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Experience with calcium antagonist drugs in congestive heart failure
Experiencewith CalciumAntagonist Drugs in CongestiveHeart Failure ROBERT
A.
O’ROURKE,
MD,
Several clinical studies have demonstrated beneficial hemodynamic effects of calcium antagonist drugs when used as arterial vasodilators in the treatment of certain patients with moderate to severe congestive heart failure. These drugs usually decrease systemic vascular resistance and improve ejection phase indexes of left ventricular function in
and
RICHARD
A.
WALSH,
MD
such patients. However, calcium antagonists have intrinsic negative inotropic effects and other vasodilators such as nitroprusside, hydralazine and captopril appear to be more beneficial when used in the treatment of severe congestive heart failure. (Am J Cardiol 1987;59:846-896)
J
trations.gJOWe studied the differential effects of intravenous, equimolar, equihypotensive doses of nifedipine, verapamil, and diltiazem on LV performance in healthy, unsedated, preinstrumented dogs;4we sought to separate their direct myocardial effects from reflex and peripheral actions by using intracoronary equimolar drug administration in additional animals. With
ustifiable caution exists regarding the use of the calcium antagonist drugs in patients with depressed left ventricular (LV) performance because of their potentially negative inotropic properties. Nevertheless, these arterial vasodilators have improved symptoms and hemodynamic parameters in some patients with congestive heart failure (CHF]. The calcium antagonists are structurally heterogeneous compounds that share 3 basic hemodynamic characteristics to different degrees. These include peripheral and coronary artery vasodilation, reflex sympathetic stimulation and myocardial depression. Iv2 The first 2 factors tend to augment LV performance and moderate or abrogate drug-induced negative inotropism under usual circumstance&3 [Fig. 1). However, the overall cardiovascular effects of such drugs may vary depending on the calcium antagonist, 4,5the dose, the use of concomitant cardioactive drugs617and the hemodynamic status of the patient8
Potential Effects of The Calcium Entry Blockers Upon Left Ventricular Performance
Effectsof CalciumAntagonists on left VentricularPerformance
LV Performance
In vitro studies assessing the direct effects of these agents on isolated papillary muscles have shown that nifedipine has the most potent and diltiazem the least potent negative inotropic properties of the 3 available calcium antagonists when given in equimolar concenFrom the Division of Cardiology. the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas. Address for reprints: Robert A. O’Rourke, MD, Division of Cardiology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284.
FIGURE 1. Differential effects of the available calcium antagonists on the major determinants of left ventricular (LV) function. D = diltiazem; N = nifedipine; V = verapamil. Reproduced with permission from Curr Prob Cardiol.* 648
January 30. 1987
equivalent dose-related decrements in arterial pressure and increases in heart rate, intravenous nifedipine and verapamil, but not diltiazem, depressed LV function. Both equimolar nifedipine and verapamil reduced the rate of LV pressure development and the extent of LV chamber shortening. By contrast, intravenous equimolar diltiazem produced no change in either index of LV function, even after pretreatment with full P-blocking doses of propranolol.” Moreover, intracoronary administration of equimolar calcium antagonists produced dose-related decreases in percent of regional myocardial shortening, which were most marked with nifedipine and least marked with diltiazem.” In subsequent studies in the same animal model, using clinically relevant, equihypotensive, but not equimolar, doses of the calcium antagonists, we showed that verapamil [not nifedipine) had the most potent and diltiazem the least potent negative inotropit effect of such available agents’l Despite reports of acute pulmonary edema after intravenous verapamil12 and severe hypotension with reduced cardiac output after oral nifedipine,13-l7 several clinical studies showing beneficial effects of calcium antagonism as vasodilator therapy for patients with CHF have been reported.8,18m2i
Studies with Nifedipine in Heart Failure The salutary effects of nifedipine in the treatment of certain patients with CHF have been demonstrated in several clinical studies.8~18~‘1 However, problems regarding patient selection and the use of a single acute dose of nifedipine preclude extrapolation of these data to the subacute or chronic administration of calcium antagonist drugs to patients with heart failure caused by depressed myocardial function. In addition, acute pulmonary edema and hypotension with reduced cardiac output after sublingual and oral nifedipine have been reported.13m17 In patients with impaired LV performance, the acute administration of sublingual or oral nifedipine
FIGURE 2. A, effects of intravenous verapamil on left ventricular ejection fraction (EF) and mean rate of internal dimension shortening (VCF); 6, effects on mean pulmonary artery pressure (PAP), mean pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance (PVR). Reproduced with permission from Am J Cardiol.
