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Effects of histamine type 2-receptor antagonists cimetidine and famotidine on left ventricular systolic function in chronic congestive heart failure
Effects of Histamine Type P-Receptor Antagonists Cimetidine and Famotidine on Left Ventricular Systolic Function in Chronic Congestive Heart Failure Scott D. Solomon, MD, Simonetta Wolff. MD. Linda A. Jarboe. B.S. ’ ’ M. Michael Wolfe, MD, and Ridhard T. Lee, MD
Twelve patients with stable congestive heart failure and left ventricular dysfunction were enrolled in a double-blind, randomized crossover trial of fa motidine, cimetidine and placebo to determine whether histamine type 2 (HZ) antagonists adversely affect left ventricular systolic perfor mance. Two-dimensional echocardiograms were obtained at baseline, after 4 days of oral treatment with standard doses of famotidine and cimetidine, and placebo, and at the conclusion of the trial. The baseline mean ejection fraction was 19 + 7%. The changes in ejection fraction were +2 & 11% (95% confidence interval [Cl] -5 to 9%) with famotidine, +3 & 10% (95% Cl -3 to 10%) with cimetidine, and -3 f 7% (95% Cl -6 to 2%) with placebo. There were no significant diielc ences in changes in ejection fraction among the 3 experimental treatments (p = 0.22; analysis of variance). The changes in end-systolic wall stress/ volume ratios from baseline were +6 +: 21% (95% Cl d to 16%) for famotidine, +6 + 29% (95% Cl 6 to 25%) for cimetidine, and +2% & 29% (95% Cl -15 to 18%) for placebo (p = 0.69; analysis of variance). No patient had a worsening of symptoms during therapy. Despite previous reports that H2 antagonists may depress left ventricular systolic function, at standard doses these agents result in no decrease in left ventricular systolic function in patients with chronic congestive heart failure. (Am JCardiol1993;72:1163-1166)
From the Cardiovascular and Gastroenterology Divisions, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Manuscript received March 12, 1993; revised manuscript received June 18, 1993, and accepted June 23. Address for reprints: Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
he histamine type 2 (Hz)-receptor antagonistsare the most widely prescribed class of pharmacologic agents in the world. In addition, the pharmaceutical industry is currently proposing the marketing of Hz-receptor antagonists as over-the-counter drugs for acid-peptic disorders.l Histamine receptors located on the heart have been shown to contribute to positive inotrop~,~ and several studies of humans have suggeste’d that Hz-receptor antagonists adversely affect systolic function.3,4Becausechronic congestiveheart failure is a common condition, and the use of these agentsis widespread,we performed a randomized, double-blind, plalcebo-controlled, crossovertrial to evaluate the effects of the Hz-antagonists cimetidine and famotidine on left ventricular systolic function in patients with chronic congestive heart failure.
T
METHODS Patients:
Men and women with stable New York Heart Association class 2 congestive heart failure were screenedfor inclusion in the study. Patients were determined to have class 2 congestiveheart failure by a questionnaire basedon the Goldman activity scale.5Patients were excluded from the study if they reported active angina, or were receiving Hz-receptor antagonist medication, or greater than the lowest standard dose of a 13 blocker or calcium antagonist. In addition, patients with diabetes mellitus, and women of childbearing age were excluded. The study protocol was approved by the Brigham and Women’s Hospital Human ResearchCommittee, and all patients enrolled in the study gave informed consent. The 12 patients (9 men and 3 women) who fultille~d the inclusion criteria had a mean age of 58 + 12 years. Eight patients had heart failure becauseof previous myocardial infarctions, and 4 had idiopathic dilated cardiomyopathy. All patients were on cardiac medications including angiotensin-converting enzyme inhibitors, diuretics, B blockers and calcium antagonists.All patients had echocardiographic evidence of left ventricular systolic dysfunction. Study design: A randomized, placebo-controlled, double-blind crossover design was used (FQure 1). After enrollment in the study, all subjectsunderwent base:line physical examination and completed a questionnaire regarding symptoms. Before initiation of drug theraply, each subject had a baseline echocardiogram and was subsequentlyrandomly assignedto receive 1 of 3 medlications: cimetidine (400 mg twice daily), famotidine HISTAMINETYPE2 ANTAGONISTSIN HEARTFAILURE 116:3
