sefulness of Verapamil for Congestive Heart Failure Associated with Abnormal Left Ventricular Diastolic Filling and Normal Left Ventricular Systolic Performance John F. Setaro, MD, Barry L. Zaret, MD, Douglas S. Schulman, MD, Henry R. Black, MD, and Robert Soufer, MD
Normal left ventricular systolic performance with impaired left ventricular diastolic fflling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 f 5 years) with CHF, intact left ventricular function (ejection fraction >45%) and abnormal diastolic filling (peak filling rate 2.5 end-diastolic volumes per second [edv/s]). CHF was graded by a clinicoradiographic scoring system modified from Lee et a1,i5and used earlier by our group in the assessmentof diastolic CHF.’ Points were assigned for increasing grades of dyspnea, pulmonary congestion on physical examination, neck vein distention, third heart sound, peripheral edema, and CHF on an independently read chest film. The maximum score possible was 13, signifying the most severe CHF. Patients were excluded if they had sustained
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
98X
a myocardial infarction within 3 months, had angina pectoris, significant valvular disorders (stenotic lesions or regurgitant lesions >l + severity on a scale of trace to 4-t), asymmetric hypertrophic heart disease(septal/ posterior wall thickness > 1.5) by echocardiography, valve replacement, bradycardia or atrioventricular conduction delay, pacemaker, complex ventricular ectopic activity, therapy with afterload reducers or calcium antagonists, severeobstructive lung disease(forced expiratory volume in 1 second (1.5 liters), or hepatic or renal insufficiency. Protocol: After informed consent was obtained, eligible patients receiving digoxin had this therapy stopped 7 days before starting the protocoli Diuretics were continued at a constant dosage throughout. Baseline evaluation included CHF score, treadmill exercise testing on a modified Naughton protocol,17 and radionuelide measurement of global left ventricular ejection fraction by gamma camera equilibrium radionuclide angiocardiography, followed by a non-imaging nuclear probe study to evaluate peak filling rate.’ Patients also underwent screening with thallium-201 stress scintigraphy and 2-dimensional and M-mode echocardiography at initial evaluation to rule out major occult ischemic and valvular heart disease, respectively. After initial screening and baseline evaluation, patients were placed in a random double-blind fashion on either placebo or verapamil 80 mg 3 times daily for 1 week (Figure 1). If tolerated, the verapamil dosage was increased to 120 mg 3 times daily by another investigator unaware of the initial therapy. If not tolerated, the dosagewas lowered to 80 mg twice daily. Placebo doseswere also increased. After 2 weeks of treatment, patients were reevaluated by the blinded investigator, with repeat clinical examination and CHF grading, exercise testing, radionuclide angiocardiogram and nuclear probe study. The initial study period was followed by a 4-day washout interval, after which patients were crossedover into the opposite arm of the study. At the conclusion of the secondperiod patients were similarly reevaluated clinically by the blinded investigator and again underwent full laboratory assessment. Radionuclide techniques: Left ventricular ejection fraction was determined in a standard manner using equilibrium radionuclide angiocardiography and a mod-
Verapamil,
Start
CHF and Abnormal
Diastolic
982
THE AMERICAN JOURNAL OF CARDIOLOGY
RESULTS Patient characteristics: Twenty-two patients entered the study. One did not complete the study becauseof noncompliance, and a seconddevelopeda supraventricular tachyarrhythmia in the placebo phase and was treated with verapamil. Twenty patients completed the study. Their mean age was 68 f 5 years (range 59 to 79). All were men and 4 were black. Six had a past history of severeCHF (pulmonary edema). Fifteen had a history of hypertension. Five patients (including 2 who
Function
Crossover
ll------fLl *1 f *1