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reduces systemic vascular resistance, improves cardiac output, augments ejection phase indexes of ventricular function and tends to lower LV end-diastolic pressure and volume, particularly in patients with abnormally high pretreatment levels8 Thus, nifedipine produces important clinically favorable effects due predominantly to a reduction in LV afterload in patients with impaired LV function. Importantly, Matsui et aP were unable to demonstrate sustained hemodynamic improvement after 24 hours of oral nifedipine given at 4-hour intervals in patients with depressed LV function, even though a decrease in systemic vascular resistance and an increase in cardiac output were noted after the initial dose. The acute administration of nifedipine was associated with either no change or modest increases in heart rate, in contrast to the significant decreases in heart rate observed after acute intravenous and shortterm oral diltiazem in similar patient groups. These data suggest that, at least acutely, sublingual or oral nifedipine can produce beneficial hemodynamic effects by afterload reduction and reflex fi-adrenergic stimulation, even in patients with clinically advanced CHF. Whether these effects are sustained after subacute or short-term drug therapy is uncertain and reports of cardiac failure associated with nifedipine, both with6.iG and withoutt7 concomitant P-adrenergic blockade, have appeared.
Studies with Verapamil in Heart Failure Short-term studies of the effects of verapamil in patients with normal or mildly reduced LV function have demonstrated peripheral systemic vasodilation associated with a modest improvement of systolic function2s In a study of 14 patients with CHF (New York Heart Association class III to IV], Ferlinz and Citron showed that intravenous verapamil decreased the systemic vascular resistance by ETO, improved LV ejection fraction by 8 units (Fig. 2A) and increased stroke volume index by 27%. However, there was no
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significant improvement in cardiac index or in elevated LV end-diastolic pressure (Fig. ZB). Moreover, both Singh and Rochez4 and Lewis et alz5 reported decreases in LV dP/dt associated with increments in LV end-diastolic pressure in patients after intravenous verapamil. More recently, Chew et all2 reported verapamil-induced decreases in mean arterial pressure, decreases in stroke volume index and abrupt increases in mean pulmonary wedge pressure associated with clinical evidence of heart failure in 3 patients with severely reduced pretreatment ejection fractions and mean pulmonary capillary wedge pressures >20 mm Hg. These data indicate that verapamil may cause frank deterioration in LV performance in patients with severe CHF.
Studieswith Diltiazemin Heartfailure We examined the effects of intravenous and highdose oral (360 mg daily) diltiazem on LV performance in patients with severe CHF due to ischemic or dilated cardiomyopathy .26The patient group had New York Heart Association class III to IV CHF despite maximum medical management, with a mean LV biplane ejection fraction of 26% and a mean pulmonary capillary wedge pressure of 29 mm Hg. Control data for the group before intravenous diltiazem included heart rate 97 f 18 (standard deviation) beats/min, mean arterial pressure 95 f 13 mm Hg, pulmonary capillary wedge pressure 29 f 9 mm Hg, cardiac index 2.05 f 0.8 liters/min/m2 and LV enddiastolic volume index 196 f 46 ml. There were no significant differences in control hemodynamic values between the intravenous and oral phases of the investigation. The effect of intravenous diltiazem on the rate of LV pressure development (dP/dt,,,) was evaluated in 6 patients (Fig. 3). There was no significant change in dP/dt,,, from control for the group during 5, 10 or 20 minutes of drug infusion. However, dP/dt,,, was re-
T= I S.D.
OPPORTUNITIES
duced in 2 of the 6 patients during intravenous diltiazem administration. Systemic vascular resistance decreased by 34% from 2,465 f 410 to 1,637 f 460 dynes/s/cmm5 (p
ComparativeStudiesof CalciumAntagonists fN.S.+
”
Control
20 min I.V. Diltiazem
FIGURE 3.Effecls of intravenous dilliazem on left ventricular dP/dt. Reproduced with permission from JACC.26
(LV)
More recently, Packer et alz7 compared the hemodynamic effects of 90-mg oral diltiazem and 20-mg oral nifedipine in 21 patients with LV dysfunction in a random order on alternate days. As systemic vascular resistance decreased, both diltiazem and nifedipine produced similar small increments in stroke volume index (8% to 12%) without notable changes in LV filling pressure. Heart rate decreased with diltiazem but not with nifedipine. These effects occurred at the expense of a dramatic decrease of 26% in mean arterial pressure with nifedipine; LV stroke work index decreased by 27% with nifedipine but not with diltiazem despite
January 30. 1987
a greater decrease in systemic vascular resistance with nifedipine. Six of the 21 patients (29%) were worse clinically with nifedipine and only one with diltiazem. These data suggest that diltiazem has less depressant effects on myocardial contractility than nifedipine in patients with LV dysfunction.