(20 mg twice daily) or matching placebo. Patients remained on the initial study drug for a 4-day period, at the end of which another echocardiogramwas obtained. After a 4-day washout period, during which time they received no study medication, patients were randomized to receive 1 of the remaining 2 medications. This medication was also administered for 4 days, after which another echocardiogram was obtained. After a second 4-day washout period, patients received the third remaining study medication, after which another echocardiogram was obtained. After receiving all 3 study medications, and a third 4-day washout period, a poststudy baseline echocardiogramwas obtained. Echocardiographii data acquisition: Standardechocardiograms were obtained in all patients with a Hewlett-Packard Sonos 1000echocardiographicimaging system (Hewlett-Packard, Andover, Massachusetts). All standard echocardiographic views were obtained, including parastemal short- and long-axis, apical 4- and 2-chamber, and subcostal Patients completed baseline and subsequentquestionnairesat the time of each echocardiographic study regarding symptomswhile receiving study medication. In addition, blood pressure and heart rate were measured 3 times during the echocardiographic examination. Echocatiographic data analysis Echocardiograms were analyzed on an off-line echocardiographic analysis system(FreelandSystemsInc., Louisville, Colorado). The following measurementswere obtained from 3 separate cardiac cycles: from the parastemal short-axis view, left ventricular end-diastolic, end-systolic and total systolic epicardial areas at the mitral valve level; and from the apical view, diastolic and systolic ventricular lengths. In addition, from the apical view, a left ventricular volume was calculated using a modified Simpson’s rule method of discs for both end-diastole and end-systole.From left ventricular volumes calculated at both diastole and systole, left ventricular ejection fraction was obtained from Change in Ejection Fraction from Baseline zoQ e
15-
2.1% f 10.9%
3.2% k 9.9%
Famotidine
nIGURE 21 Mean change in ejection for treatment gulps. 1164
Cimetidine
fraction
3.1 f 7.1% Placebo
from baseline
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
the following formula: EF = 100 X (DV - SV)/DV; where EF = ejection fraction; DV = diastolic volume; and SV = systolic volume. Evaluating the end-systolic wall stress/volumeindex ratio provided an additional measure of left ventricular systolic function. End-systolic wall stresswas calculated from the following formula, which is a derivation of the method of Mirsky6: o,(Kdynes/cm’) =
1.33 x P X & d&-&c
%I2 x i l - Tr x (0.5 x L,)2 x (A
+ J;i-t) i
where crc= left ventricular end-systolic circumferential wall stress;P = peak left ventricular systolic pressurein mm Hg; A, = end-systolic cavity area in the parastemal short-axis view at the level of the papillary muscles in cm2; At = total left ventricular short-axis area in systole, including the left ventricular wall in the short-axis view at the papillary muscles,in cm2; and L, = left ventricular end-systolic cavity length in cm. The end-systolic wall stress/volumeindex was calculated by dividing end-systolic wall stress by end-systolic volume corrected for body surface area. Statistical analysis: Mean ejection fractions and end-systolic wall stress/volumeindex ratios were calculated for each experimental condition in each patient. Differences between experimental conditions were analyzed with a repeated-measuresanalysis of variance. Confidence intervals (CI) of the differences between groups were calculated, and a post-hoc power calculation was calculated using measuredSDS. RESULTS
All 12 patients enrolled in the study completed the protocol. No patient had a worsening of symptoms of heart failure during any treatment period, and no additional adverseeffect was reported by any patient. The mean baseline echocardiographic ejection fraction for all 12 patients was 19 f 7%. The mean ejection fraction at the completion of the study for all 12 patients was 19 + 6%. Figure 2 summarizesthe mean difference in ejection fraction from baseline for each experimental condition. Patients had a mean increasein ejection fraction of 2 * 11% on famotidine (95% CI -5 to 9%), an increaseof 3 * 10% on cimetidine (95% CI -3 to lo%), and a decreaseof 3 f 7% on placebo (95% CI -8 to 2%). There was no significant difference in change in ejection fraction among any of the 3 experimental groups (p = 0.22; analysis of variance). Because ejection fraction is an incomplete measure of left ventricular systolic function and is dependenton loading conditions, the end-systolic wall stress/volume NOVEMBER15,1993
2
FIGURE 3. Mean change in end-systolic wall stress/volume index (ESWS/ESVI) for treatment groups. In addition to ab lute change, percent change from base line is shown.