ified in vivo labeling technique.’ To analyze peak tilling rate, a high temporal resolution non-imaging nuclear probe was used.’ As previously described, this device provides high temporal resolution as well as the sensitivity necessary for the evaluation of the diastolic filling phaseof the left ventricle. The peak filling rate, reflecting the maximal rate of change in counts during early to mid-diastole (normal >2.5 edv/s), has been used in several laboratories as an index of diastolic performance.‘JOJsEquilibrium and probe studies were read separately by independent observers,each unaware of the clinical situation. Thallium-201 scintigraphy was performed with either treadmill exerciseor pharmacologic stresswith intravenous or oral dipyridamole. Stress and delayed imageswere processedfor computer quantification using a standard technique.l9 Visual interpretations were confirmed by quantitative distribution profile analysis. Echocardiography and chest radiography: M-mode and 2-dimensional echocardiogramswith conventional and color flow Doppler were interpreted without knowledge of clinical circumstances. Chest films were read independently by a radiologist. Each film was evaluated for pulmonary vascular congestion. Statistical analysis: Data are expressedas mean f standard deviation, and were evaluated by paired t tests and analysis of variance, with corrections for multiple comparison. Dunnett’s test was then used to compare 2 treatment options to a single control. Becauseit is a non-continuous variable, CHF score was evaluated in terms of degree of change from baseline using Wilcoxon’s paired signed rank sum test. A p value I.5 liters. Total patients screened: Between January 1986 and July 1988, 419 patients with a diagnosis of CHF of 23 months’ duration were screened. Of these, 182 (43%) had preservedsystolic function as assessedby radionuelide ejection fraction >45%. Of the 160 patients who did not participate in the study, 38 were ineligible becauseof competing therapy, including calcium antagonists, afterload reducers or experimental agents. Fortyfive were excluded for reasons relating to cardiac rhythm, including bradycardia, abnormal atrioventricular conduction, pacemaker or complex ventricular ectopy. Becauseof evidenceof active myocardial ischemia or infarction within 6 months, 56 were ineligible, and 10 did not enter because of significant valvular disease. Twelve patients were excluded becauseof recent general surgery, psychiatric disorders, lung disease,renal or hepatic failure, and refusal or inability to give consent. Stress scintigraphy
and echocardiographic
screen-
To exclude major active ischemia as a cause for impaired diastolic function, screening thallium-201 stressscintigraphy was done in 19 of 20 patients. One patient had a normal coronary arteriogram within 6 months of the trial with no change in clinical status and thallium-201 study was therefore not performed. In capable patients (n = 12) a treadmill exercise thallium study was performed. In the 8 patients unable to exercise becauseof noncardiac reasons,dipyridamole thallium-201 scintigraphy was done. All tests were negative for inducible chest pain or electrocardiographic findings. Seventeenof 19 patients had no reversible thallium defects.Two patients had small reversible defects that were not associatedwith symptoms. The perfusion defects observedin these 2 patients representedextremely small zones of apparent hypoperfusion involving only the inferoapical segmentand seenin only 1 view. These defects were judged to be of limited functional significance. All patients underwent echocardiography to assess wall thickness and valvular function. Of 16 patients in whom technically adequate studies could be obtained, 13 had symmetric left ventricular hypertrophy, defined as wall thickness >I.2 cm. All hypertrophic patients had a history of hypertension. For the entire group, the mean wall thickness was 1.4 f 0.4 cm (range 1.0 to 2.3). None had asymmetric hypertrophy, defined as septumto posterior wall thickness ratio > 1.5 , or significant regurgitant valvular diseaseby color flow, defined as >I+ on a scale of trace to 4-l-. e: The mean daily total dose of verapamil was 256 mg (range 160 to 360 mg). Bradycaring:
dia or asymptomatic atrioventricular conduction delay prevented maximization of dose (360 mg) in most patients. Occasional, mild episodes of constipation occurred in 5 patients. Otherwise, verapamil was well tolerated, without any cardiovascular complications. Ejection fraction: The left ventricular ejection fraction remained constant throughout the trial. At baseline, the mean ejection fraction was 60 f 9%; the active treatment and placebo values were 62 f 8%, and 60 f lo%, respectively (difference not significant for both versus baseline) (Table I). Congestive heart failure score: Mean baseline CHF score was 6.7 f 1.7. After verapamil therapy, CHF score decreasedsignificantly to 3.8 f 1.6 vs 6.1 f 1.9 with placebo, a median improvement in CHF score of 3 versus 1 with placebo (p CO.01 by Wilcoxon’s paired signed rank sum test). When normalized to evaluate change, the verapamil value was also significant (Table 0. Exercise data: In the 12 patients capableof exercise, there was an increase in mean exercise time of 33% (13.9 f 4.3 vs 10.7 f 3.4 minutes at baseline) with verapamil therapy (p