CalciumAntagonistsCompared with OtherVasodilators We have compared the hemodynamic effects of diltiazem with those of nitroprusside, a conventional vasodilator, in the awake preinstrumented dog before and after the production of experimental chronic volume overload and CHF by creation of an infrarenal aortocaval fistula.28 Diltiazem had no effect on ventricular preload either before or after chronic volume overloading. Left ventricular dP/dt,,, was also unaffected by diltiazem before the aortocaval fistula but was significantly reduced by diltiazem after the chronic volume overload. By contrast, at matched aortic pressures, nitroprusside significantly reduced LV enddiastolic size and pressure in the same animals before and after chronic volume overload without altering dP/dt,,,,. We concluded from these studies that calcium antagonists, unlike conventional vasodilators, may depress LV function in CHF by direct negative inotropit properties in doses that do not depress ventricular performance in the presence of normal pretreatment ventricular function, Recently, Elkayam et a12gs30 compared the hemodynamic responses to nifedipine and nitroprusside in 1 group of 11 patients with severe chronic CHF and to nifedipine and hydralazine in a second group of 15 similar patients. In the former studies, the doses of oral nifedipine and intravenous nitroprusside chosen produced similar decreases in systemic vascular resistance (Fig. 5).2gHowever, nifedipine caused a smaller increase in cardiac index and a larger decrease in mean blood pressure than nitroprusside. Moreover, nifedipine produced a smaller decrease in LV filling
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pressure and did not cause a similar decrease in right atria1 pressure as did nitroprusside; LV stroke work index increased with nitroprusside but not with nifedipine. When nifedipine and hydralazine were compared by the same investigators, 11 of 15 patients had the same hemodynamic responses to the 2 drugs.“O However, nifedipine caused a smaller increment in stroke volume index, cardiac index and stroke work index compared with hydralazine. In the remaining 4 patients, whose systemic vascular resistance was not reduced by at least 25% with nifedipine, the hemodynamic status actually worsened. Thus, hydralazine appeared better than nifedipine for reducing LV afterload in patients with severe CHF. More recently, Agostoni et a131compared the effects of nifedipine (20 mg 3 times daily] and captopril (50 mg 3 times daily] when added to standard therapy in a double-blind, crossover trial in 18 patients with dilated cardiomyopathy. At the end of 8 weeks of treatment with each agent, New York Heart Association functional class rating symptoms and exercise tolerance times improved with captopril but not with nifedipine. The 8-week pulmonary capillary wedge pressure was significantly decreased and the cardiac output significantly improved only with captopril therapy. Although there were similar decreases in systemic vascular resistance at 8 weeks of therapy with each drug, only captopril reduced LV size and wall stress. These results suggest that nifedipine and captopril have different effects on afterload and contractility and that captopril is the superior drug for the treatment of severe CHF.
ClinicalImplications Although the calcium antagonist drugs decrease systemic vascular resistance and improve ejection phase indexes of LV performance in many patients with CHF, they have intrinsic negative inotropic properties. Other vasodilators appear to be more benefi-
B P< 001 w
P
50
1 Pi 001 ’ N=8
PS 01
’
’
N=?
’
I
I
Cl
20 min
lnir0venous DllllOZ~~ (I3#AqIkglmm)
FIGURE 4. Relative effects of intravenous and oral diltiazem on systemic vascular resistance, in patients with severe heart failure. Reproduced with permission from JACC.26
CZ
24 hr
OVA Ddtlozem (360mg/24hrl
A, stroke volume index, B, and heart rate, C,
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SW1 (g.m/m2)
PAW
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(mm Hg)
25 20 -
Cl
c2
N NP
N NP
SVR (dynes.sec.cm-5)
RA (mm t-ig) 25 20 -
l PC0 **PC0 + P’O
05 05 05
Vr Cl vs c2 Vs N
FIGURE 5. Effects of oral nlfedipine (N) and intravenous nitroprusside (NP) on stroke work index (SWI), pulmonary artery wedge (PAW) pressure, right atrlal (RA) pressure and systemic vascular resistance (SVR). Control values before N(C,) and before NP(&) were not dlfferent. Reproduced with permisslon from Am J Cardiol.29
15 10 5OL
’ Cl
’ c2
1
1
N NP
500 I Cl
c2
N NP
cial. Of the calcium antagonists studied thus far in patients with severe CHF, diltiazem appears to be the less likely to produce detrimental effects. The determinants of myocardial oxygen are favorably influenced by calcium antagonists in the absence of any significant drug-induced negative inotropic effects. It should be emphasized that the favorable hemodynamic actions observed in several small patient groups do not preclude the possibility of adverse hemodynamic or electrophysiologic effects in an individual patient. Until more experience is gained, all calcium antagonist agents should be used with caution in patients with LV dysfunction. Clearly, additional studies are needed to demonstrate potential long-term hemodynamic benefits and further delineate the pharmacokinetics of these agents in CHF. It is unlikely that calcium antagonists will replace vasodilators with no direct negative inotropic effects for the chronic treatment of most patients with moderate to severe CHF.