1
+5.9% c 21%
+8.4% + 29%
+1.5% +29%
T _
Famotidine
Cimetidine
-
Placebo
l-
-2 1 -3 1
index was used as an additional measureof left ventricular systolic function7 End-systolic wall stresswas calculated using systolic blood pressure as a surrogate for peak left ventricular pressure. The mean baseline endsystolic wall stress/volume index ratio was 4.7 -t 1.7 Kdynes/cm2/ml/m2. The mean poststudy end-systolic wall stress/volume index ratio was 5.1 + 2.2 Kdynes/ cm2/ml/m2.Figure 3 shows the mean dilferences in endsystolic wall stress/volumeindex ratio for the 3 experimental groups. The change in end-systolic wall stress/ volume index ratio from baseline was +6 f 21% for famotidine (95% CI -6 to 18%), +8 f 29% for cimetidine (95% CI -8 to 25%), and +2 f 29% for placebo (95% CI -15 to 18%). There were no significant dilferencesamong treatment groups for changein end-systolic wall stress/volume index ratio (p = 0.69; analysis of variance). A post-hoc power calculation performed using the SDS of ejection fraction obtained from pre- and poststudy baseline echocardiograms demonstrated an 86% power to detect a 5% change in ejection fraction. DISCUSSION
The results of this study suggestthat neither famotidine nor cimetidine administered in standard doses significantly affect left ventricular systolic function in patients with stable congestive heart failure. The data conlirm the previously reported fmdings of Borow et aL8 who found no evidence for a negative inotropic effect of famotidine in normal subjects,and extend these findings to patients with clinical heart failure. Thus, despite experimental evidence that histamine has a positive inotropic effect due to stimulation of myocardial HZ receptors, it appearsthat this effect may not have an important compensatoryrole in patients with heart failure and that Hz-receptor antagonists do not significantly affect left ventricular systolic function in these patients. Despite some minor pharmacologic differences, as a class, the Hz-receptor antagonistsappearto be very safe agents with an unsurpassedclinical safety record. Because of the careful scrutiny these agents have received as a result of their widespread use, they will be available to patients without prescription within the next decade.Despite concerns suggestedby previous studies regarding the negative effect of this class of drugs on parametersof left ventricular systolic function, this study
indicates that at standard doses,these agents do not result in an echocardiographically demonstrablechange lin left ventricular function. Because of the small numbers of patients in this study, we cannot unequivocally exclude the possibility of a significant negative inotropic effect in somepatients with congestive heart failure. However, the study reasonably excludes the possibility that either cimetidine or famotidine decreases ejection fraction by >5%, am amount that could be considered clinically relevant. In addition, analysis of the end-systolic stress/volumerelation, which may be a more load-independentmeasureof left ventricular systolic function, also did not lind differencesbetween the Hz-receptorantagonistsand placebo. Becausethe dosesused in this study were the most common, but not necessarily the highest clinically use:d doses, we cannot exclude a negative inotropic effect at very high doses of these medications. In addition, although the 4-day trial period was probably sufficient to achieve steady-stateserum levels, it is possible that therapy of >4 days, which may result in clinically important changesin the myocardial histamine receptor density or tone, may have cardiac effects that this study was unable to assess. It remains unclear whether the Hz receptor has a ro1.e in the normal physiology of left ventricular contraction or in the pathophysiology of left ventricular dysfunction. The Hz-receptor agonist impromidine increased cardiac output and decreasedpulmonary capillary wedge pressure in patients with severe refractory left ventricular dysfunction.9J0 In addition, hypotension and bradycardia has been reported after the rapid intravenous infusion of Hz-receptor antagonists.l’ However, in a recent report, famotidine did not alter blood pressure,left ventricular percent fractional shortening, circumferential end-systolic wall stress,cardiac index or ventricular contractile state in healthy subjects,and Borow et al8 corteluded that in humans, the basal left ventricular contractile state is not dependenton the H2 receptor-mediated effectsof histamine. Those results, however, are not necessarily applicable to patients with congestive heart failure in whom various pathophysiologic changeshave occurred and in whom histamine may have a compensatory role in heart failure. The results of this study suggest that histamine has a minimal role in the compenHISTAMINE TYPE 2 ANTAGONISTS IN HEART FAILURE
1165
satory response in patients with stable congestive heart failure. 1. Gerry R. Prescription drugs invade the over-the-counter market. Pharmaceuticd News Capsule 1992$X3-9. 2. Feldman M. Burton ME. Histamine 2 receutor antaeonists. N Enal J Med 1990; 323:1672-1680. 3. Kirch W, Halabi A, Himichsen H. Hemodynamic effects of quinidine and famotidine in patients with congestive heart fail=. Clin Pharmacol Ther 199251: 32S333. 4. Matsukawa M, Hoshi K, Minase A. The effects of famotidine on the circulatory system. Intensive Care Med 1986;10:763-766. 5. Goldman L, Hashimoto B,Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular function class: advantages of a new specific activity scale. Circulation 1981;&1:1227-1234. 6. Musky I. Review of various theories for the evaluation of left ventricular wall stresses. In: Mirsky I, Ghista DN, Sandier H, eds. Cardiac Mechanics: Physiolog.