Normal left ventricular systolic performance with impaired left ventricular diastolic fflling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset, 20 men (mean age 68 f 5 years) with CHF, intact left ventricular function (ejection fraction >45%) and abnormal diastolic filling (peak filling rate 2.5 end-diastolic volumes per second [edv/s]). CHF was graded by a clinicoradiographic scoring system modified from Lee et a1,i5and used earlier by our group in the assessmentof diastolic CHF.’ Points were assigned for increasing grades of dyspnea, pulmonary congestion on physical examination, neck vein distention, third heart sound, peripheral edema, and CHF on an independently read chest film. The maximum score possible was 13, signifying the most severe CHF. Patients were excluded if they had sustained
THE AMERICAN JOURNAL OF CARDIOLOGY OCTOBER 15, 1990
98X
a myocardial infarction within 3 months, had angina pectoris, significant valvular disorders (stenotic lesions or regurgitant lesions >l + severity on a scale of trace to 4-t), asymmetric hypertrophic heart disease(septal/ posterior wall thickness > 1.5) by echocardiography, valve replacement, bradycardia or atrioventricular conduction delay, pacemaker, complex ventricular ectopic activity, therapy with afterload reducers or calcium antagonists, severeobstructive lung disease(forced expiratory volume in 1 second (1.5 liters), or hepatic or renal insufficiency. Protocol: After informed consent was obtained, eligible patients receiving digoxin had this therapy stopped 7 days before starting the protocoli Diuretics were continued at a constant dosage throughout. Baseline evaluation included CHF score, treadmill exercise testing on a modified Naughton protocol,17 and radionuelide measurement of global left ventricular ejection fraction by gamma camera equilibrium radionuclide angiocardiography, followed by a non-imaging nuclear probe study to evaluate peak filling rate.’ Patients also underwent screening with thallium-201 stress scintigraphy and 2-dimensional and M-mode echocardiography at initial evaluation to rule out major occult ischemic and valvular heart disease, respectively. After initial screening and baseline evaluation, patients were placed in a random double-blind fashion on either placebo or verapamil 80 mg 3 times daily for 1 week (Figure 1). If tolerated, the verapamil dosage was increased to 120 mg 3 times daily by another investigator unaware of the initial therapy. If not tolerated, the dosagewas lowered to 80 mg twice daily. Placebo doseswere also increased. After 2 weeks of treatment, patients were reevaluated by the blinded investigator, with repeat clinical examination and CHF grading, exercise testing, radionuclide angiocardiogram and nuclear probe study. The initial study period was followed by a 4-day washout interval, after which patients were crossedover into the opposite arm of the study. At the conclusion of the secondperiod patients were similarly reevaluated clinically by the blinded investigator and again underwent full laboratory assessment. Radionuclide techniques: Left ventricular ejection fraction was determined in a standard manner using equilibrium radionuclide angiocardiography and a mod-
Verapamil,
Start
CHF and Abnormal
Diastolic
982
THE AMERICAN JOURNAL OF CARDIOLOGY
RESULTS Patient characteristics: Twenty-two patients entered the study. One did not complete the study becauseof noncompliance, and a seconddevelopeda supraventricular tachyarrhythmia in the placebo phase and was treated with verapamil. Twenty patients completed the study. Their mean age was 68 f 5 years (range 59 to 79). All were men and 4 were black. Six had a past history of severeCHF (pulmonary edema). Fifteen had a history of hypertension. Five patients (including 2 who
Function
Crossover
ll------fLl *1 f *1
ified in vivo labeling technique.’ To analyze peak tilling rate, a high temporal resolution non-imaging nuclear probe was used.’ As previously described, this device provides high temporal resolution as well as the sensitivity necessary for the evaluation of the diastolic filling phaseof the left ventricle. The peak filling rate, reflecting the maximal rate of change in counts during early to mid-diastole (normal >2.5 edv/s), has been used in several laboratories as an index of diastolic performance.