References 1. Fleckenstein A. Specific pharmacology of calcium in myocordium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxic01 1977;17:149-165. 2. McCall D. Walsh RA, Frohlich ED, O’Rourke RA. Calcium entry blocking drugs: mechanisms of action, experimental studies and clinical uses. Curr Probl Cardiol 1985;10:1-80. 3. Fabiato A, Fabiato F. Calcium and cardiac excitation contraction coupling. Annu Rev Physiol 1979;41:473-484. 4. Walsh RA, Badke FR, O’Rourke RA. Differential effects of systemic and intracoronary calcium channel blocking agents on global and regional left ventricular function in conscious dogs. Am Heart J 1981;102:341-350. 5. Nakaya H. Schwartz A, Millard R. Reflex chronotropic and inotropic effects of calcium channel blocking agents in conscious dogs. Circ Res 19t?3;52:302-311, 6. Joshi PL, Dalal JJ,Ruttky MS, Sheridan DJ. Henderson AH. Nifedipine and left ventricular function in beta blocked patients. Br Heart J 1981;45:457-459. 7. Kieval J, Kirotein E, Kessler K, Mallon SM, Myerburg RJ. The effects of
intravenous verapamif on hemodynamic status of patients with coronary artery disease receiving propranolol, Circulation 1982;65:653-658. 8. Ludbrook PA, Tieffenbrunn A, Reed FR, Sobel B. Acute hemodynamic responses to sublingual nifedipine: dependence of left ventricular function. Circulation 1982:65:489-498. 9. Schwartz A, Taiora N, eds. Symposium on calcium channel blocking drugs: a novel intervention for the treatment of cardiac disease. Circ Res 1983; 52:suppl l:l-18. 10. Henry PD. Comparative pharmacology of calcium antagonists: nifedipine. verapamil, diltiazem. Am J Cardiol 1980;46:1047-1058. 11. Walsh RA, O’Rourke RA. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest 1985;75:1426-1434. 12. Chew C, Hecht H. Colett J, McCallister R, Singh B. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;47:917-922. 13. Anastassiades CJ. Nifedipine and beta-blocker drugs. Br Med J 1980;281: 1251-1252. 14. Opie LH, White DA. Adverse interaction between nifedipine and beta
blockade. Br Med J 1980;218:1462. 15. Staffurth JS, Emery P. Adverse interaction between nifedipine and beta blockade. Br Med J 1981;282:225. 16. Robson RH. Vishwanath MC. Nifedipine and beta-blockade as a cause of cardiac failure. Br Med J 1982;284:104. 17. Gilmer DJ, Kark P. Pulmonary edema precipitated by nifedipine. Br Med J 1980;280:1420-1421. 18. Klugman S. Salvi A, Camerini F. Hemodynamic effect of nifedipine in heart failure. Br Heart J 1980;43:440-446. 19. Matsumoto S, Ito T, Sada T, Takahashi M, Su K, Veda A, Okabe F, Sate M, Sekine I, Ito Y. Hemodynamic effects of nifedipine in congestive heart failure. Am J Cardiol 1980;46:476-480. 20. Polese A, Fiorentini C. Olivara MT, Cuazzi MD. Clinical use of a calcium antagonistic agent [nifedipine) in acute pulmonary edema. Am J Med 1979;66:825-830, 21. Fioretti P. Benussi B, Scardi S, Klugman S, Brower RW. Afterload reduction with nifedipine in aortic insufficiency. Am J Cardiol I982;49:1728-1732. 22. Matsui S, Marakami E, Takekoshi N, Hiramaru Y, Murakami H. Kitano E. Masuya K, Saga T, Nomura M, Fujitas S, Tsuji S. Hemodynamic effects of sublingual nifedipine in congestive heart failure. Jpn Circ f 1979;43:1081-1088. 23. Ferlinz J, Easthope J, Aronow W. Effects of verapamil on myocardial performance in coronary disease. Circulation I979;59:313-319. 24. Singh 8, Roche AH. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977;94:593-599. 25. Lewis BS. Mitha AS, Go&man MS. Immediate hemodynamic effects of verapamil in man. Cardiology 1976;60:366-376. 26. Walsh RA. Porter CB, Starling MR, O’Rourke RA. Beneficial hemody-
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nomic effects of intravenous and oral diltiazem in severe congestive heart failure. JACC 1984;3:1044-1050. 27. Packer M. Lee WH, Medina N, Yusak M. Comparative negative inotropic effects of nifedipine and diltiozem in potients with severe left ventricular dysfunction [abstr]. Circulation 1985;72:suppl III:275. 28. Porter CB. Walsh RA, Badke FR. O’Rourke RA. Differential effects of diltiozem and nitroprusside on left ventricular function in experimental chronic volume overload. Circulation 1983;68:685-692, 29. Elkayam U, Weber L, Torkan B, McKay CR, Rahimtoola S. Comparison of
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hemodynamic responses to nifedipine and nitroprusside in severe chronic congestive heart failure. Am J Cardiol 1984:53:13X-1325. 30. Elkayam U, Weber L, McKay CR, Turkan 9, Rahimtoola S. Differences in hemodynomic response to vosodilation due to calcium channel antagonism with nifedipine and direct-acting ogonism with hydralozine in chronic refractory congestive heart failure. Am J Cardiol 1984;54:126-131. 31. Agostoni PG, De Cesare N, Doria E, Polese A, Tamorini G, Guazzi MD. Afterload reduction: o comparison of coptopril and nifedipine in dilated cardiomyopathy. Br Heart J 1986:55:391-399.