1166
I
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
ic, Clinical and Mathematical Considerations. New York: John Wiley & Sons, 1974: 388. 7. Roman MJ, Devereux RB Comparison of noninvasive measures of contractility in dilated cardiomyopathy. Echocardiography 1991;s: 139-150. 5. Borow KM, Ehler D, Berlin R, Neumann A. Influence of histamine receptors on basal left ventricular contractile tone in humans: assessment using the H2 receptor antagonist famotidine and the beta-adreneceptor antagonist esmolol as pharmacologic probes. J Am Coil Cardiol 1992;19:1229-1236. 9. Baumann G, Permanetter B, Wirtzfeld A. Possible value of H2 receptor agonists for treatment of catecholamine-insensitive congestive. heart failure. Pharmacol Ther 1984;24:165-177. 10. Baumann G, Felix SB, Heidecke CD. Apparent superiority of H2 receptor stinelation and simultaneous B-blockade over conventional treatment with B-sympathomimetic drugs in post-acute myocardial infarction: cardiac effects of impromidine-a new specific H2-receptor agonist. Agents Actions 1984;15:216-228. 11. Kiich W, Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989;86:1388-1392.
NOVEMBER15,1993
Twelve patients with stable congestive heart failure and left ventricular dysfunction were enrolled in a double-blind, randomized crossover trial of fa motidine, cimetidine and placebo to determine whether histamine type 2 (HZ) antagonists adversely affect left ventricular systolic perfor mance. Two-dimensional echocardiograms were obtained at baseline, after 4 days of oral treatment with standard doses of famotidine and cimetidine, and placebo, and at the conclusion of the trial. The baseline mean ejection fraction was 19 + 7%. The changes in ejection fraction were +2 & 11% (95% confidence interval [Cl] -5 to 9%) with famotidine, +3 & 10% (95% Cl -3 to 10%) with cimetidine, and -3 f 7% (95% Cl -6 to 2%) with placebo. There were no significant diielc ences in changes in ejection fraction among the 3 experimental treatments (p = 0.22; analysis of variance). The changes in end-systolic wall stress/ volume ratios from baseline were +6 +: 21% (95% Cl d to 16%) for famotidine, +6 + 29% (95% Cl 6 to 25%) for cimetidine, and +2% & 29% (95% Cl -15 to 18%) for placebo (p = 0.69; analysis of variance). No patient had a worsening of symptoms during therapy. Despite previous reports that H2 antagonists may depress left ventricular systolic function, at standard doses these agents result in no decrease in left ventricular systolic function in patients with chronic congestive heart failure. (Am JCardiol1993;72:1163-1166)
From the Cardiovascular and Gastroenterology Divisions, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. Manuscript received March 12, 1993; revised manuscript received June 18, 1993, and accepted June 23. Address for reprints: Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
he histamine type 2 (Hz)-receptor antagonistsare the most widely prescribed class of pharmacologic agents in the world. In addition, the pharmaceutical industry is currently proposing the marketing of Hz-receptor antagonists as over-the-counter drugs for acid-peptic disorders.l Histamine receptors located on the heart have been shown to contribute to positive inotrop~,~ and several studies of humans have suggeste’d that Hz-receptor antagonists adversely affect systolic function.3,4Becausechronic congestiveheart failure is a common condition, and the use of these agentsis widespread,we performed a randomized, double-blind, plalcebo-controlled, crossovertrial to evaluate the effects of the Hz-antagonists cimetidine and famotidine on left ventricular systolic function in patients with chronic congestive heart failure.
