuhnert L, Campbell WB, Anderson RJ. tions and complex ventricular arrhythmias than do Synergistic effect of captopril with hydrochlorothia- 37 patients without LVH or normotensive patients. zide for treatment of low-renin hypertensive black The reduction of LVH in hypertensive patients has patients. Hypertension 1983; 5: 235–239. been shown to diminish the ventricular arrhyth- 8 Nicholson J, Resnick LM, Laragh JH. Hydrochlorothia- mias.38,39 This ‘antiarrhythmic’ effect seems to be zide is not additive to verapamil in treating essential non-specific and independent of the drug used to hypertension. Arch Intern Med 1989; 149: 125–128. reduce LVH. When treating coincidental arrhyth- 9 Aepfelbacher FC et al. Combination therapy in hyper- mias in the hypertensive patient, one should tension: observed vs predicted blood pressure remember that there are two drug classes that are reduction. Abstract. 16th Scientific Meeting of the electrophysiologically active which are commonly International Society of Hypertension. Glasgow 23–27 used to treat high BP, ie, the beta-blockers and the June 1996. 10 Weinberger MH. Blood pressure and metabolic heart rate lowering calcium antagonists. It seems responses to hydrochlorothiazide, captopril, and the logical, therefore, to consider either a heart rate low- combination in black and white mild-to-moderate ering calcium antagonist or a beta-blocker in the hypertensive patients. J Cardiovasc Pharmacol 1985; 7 hypertensive patient who is concomitantly suffering (Suppl 1): S52–S55. ¨ from symptomatic arrhythmias who needs 11 Bohlen L et al. Antihypertensive drug effects on left additional therapy for lowering of arterial pressure, ventricular hypertrophy: meta-analysis considering based on the electrophysiological indication or duration of treatment (Abstract). J Hypertens 1994; 12 contraindication. (Suppl 3): S140. 12 Cruickshank JM, Lewis J, Moore V, Dodd C. Reversi- bility of left ventricular hypertrophy by differing types Conclusions of antihypertensive therapy. J Hum Hypertens 1992; 6 (2): 85–90. Although combining drugs with different mech- 13 Schmieder RE, Martus P, Klingbeil A. Reversal of left anisms of action seems to be a reasonable and effec- ventricular hypertrophy in essential hypertension. tive way of treating hypertension, especially when JAMA 1996; 275: 1507–1513. hypertension coexists with other concomitant 14 Pfeffer MA et al. Effect of captopril on mortality and pathophysiologic conditions, effects of combination morbidity in patients with LV dysfunction after myo- therapy on the heart and specifically on hyperten- cardial infarction. Results of the survival and ventricu- sive heart disease remain poorly documented. Much lar enlargement trial. The SAVE Investigators. N Engl of what we know with regard to the effects of combi- J Med 1992; 327: 669–677. nation therapy on the heart is based on extrapolation 15 Dzau VJ. Local expression and pathophysiological role from monotherapy. Given the fact that two drugs of renin angiotensin in the blood vessels and heart. In: when used separately are beneficial in a disorder Grobecker H, Heusch G, Strauer BE (eds). Angiotensin does not necessarily mean that their combination is and Heart. Springer Verlag: New York, 1993, pp 1–14. equally or more beneficial. We therefore urge phys- 16 Gottdiener JS et al for the VA Cooperative Study Group on Antihypertensive Agents. Regression of left icians to restrain the use of combination therapy ventricular mass with monotherapy in mild-moderate primarily for the lowering of arterial pressure and hypertension: interaction of drug with systolic blood only secondarily to consider concomitant patho- pressure, age, race and weight (Abstract). Circulation physiologic conditions associated with hypertensive 1994; 90 (Suppl): I–565. ¨ heart disease. 17 Dahlof B, Hansson L. Regression of left ventricular hypertrophy in previously untreated essential hyper- References tension: different effects of enalapril and hydrochlorothiazide. J Hypertens 1992; 10: 1513–1524. ¨ 1 Messerli FH, Devereux RB. Left ventricular hypertro- 18 Dahlof B, Hansson L. The influence of antihyperten- phy: good or evil? Proceedings of a symposium: left sive therapy on the structural arteriolar changes in ventricular hypertrophy in essential hypertension— essential hypertension: different effects of enalapril Effects of combination therapy on the heart FH Messerli and L Michalewicz 33 and hydrochlorothiazide. J Intern Med 1993; 234: 30 Messerli FH. Combination antihypertensive therapy. 