A.
O’ROURKE,
MD,
Several clinical studies have demonstrated beneficial hemodynamic effects of calcium antagonist drugs when used as arterial vasodilators in the treatment of certain patients with moderate to severe congestive heart failure. These drugs usually decrease systemic vascular resistance and improve ejection phase indexes of left ventricular function in
and
RICHARD
A.
WALSH,
MD
such patients. However, calcium antagonists have intrinsic negative inotropic effects and other vasodilators such as nitroprusside, hydralazine and captopril appear to be more beneficial when used in the treatment of severe congestive heart failure. (Am J Cardiol 1987;59:846-896)
J
trations.gJOWe studied the differential effects of intravenous, equimolar, equihypotensive doses of nifedipine, verapamil, and diltiazem on LV performance in healthy, unsedated, preinstrumented dogs;4we sought to separate their direct myocardial effects from reflex and peripheral actions by using intracoronary equimolar drug administration in additional animals. With
ustifiable caution exists regarding the use of the calcium antagonist drugs in patients with depressed left ventricular (LV) performance because of their potentially negative inotropic properties. Nevertheless, these arterial vasodilators have improved symptoms and hemodynamic parameters in some patients with congestive heart failure (CHF]. The calcium antagonists are structurally heterogeneous compounds that share 3 basic hemodynamic characteristics to different degrees. These include peripheral and coronary artery vasodilation, reflex sympathetic stimulation and myocardial depression. Iv2 The first 2 factors tend to augment LV performance and moderate or abrogate drug-induced negative inotropism under usual circumstance&3 [Fig. 1). However, the overall cardiovascular effects of such drugs may vary depending on the calcium antagonist, 4,5the dose, the use of concomitant cardioactive drugs617and the hemodynamic status of the patient8
Potential Effects of The Calcium Entry Blockers Upon Left Ventricular Performance
Effectsof CalciumAntagonists on left VentricularPerformance
LV Performance
In vitro studies assessing the direct effects of these agents on isolated papillary muscles have shown that nifedipine has the most potent and diltiazem the least potent negative inotropic properties of the 3 available calcium antagonists when given in equimolar concenFrom the Division of Cardiology. the Department of Medicine, University of Texas Health Science Center, San Antonio, Texas. Address for reprints: Robert A. O’Rourke, MD, Division of Cardiology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284.
FIGURE 1. Differential effects of the available calcium antagonists on the major determinants of left ventricular (LV) function. D = diltiazem; N = nifedipine; V = verapamil. Reproduced with permission from Curr Prob Cardiol.* 648
January 30. 1987
equivalent dose-related decrements in arterial pressure and increases in heart rate, intravenous nifedipine and verapamil, but not diltiazem, depressed LV function. Both equimolar nifedipine and verapamil reduced the rate of LV pressure development and the extent of LV chamber shortening. By contrast, intravenous equimolar diltiazem produced no change in either index of LV function, even after pretreatment with full P-blocking doses of propranolol.” Moreover, intracoronary administration of equimolar calcium antagonists produced dose-related decreases in percent of regional myocardial shortening, which were most marked with nifedipine and least marked with diltiazem.” In subsequent studies in the same animal model, using clinically relevant, equihypotensive, but not equimolar, doses of the calcium antagonists, we showed that verapamil [not nifedipine) had the most potent and diltiazem the least potent negative inotropit effect of such available agents’l Despite reports of acute pulmonary edema after intravenous verapamil12 and severe hypotension with reduced cardiac output after oral nifedipine,13-l7 several clinical studies showing beneficial effects of calcium antagonism as vasodilator therapy for patients with CHF have been reported.8,18m2i
Studies with Nifedipine in Heart Failure The salutary effects of nifedipine in the treatment of certain patients with CHF have been demonstrated in several clinical studies.8~18~‘1 However, problems regarding patient selection and the use of a single acute dose of nifedipine preclude extrapolation of these data to the subacute or chronic administration of calcium antagonist drugs to patients with heart failure caused by depressed myocardial function. In addition, acute pulmonary edema and hypotension with reduced cardiac output after sublingual and oral nifedipine have been reported.13m17 In patients with impaired LV performance, the acute administration of sublingual or oral nifedipine
FIGURE 2. A, effects of intravenous verapamil on left ventricular ejection fraction (EF) and mean rate of internal dimension shortening (VCF); 6, effects on mean pulmonary artery pressure (PAP), mean pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance (PVR). Reproduced with permission from Am J Cardiol.