T
METHODS Patients:
Men and women with stable New York Heart Association class 2 congestive heart failure were screenedfor inclusion in the study. Patients were determined to have class 2 congestiveheart failure by a questionnaire basedon the Goldman activity scale.5Patients were excluded from the study if they reported active angina, or were receiving Hz-receptor antagonist medication, or greater than the lowest standard dose of a 13 blocker or calcium antagonist. In addition, patients with diabetes mellitus, and women of childbearing age were excluded. The study protocol was approved by the Brigham and Women’s Hospital Human ResearchCommittee, and all patients enrolled in the study gave informed consent. The 12 patients (9 men and 3 women) who fultille~d the inclusion criteria had a mean age of 58 + 12 years. Eight patients had heart failure becauseof previous myocardial infarctions, and 4 had idiopathic dilated cardiomyopathy. All patients were on cardiac medications including angiotensin-converting enzyme inhibitors, diuretics, B blockers and calcium antagonists.All patients had echocardiographic evidence of left ventricular systolic dysfunction. Study design: A randomized, placebo-controlled, double-blind crossover design was used (FQure 1). After enrollment in the study, all subjectsunderwent base:line physical examination and completed a questionnaire regarding symptoms. Before initiation of drug theraply, each subject had a baseline echocardiogram and was subsequentlyrandomly assignedto receive 1 of 3 medlications: cimetidine (400 mg twice daily), famotidine HISTAMINETYPE2 ANTAGONISTSIN HEARTFAILURE 116:3
(20 mg twice daily) or matching placebo. Patients remained on the initial study drug for a 4-day period, at the end of which another echocardiogramwas obtained. After a 4-day washout period, during which time they received no study medication, patients were randomized to receive 1 of the remaining 2 medications. This medication was also administered for 4 days, after which another echocardiogram was obtained. After a second 4-day washout period, patients received the third remaining study medication, after which another echocardiogram was obtained. After receiving all 3 study medications, and a third 4-day washout period, a poststudy baseline echocardiogramwas obtained. Echocardiographii data acquisition: Standardechocardiograms were obtained in all patients with a Hewlett-Packard Sonos 1000echocardiographicimaging system (Hewlett-Packard, Andover, Massachusetts). All standard echocardiographic views were obtained, including parastemal short- and long-axis, apical 4- and 2-chamber, and subcostal Patients completed baseline and subsequentquestionnairesat the time of each echocardiographic study regarding symptomswhile receiving study medication. In addition, blood pressure and heart rate were measured 3 times during the echocardiographic examination. Echocatiographic data analysis Echocardiograms were analyzed on an off-line echocardiographic analysis system(FreelandSystemsInc., Louisville, Colorado). The following measurementswere obtained from 3 separate cardiac cycles: from the parastemal short-axis view, left ventricular end-diastolic, end-systolic and total systolic epicardial areas at the mitral valve level; and from the apical view, diastolic and systolic ventricular lengths. In addition, from the apical view, a left ventricular volume was calculated using a modified Simpson’s rule method of discs for both end-diastole and end-systole.From left ventricular volumes calculated at both diastole and systole, left ventricular ejection fraction was obtained from Change in Ejection Fraction from Baseline zoQ e
15-
2.1% f 10.9%
3.2% k 9.9%
Famotidine
nIGURE 21 Mean change in ejection for treatment gulps. 1164
Cimetidine
fraction
3.1 f 7.1% Placebo
from baseline
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
the following formula: EF = 100 X (DV - SV)/DV; where EF = ejection fraction; DV = diastolic volume; and SV = systolic volume. Evaluating the end-systolic wall stress/volumeindex ratio provided an additional measure of left ventricular systolic function. End-systolic wall stresswas calculated from the following formula, which is a derivation of the method of Mirsky6: o,(Kdynes/cm’) =
1.33 x P X & d&-&c
%I2 x i l - Tr x (0.5 x L,)2 x (A
+ J;i-t) i