‘JOJsEquilibrium and probe studies were read separately by independent observers,each unaware of the clinical situation. Thallium-201 scintigraphy was performed with either treadmill exerciseor pharmacologic stresswith intravenous or oral dipyridamole. Stress and delayed imageswere processedfor computer quantification using a standard technique.l9 Visual interpretations were confirmed by quantitative distribution profile analysis. Echocardiography and chest radiography: M-mode and 2-dimensional echocardiogramswith conventional and color flow Doppler were interpreted without knowledge of clinical circumstances. Chest films were read independently by a radiologist. Each film was evaluated for pulmonary vascular congestion. Statistical analysis: Data are expressedas mean f standard deviation, and were evaluated by paired t tests and analysis of variance, with corrections for multiple comparison. Dunnett’s test was then used to compare 2 treatment options to a single control. Becauseit is a non-continuous variable, CHF score was evaluated in terms of degree of change from baseline using Wilcoxon’s paired signed rank sum test. A p value I.5 liters. Total patients screened: Between January 1986 and July 1988, 419 patients with a diagnosis of CHF of 23 months’ duration were screened. Of these, 182 (43%) had preservedsystolic function as assessedby radionuelide ejection fraction >45%. Of the 160 patients who did not participate in the study, 38 were ineligible becauseof competing therapy, including calcium antagonists, afterload reducers or experimental agents. Fortyfive were excluded for reasons relating to cardiac rhythm, including bradycardia, abnormal atrioventricular conduction, pacemaker or complex ventricular ectopy. Becauseof evidenceof active myocardial ischemia or infarction within 6 months, 56 were ineligible, and 10 did not enter because of significant valvular disease. Twelve patients were excluded becauseof recent general surgery, psychiatric disorders, lung disease,renal or hepatic failure, and refusal or inability to give consent. Stress scintigraphy
and echocardiographic
screen-
To exclude major active ischemia as a cause for impaired diastolic function, screening thallium-201 stressscintigraphy was done in 19 of 20 patients. One patient had a normal coronary arteriogram within 6 months of the trial with no change in clinical status and thallium-201 study was therefore not performed. In capable patients (n = 12) a treadmill exercise thallium study was performed. In the 8 patients unable to exercise becauseof noncardiac reasons,dipyridamole thallium-201 scintigraphy was done. All tests were negative for inducible chest pain or electrocardiographic findings. Seventeenof 19 patients had no reversible thallium defects.Two patients had small reversible defects that were not associatedwith symptoms. The perfusion defects observedin these 2 patients representedextremely small zones of apparent hypoperfusion involving only the inferoapical segmentand seenin only 1 view. These defects were judged to be of limited functional significance. All patients underwent echocardiography to assess wall thickness and valvular function. Of 16 patients in whom technically adequate studies could be obtained, 13 had symmetric left ventricular hypertrophy, defined as wall thickness >I.2 cm. All hypertrophic patients had a history of hypertension. For the entire group, the mean wall thickness was 1.4 f 0.4 cm (range 1.0 to 2.3). None had asymmetric hypertrophy, defined as septumto posterior wall thickness ratio > 1.5 , or significant regurgitant valvular diseaseby color flow, defined as >I+ on a scale of trace to 4-l-. e: The mean daily total dose of verapamil was 256 mg (range 160 to 360 mg). Bradycaring:
dia or asymptomatic atrioventricular conduction delay prevented maximization of dose (360 mg) in most patients. Occasional, mild episodes of constipation occurred in 5 patients. Otherwise, verapamil was well tolerated, without any cardiovascular complications. Ejection fraction: The left ventricular ejection fraction remained constant throughout the trial. At baseline, the mean ejection fraction was 60 f 9%; the active treatment and placebo values were 62 f 8%, and 60 f lo%, respectively (difference not significant for both versus baseline) (Table I). Congestive heart failure score: Mean baseline CHF score was 6.7 f 1.7. After verapamil therapy, CHF score decreasedsignificantly to 3.8 f 1.6 vs 6.1 f 1.9 with placebo, a median improvement in CHF score of 3 versus 1 with placebo (p CO.01 by Wilcoxon’s paired signed rank sum test). When normalized to evaluate change, the verapamil value was also significant (Table 0. Exercise data: In the 12 patients capableof exercise, there was an increase in mean exercise time of 33% (13.9 f 4.3 vs 10.7 f 3.4 minutes at baseline) with verapamil therapy (p