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reduces systemic vascular resistance, improves cardiac output, augments ejection phase indexes of ventricular function and tends to lower LV end-diastolic pressure and volume, particularly in patients with abnormally high pretreatment levels8 Thus, nifedipine produces important clinically favorable effects due predominantly to a reduction in LV afterload in patients with impaired LV function. Importantly, Matsui et aP were unable to demonstrate sustained hemodynamic improvement after 24 hours of oral nifedipine given at 4-hour intervals in patients with depressed LV function, even though a decrease in systemic vascular resistance and an increase in cardiac output were noted after the initial dose. The acute administration of nifedipine was associated with either no change or modest increases in heart rate, in contrast to the significant decreases in heart rate observed after acute intravenous and shortterm oral diltiazem in similar patient groups. These data suggest that, at least acutely, sublingual or oral nifedipine can produce beneficial hemodynamic effects by afterload reduction and reflex fi-adrenergic stimulation, even in patients with clinically advanced CHF. Whether these effects are sustained after subacute or short-term drug therapy is uncertain and reports of cardiac failure associated with nifedipine, both with6.iG and withoutt7 concomitant P-adrenergic blockade, have appeared.
Studies with Verapamil in Heart Failure Short-term studies of the effects of verapamil in patients with normal or mildly reduced LV function have demonstrated peripheral systemic vasodilation associated with a modest improvement of systolic function2s In a study of 14 patients with CHF (New York Heart Association class III to IV], Ferlinz and Citron showed that intravenous verapamil decreased the systemic vascular resistance by ETO, improved LV ejection fraction by 8 units (Fig. 2A) and increased stroke volume index by 27%. However, there was no
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significant improvement in cardiac index or in elevated LV end-diastolic pressure (Fig. ZB). Moreover, both Singh and Rochez4 and Lewis et alz5 reported decreases in LV dP/dt associated with increments in LV end-diastolic pressure in patients after intravenous verapamil. More recently, Chew et all2 reported verapamil-induced decreases in mean arterial pressure, decreases in stroke volume index and abrupt increases in mean pulmonary wedge pressure associated with clinical evidence of heart failure in 3 patients with severely reduced pretreatment ejection fractions and mean pulmonary capillary wedge pressures >20 mm Hg. These data indicate that verapamil may cause frank deterioration in LV performance in patients with severe CHF.
Studieswith Diltiazemin Heartfailure We examined the effects of intravenous and highdose oral (360 mg daily) diltiazem on LV performance in patients with severe CHF due to ischemic or dilated cardiomyopathy .26The patient group had New York Heart Association class III to IV CHF despite maximum medical management, with a mean LV biplane ejection fraction of 26% and a mean pulmonary capillary wedge pressure of 29 mm Hg. Control data for the group before intravenous diltiazem included heart rate 97 f 18 (standard deviation) beats/min, mean arterial pressure 95 f 13 mm Hg, pulmonary capillary wedge pressure 29 f 9 mm Hg, cardiac index 2.05 f 0.8 liters/min/m2 and LV enddiastolic volume index 196 f 46 ml. There were no significant differences in control hemodynamic values between the intravenous and oral phases of the investigation. The effect of intravenous diltiazem on the rate of LV pressure development (dP/dt,,,) was evaluated in 6 patients (Fig. 3). There was no significant change in dP/dt,,, from control for the group during 5, 10 or 20 minutes of drug infusion. However, dP/dt,,, was re-
T= I S.D.
OPPORTUNITIES
duced in 2 of the 6 patients during intravenous diltiazem administration. Systemic vascular resistance decreased by 34% from 2,465 f 410 to 1,637 f 460 dynes/s/cmm5 (p
ComparativeStudiesof CalciumAntagonists fN.S.+
”
Control
20 min I.V. Diltiazem
FIGURE 3.Effecls of intravenous dilliazem on left ventricular dP/dt. Reproduced with permission from JACC.26
(LV)
More recently, Packer et alz7 compared the hemodynamic effects of 90-mg oral diltiazem and 20-mg oral nifedipine in 21 patients with LV dysfunction in a random order on alternate days. As systemic vascular resistance decreased, both diltiazem and nifedipine produced similar small increments in stroke volume index (8% to 12%) without notable changes in LV filling pressure. Heart rate decreased with diltiazem but not with nifedipine. These effects occurred at the expense of a dramatic decrease of 26% in mean arterial pressure with nifedipine; LV stroke work index decreased by 27% with nifedipine but not with diltiazem despite
January 30. 1987
a greater decrease in systemic vascular resistance with nifedipine. Six of the 21 patients (29%) were worse clinically with nifedipine and only one with diltiazem. These data suggest that diltiazem has less depressant effects on myocardial contractility than nifedipine in patients with LV dysfunction.