where crc= left ventricular end-systolic circumferential wall stress;P = peak left ventricular systolic pressurein mm Hg; A, = end-systolic cavity area in the parastemal short-axis view at the level of the papillary muscles in cm2; At = total left ventricular short-axis area in systole, including the left ventricular wall in the short-axis view at the papillary muscles,in cm2; and L, = left ventricular end-systolic cavity length in cm. The end-systolic wall stress/volumeindex was calculated by dividing end-systolic wall stress by end-systolic volume corrected for body surface area. Statistical analysis: Mean ejection fractions and end-systolic wall stress/volumeindex ratios were calculated for each experimental condition in each patient. Differences between experimental conditions were analyzed with a repeated-measuresanalysis of variance. Confidence intervals (CI) of the differences between groups were calculated, and a post-hoc power calculation was calculated using measuredSDS. RESULTS
All 12 patients enrolled in the study completed the protocol. No patient had a worsening of symptoms of heart failure during any treatment period, and no additional adverseeffect was reported by any patient. The mean baseline echocardiographic ejection fraction for all 12 patients was 19 f 7%. The mean ejection fraction at the completion of the study for all 12 patients was 19 + 6%. Figure 2 summarizesthe mean difference in ejection fraction from baseline for each experimental condition. Patients had a mean increasein ejection fraction of 2 * 11% on famotidine (95% CI -5 to 9%), an increaseof 3 * 10% on cimetidine (95% CI -3 to lo%), and a decreaseof 3 f 7% on placebo (95% CI -8 to 2%). There was no significant difference in change in ejection fraction among any of the 3 experimental groups (p = 0.22; analysis of variance). Because ejection fraction is an incomplete measure of left ventricular systolic function and is dependenton loading conditions, the end-systolic wall stress/volume NOVEMBER15,1993
2
FIGURE 3. Mean change in end-systolic wall stress/volume index (ESWS/ESVI) for treatment groups. In addition to ab lute change, percent change from base line is shown.
1
+5.9% c 21%
+8.4% + 29%
+1.5% +29%
T _
Famotidine
Cimetidine
-
Placebo
l-
-2 1 -3 1
index was used as an additional measureof left ventricular systolic function7 End-systolic wall stresswas calculated using systolic blood pressure as a surrogate for peak left ventricular pressure. The mean baseline endsystolic wall stress/volume index ratio was 4.7 -t 1.7 Kdynes/cm2/ml/m2. The mean poststudy end-systolic wall stress/volume index ratio was 5.1 + 2.2 Kdynes/ cm2/ml/m2.Figure 3 shows the mean dilferences in endsystolic wall stress/volumeindex ratio for the 3 experimental groups. The change in end-systolic wall stress/ volume index ratio from baseline was +6 f 21% for famotidine (95% CI -6 to 18%), +8 f 29% for cimetidine (95% CI -8 to 25%), and +2 f 29% for placebo (95% CI -15 to 18%). There were no significant dilferencesamong treatment groups for changein end-systolic wall stress/volume index ratio (p = 0.69; analysis of variance). A post-hoc power calculation performed using the SDS of ejection fraction obtained from pre- and poststudy baseline echocardiograms demonstrated an 86% power to detect a 5% change in ejection fraction. DISCUSSION
The results of this study suggestthat neither famotidine nor cimetidine administered in standard doses significantly affect left ventricular systolic function in patients with stable congestive heart failure. The data conlirm the previously reported fmdings of Borow et aL8 who found no evidence for a negative inotropic effect of famotidine in normal subjects,and extend these findings to patients with clinical heart failure. Thus, despite experimental evidence that histamine has a positive inotropic effect due to stimulation of myocardial HZ receptors, it appearsthat this effect may not have an important compensatoryrole in patients with heart failure and that Hz-receptor antagonists do not significantly affect left ventricular systolic function in these patients. Despite some minor pharmacologic differences, as a class, the Hz-receptor antagonistsappearto be very safe agents with an unsurpassedclinical safety record. Because of the careful scrutiny these agents have received as a result of their widespread use, they will be available to patients without prescription within the next decade.Despite concerns suggestedby previous studies regarding the negative effect of this class of drugs on parametersof left ventricular systolic function, this study