271–279. In: Messerli FH (ed). The ABCs of Antihypertensive 19 Gottdiener J, Reda D, Notagiacomo A, Materson B, VA Therapy, 2nd Edition, Chapter 24. Authors’ Publishing Cooperative Study Group. Comparison of monother- House and Raven Press: New York, 1994, pp 247–260. ¨ apy on LV mass regression in mild-to-moderate hyper- 31 DahlofBet al. Improved antihypertensive efficacy of tension: echocardiographic results of a multicenter the felodipine-metoprolol extended-release tablet trial (abstract). J Am Coll Cardiol 1991; 17 (Suppl A): compared with each drug alone. Blood Press 1993; 1: 178A. 37–45. 20 Grossman E, Oren S, Messerli FH. Left ventricular 32 Yusuf S et al. Beta-blockade during and after myocar- mass and cardiac function in patients with essential dial infarction. An overview of the randomized trials. hypertension. J Hum Hypertens 1994; 8: 417–421. Prog Cardiovasc Dis 1985; 27: 335–371. 21 Kannel WB et al. Role of blood pressure in the devel- 33 Pfeffer MA et al. Effect of captopril on mortality and opment of congestive heart failure. The Framingham morbidity in patients with left ventricular dysfunction Study. N Engl J Med 1972; 287 (16): 781–787. after myocardial infarction. Results of the survival and 22 Carlson WD, Gilbert EM. Carvedilol. In: Messerli FH ventricular enlargement trial. The SAVE Investigators. (ed). Cardiovascular Drug Therapy, 2nd ed. WB Saun- N Engl J Med 1992; 327: 669–677. ders: Philadelphia, 1996, pp 583–600. 34 The Danish Study Group on Verapamil in Myocardial 23 Frishman WH, Hershman D. Amlodipine. In: Messerli Infarction. Effect of verapamil on mortality and major FH (ed). Cardiovascular Drug Therapy, 2nd ed. WB events after acute myocardial infarction (The Danish Saunders: Philadelphia, 1996, pp 1024–1040. Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 24 Smith VE et al. Rapid ventricular filling in left ven- 1990; 66: 779–785. tricular hypertrophy: II. Pathologic hypertrophy. JAm 35 Moss AJ et al and the Multicenter Diltiazem Postin- Coll Cardiol 1985; 5: 869–874. farction Trial (MDPIT) Research Group. Effect of diltia- 25 White WB, Schulman P, Karimeddini MK, Smith V-E. zem on long-term outcome in post-infarction patients Regression of left ventricular mass is accompanied by with a history of hypertension (abstract). Circulation improvement in rapid left ventricular filling following 1989; 80 (Suppl II): II–268. antihypertensive therapy with metoprolol. Am Heart J 36 Messerli FH, Boden WE, Fischer Hansen J, Schecht- 1989; 117: 145–150. 26 Wikstrand J. Left ventricular function in early primary man B. Heart rate lowering calcium antagonists (HRL- hypertension. Functional consequences of cardio- CA) in hypertensive post MI patients. (abstract). Sup- vascular structural changes. Hypertension 1984; 6 (6 plement to Journal of the American College of Cardi- pt 2): III108–III116. ology, 45th Annual Scientific Session, Orlando, Flor- 27 Opie LH. ACE inhibitors and the heart. Angiotensin- ida, March 24–27, 1996. Converting Enzyme Inhibitors: Scientific Basis For 37 Messerli FH et al. Hypertension and sudden death: Clinical Use, 2nd ed. Wiley-Liss: New York, 1994, increased ventricular ectopic activity in left ventricu- pp 94–97. lar hypertrophy. Am J Med 1984; 77: 18–22. 28 Kannel WB, Gordon T, Castelli WP, Margolis JR. Elec- 38 Messerli FH et al. Hypertension and sudden death. trocardiographic left ventricular hypertrophy and risk Disparate effects of calcium entry blocker and diuretic of coronary heart disease. The Framingham Study. therapy on cardiac dysrhythmias. Arch Intern Med Ann Intern Med 1970; 72: 813–822. 1989; 149 (Suppl 6): 1263–1267. ´ ´ 29 Strauer BE. Left ventricular hypertrophy, myocardial 39 Gonzales-Fernandez RA et al. Prevalence of ectopic blood flow and coronary reserve. Cardiology 1992; 81: ventricular activity after left ventricular mass 274–282. regression. Am J Hypertens 1993; 6 (Suppl): 308–313.