CalciumAntagonistsCompared with OtherVasodilators We have compared the hemodynamic effects of diltiazem with those of nitroprusside, a conventional vasodilator, in the awake preinstrumented dog before and after the production of experimental chronic volume overload and CHF by creation of an infrarenal aortocaval fistula.28 Diltiazem had no effect on ventricular preload either before or after chronic volume overloading. Left ventricular dP/dt,,, was also unaffected by diltiazem before the aortocaval fistula but was significantly reduced by diltiazem after the chronic volume overload. By contrast, at matched aortic pressures, nitroprusside significantly reduced LV enddiastolic size and pressure in the same animals before and after chronic volume overload without altering dP/dt,,,,. We concluded from these studies that calcium antagonists, unlike conventional vasodilators, may depress LV function in CHF by direct negative inotropit properties in doses that do not depress ventricular performance in the presence of normal pretreatment ventricular function, Recently, Elkayam et a12gs30 compared the hemodynamic responses to nifedipine and nitroprusside in 1 group of 11 patients with severe chronic CHF and to nifedipine and hydralazine in a second group of 15 similar patients. In the former studies, the doses of oral nifedipine and intravenous nitroprusside chosen produced similar decreases in systemic vascular resistance (Fig. 5).2gHowever, nifedipine caused a smaller increase in cardiac index and a larger decrease in mean blood pressure than nitroprusside. Moreover, nifedipine produced a smaller decrease in LV filling
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pressure and did not cause a similar decrease in right atria1 pressure as did nitroprusside; LV stroke work index increased with nitroprusside but not with nifedipine. When nifedipine and hydralazine were compared by the same investigators, 11 of 15 patients had the same hemodynamic responses to the 2 drugs.“O However, nifedipine caused a smaller increment in stroke volume index, cardiac index and stroke work index compared with hydralazine. In the remaining 4 patients, whose systemic vascular resistance was not reduced by at least 25% with nifedipine, the hemodynamic status actually worsened. Thus, hydralazine appeared better than nifedipine for reducing LV afterload in patients with severe CHF. More recently, Agostoni et a131compared the effects of nifedipine (20 mg 3 times daily] and captopril (50 mg 3 times daily] when added to standard therapy in a double-blind, crossover trial in 18 patients with dilated cardiomyopathy. At the end of 8 weeks of treatment with each agent, New York Heart Association functional class rating symptoms and exercise tolerance times improved with captopril but not with nifedipine. The 8-week pulmonary capillary wedge pressure was significantly decreased and the cardiac output significantly improved only with captopril therapy. Although there were similar decreases in systemic vascular resistance at 8 weeks of therapy with each drug, only captopril reduced LV size and wall stress. These results suggest that nifedipine and captopril have different effects on afterload and contractility and that captopril is the superior drug for the treatment of severe CHF.
ClinicalImplications Although the calcium antagonist drugs decrease systemic vascular resistance and improve ejection phase indexes of LV performance in many patients with CHF, they have intrinsic negative inotropic properties. Other vasodilators appear to be more benefi-
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’
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’
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I
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FIGURE 4. Relative effects of intravenous and oral diltiazem on systemic vascular resistance, in patients with severe heart failure. Reproduced with permission from JACC.26
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24 hr
OVA Ddtlozem (360mg/24hrl
A, stroke volume index, B, and heart rate, C,
688
A SYMPOSIUM:
CALCIUM
ANTAGONISTS-EMERGING
SW1 (g.m/m2)
PAW
CLINICAL
OPPORTUNITIES
(mm Hg)
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N NP
SVR (dynes.sec.cm-5)
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FIGURE 5. Effects of oral nlfedipine (N) and intravenous nitroprusside (NP) on stroke work index (SWI), pulmonary artery wedge (PAW) pressure, right atrlal (RA) pressure and systemic vascular resistance (SVR). Control values before N(C,) and before NP(&) were not dlfferent. Reproduced with permisslon from Am J Cardiol.29
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cial. Of the calcium antagonists studied thus far in patients with severe CHF, diltiazem appears to be the less likely to produce detrimental effects. The determinants of myocardial oxygen are favorably influenced by calcium antagonists in the absence of any significant drug-induced negative inotropic effects. It should be emphasized that the favorable hemodynamic actions observed in several small patient groups do not preclude the possibility of adverse hemodynamic or electrophysiologic effects in an individual patient. Until more experience is gained, all calcium antagonist agents should be used with caution in patients with LV dysfunction. Clearly, additional studies are needed to demonstrate potential long-term hemodynamic benefits and further delineate the pharmacokinetics of these agents in CHF. It is unlikely that calcium antagonists will replace vasodilators with no direct negative inotropic effects for the chronic treatment of most patients with moderate to severe CHF.