indicates that at standard doses,these agents do not result in an echocardiographically demonstrablechange lin left ventricular function. Because of the small numbers of patients in this study, we cannot unequivocally exclude the possibility of a significant negative inotropic effect in somepatients with congestive heart failure. However, the study reasonably excludes the possibility that either cimetidine or famotidine decreases ejection fraction by >5%, am amount that could be considered clinically relevant. In addition, analysis of the end-systolic stress/volumerelation, which may be a more load-independentmeasureof left ventricular systolic function, also did not lind differencesbetween the Hz-receptorantagonistsand placebo. Becausethe dosesused in this study were the most common, but not necessarily the highest clinically use:d doses, we cannot exclude a negative inotropic effect at very high doses of these medications. In addition, although the 4-day trial period was probably sufficient to achieve steady-stateserum levels, it is possible that therapy of >4 days, which may result in clinically important changesin the myocardial histamine receptor density or tone, may have cardiac effects that this study was unable to assess. It remains unclear whether the Hz receptor has a ro1.e in the normal physiology of left ventricular contraction or in the pathophysiology of left ventricular dysfunction. The Hz-receptor agonist impromidine increased cardiac output and decreasedpulmonary capillary wedge pressure in patients with severe refractory left ventricular dysfunction.9J0 In addition, hypotension and bradycardia has been reported after the rapid intravenous infusion of Hz-receptor antagonists.l’ However, in a recent report, famotidine did not alter blood pressure,left ventricular percent fractional shortening, circumferential end-systolic wall stress,cardiac index or ventricular contractile state in healthy subjects,and Borow et al8 corteluded that in humans, the basal left ventricular contractile state is not dependenton the H2 receptor-mediated effectsof histamine. Those results, however, are not necessarily applicable to patients with congestive heart failure in whom various pathophysiologic changeshave occurred and in whom histamine may have a compensatory role in heart failure. The results of this study suggest that histamine has a minimal role in the compenHISTAMINE TYPE 2 ANTAGONISTS IN HEART FAILURE
1165
satory response in patients with stable congestive heart failure. 1. Gerry R. Prescription drugs invade the over-the-counter market. Pharmaceuticd News Capsule 1992$X3-9. 2. Feldman M. Burton ME. Histamine 2 receutor antaeonists. N Enal J Med 1990; 323:1672-1680. 3. Kirch W, Halabi A, Himichsen H. Hemodynamic effects of quinidine and famotidine in patients with congestive heart fail=. Clin Pharmacol Ther 199251: 32S333. 4. Matsukawa M, Hoshi K, Minase A. The effects of famotidine on the circulatory system. Intensive Care Med 1986;10:763-766. 5. Goldman L, Hashimoto B,Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular function class: advantages of a new specific activity scale. Circulation 1981;&1:1227-1234. 6. Musky I. Review of various theories for the evaluation of left ventricular wall stresses. In: Mirsky I, Ghista DN, Sandier H, eds. Cardiac Mechanics: Physiolog.
1166
I
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
ic, Clinical and Mathematical Considerations. New York: John Wiley & Sons, 1974: 388. 7. Roman MJ, Devereux RB Comparison of noninvasive measures of contractility in dilated cardiomyopathy. Echocardiography 1991;s: 139-150. 5. Borow KM, Ehler D, Berlin R, Neumann A. Influence of histamine receptors on basal left ventricular contractile tone in humans: assessment using the H2 receptor antagonist famotidine and the beta-adreneceptor antagonist esmolol as pharmacologic probes. J Am Coil Cardiol 1992;19:1229-1236. 9. Baumann G, Permanetter B, Wirtzfeld A. Possible value of H2 receptor agonists for treatment of catecholamine-insensitive congestive. heart failure. Pharmacol Ther 1984;24:165-177. 10. Baumann G, Felix SB, Heidecke CD. Apparent superiority of H2 receptor stinelation and simultaneous B-blockade over conventional treatment with B-sympathomimetic drugs in post-acute myocardial infarction: cardiac effects of impromidine-a new specific H2-receptor agonist. Agents Actions 1984;15:216-228. 11. Kiich W, Halabi A, Linde M, Santos SR, Ohnhaus EE. Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements. Gastroenterology 1989;86:1388-1392.
NOVEMBER15,1993