References 1. Fleckenstein A. Specific pharmacology of calcium in myocordium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxic01 1977;17:149-165. 2. McCall D. Walsh RA, Frohlich ED, O’Rourke RA. Calcium entry blocking drugs: mechanisms of action, experimental studies and clinical uses. Curr Probl Cardiol 1985;10:1-80. 3. Fabiato A, Fabiato F. Calcium and cardiac excitation contraction coupling. Annu Rev Physiol 1979;41:473-484. 4. Walsh RA, Badke FR, O’Rourke RA. Differential effects of systemic and intracoronary calcium channel blocking agents on global and regional left ventricular function in conscious dogs. Am Heart J 1981;102:341-350. 5. Nakaya H. Schwartz A, Millard R. Reflex chronotropic and inotropic effects of calcium channel blocking agents in conscious dogs. Circ Res 19t?3;52:302-311, 6. Joshi PL, Dalal JJ,Ruttky MS, Sheridan DJ. Henderson AH. Nifedipine and left ventricular function in beta blocked patients. Br Heart J 1981;45:457-459. 7. Kieval J, Kirotein E, Kessler K, Mallon SM, Myerburg RJ. The effects of
intravenous verapamif on hemodynamic status of patients with coronary artery disease receiving propranolol, Circulation 1982;65:653-658. 8. Ludbrook PA, Tieffenbrunn A, Reed FR, Sobel B. Acute hemodynamic responses to sublingual nifedipine: dependence of left ventricular function. Circulation 1982:65:489-498. 9. Schwartz A, Taiora N, eds. Symposium on calcium channel blocking drugs: a novel intervention for the treatment of cardiac disease. Circ Res 1983; 52:suppl l:l-18. 10. Henry PD. Comparative pharmacology of calcium antagonists: nifedipine. verapamil, diltiazem. Am J Cardiol 1980;46:1047-1058. 11. Walsh RA, O’Rourke RA. Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs. J Clin Invest 1985;75:1426-1434. 12. Chew C, Hecht H. Colett J, McCallister R, Singh B. Influence of severity of ventricular dysfunction on hemodynamic responses to intravenously administered verapamil in ischemic heart disease. Am J Cardiol 1981;47:917-922. 13. Anastassiades CJ. Nifedipine and beta-blocker drugs. Br Med J 1980;281: 1251-1252. 14. Opie LH, White DA. Adverse interaction between nifedipine and beta
blockade. Br Med J 1980;218:1462. 15. Staffurth JS, Emery P. Adverse interaction between nifedipine and beta blockade. Br Med J 1981;282:225. 16. Robson RH. Vishwanath MC. Nifedipine and beta-blockade as a cause of cardiac failure. Br Med J 1982;284:104. 17. Gilmer DJ, Kark P. Pulmonary edema precipitated by nifedipine. Br Med J 1980;280:1420-1421. 18. Klugman S. Salvi A, Camerini F. Hemodynamic effect of nifedipine in heart failure. Br Heart J 1980;43:440-446. 19. Matsumoto S, Ito T, Sada T, Takahashi M, Su K, Veda A, Okabe F, Sate M, Sekine I, Ito Y. Hemodynamic effects of nifedipine in congestive heart failure. Am J Cardiol 1980;46:476-480. 20. Polese A, Fiorentini C. Olivara MT, Cuazzi MD. Clinical use of a calcium antagonistic agent [nifedipine) in acute pulmonary edema. Am J Med 1979;66:825-830, 21. Fioretti P. Benussi B, Scardi S, Klugman S, Brower RW. Afterload reduction with nifedipine in aortic insufficiency. Am J Cardiol I982;49:1728-1732. 22. Matsui S, Marakami E, Takekoshi N, Hiramaru Y, Murakami H. Kitano E. Masuya K, Saga T, Nomura M, Fujitas S, Tsuji S. Hemodynamic effects of sublingual nifedipine in congestive heart failure. Jpn Circ f 1979;43:1081-1088. 23. Ferlinz J, Easthope J, Aronow W. Effects of verapamil on myocardial performance in coronary disease. Circulation I979;59:313-319. 24. Singh 8, Roche AH. Effects of intravenous verapamil on hemodynamics in patients with heart disease. Am Heart J 1977;94:593-599. 25. Lewis BS. Mitha AS, Go&man MS. Immediate hemodynamic effects of verapamil in man. Cardiology 1976;60:366-376. 26. Walsh RA. Porter CB, Starling MR, O’Rourke RA. Beneficial hemody-
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nomic effects of intravenous and oral diltiazem in severe congestive heart failure. JACC 1984;3:1044-1050. 27. Packer M. Lee WH, Medina N, Yusak M. Comparative negative inotropic effects of nifedipine and diltiozem in potients with severe left ventricular dysfunction [abstr]. Circulation 1985;72:suppl III:275. 28. Porter CB. Walsh RA, Badke FR. O’Rourke RA. Differential effects of diltiozem and nitroprusside on left ventricular function in experimental chronic volume overload. Circulation 1983;68:685-692, 29. Elkayam U, Weber L, Torkan B, McKay CR, Rahimtoola S. Comparison of
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hemodynamic responses to nifedipine and nitroprusside in severe chronic congestive heart failure. Am J Cardiol 1984:53:13X-1325. 30. Elkayam U, Weber L, McKay CR, Turkan 9, Rahimtoola S. Differences in hemodynomic response to vosodilation due to calcium channel antagonism with nifedipine and direct-acting ogonism with hydralozine in chronic refractory congestive heart failure. Am J Cardiol 1984;54:126-131. 31. Agostoni PG, De Cesare N, Doria E, Polese A, Tamorini G, Guazzi MD. Afterload reduction: o comparison of coptopril and nifedipine in dilated cardiomyopathy. Br Heart J 1986:55:391-399.