hemodynamic effects of nifedipine given alone and in combination with atenolol in patients with...

Hemodynamic Effects of Nifedipine Given Alone and in Combination with Atenolol in Patients

with Impaired Left Ventricular Function

MICHAEL de BUITLEIR, MB, MRCPI, EDWARD ROWLAND, MB, and DENNIS M. KRIKLER, MD

The acute intravenous (IV) (0.1, 0.2 and 0.4 pg/kg/min over 10 minutes each) and chronic oral (60 mg/day) administration of nifedipine was examined in 9 patients with significantly impaired left ventricular (LV) function (ejection fraction [EF] on radionuclide scannin was 0.20 to 0.40) who were already receiving B -blocker therapy (>25 % reduction in peak exercise heart rate) with atenolol, 100 to 200 mg/day. The mean control LV end-diastolic pressure (EDP) at cardiac catheterization and EF for the group as a whole were 30 f 3 mm Hg (range 20 to 42) (mean f standard error of the mean) and 26.5 f 2.4%, respectively. Three of the 9 patients had hemodynamic deterioration and LV failure at some.stage during the study, and their mean LVEDP and EF were 38 f 3 mm Hg (range 33 to 42) and 22.6 f 2.7 % , respectively. In the 6 patients who tolerated the full treatment protocol, the

mean LVEDP and EF were 26.5 f 2.0 mm Hg (range 20 to 35) and 31.5 f 2.8 %, respectively. Seven patients received IV nifedlpine, which had a nega- trive inotropic action but did not precipitate cardiac decompensation. Chronic oral admlnlstratlon of nlfedlplne in combination with atenolol precipitated LV failure only in those with the lowest EF and highest LVEDP; usually LV failure was present with atenolol alone. Extensive infarction, frequently complicated by LV failure at the time, LVEDP >32 mm Hg and control resting EF <30 % were associ- ated with LV failure. Removal of sympathetic nervous system support for the impaired ventricle by /? blockade may be the decisive factor in precipitating hemodynamic deterioration in patients with severe impairment of LV function.

(Am J Cardiol 1985:55:15E-20E)

Recent reports have underlined the important role that medical treatment has to play in the management of ischemic heart disease.1-3 Both calcium antagonists and /3-adrenoceptor blocking drugs, given separately or together, may be effective in reducing the subjective and objective manifestations of myocardial ischemia in patients with this condition.4,5 With increasing use of these drugs in combination, fears have been expressed about possible deleterious effects resulting from sum- mation of their well-recognized negative inotropic ac- tions.6 These fears have been fueled by individual case reports documenting the occurrence of occasional se- rious adverse hemodynamic interactions with combination therapy.7-10 Several studies have shown that calcium antagonists and fl-adrenoceptor blockers can

From the Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England. This study was supported in part by grants from ICI Pharmaceuticals, Cheshire, England, and Pfizer Laboratories, New York, New York.

Address for reprints: Edward Rowland, MB, National Heart Hospital, Westmoreland Street, London WI, England.

be combined safely in patients with normal or near- normal cardiac function,ll-l5 but there are few data regarding their use in patients with impaired left ventricular (LV) contractility.6 We undertook this study to examine the effect of nifedipine and atenolol given separately and together in patients with coronary artery disease (CAD) and significantly impaired myocardial function.

Met hods Nine patients (8 men, 1 woman), aged 43 to 63 years (mean

54), undergoing routine cardiac catheterization for the in- vestigation of CAD and with ejection fractions (EFs) of 0.20 to 0.40 as assessed by radionuclide angiography, were recruited into the study. All 9 patients had angina pectoris, which was mild in most (New York Heart Association functional class IIa), and a history of anterior myocardial infarction; addi- tionally 3 patients had a history of inferior myocardial infarction. Exclusion criteria included clinical evidence of congestive heart failure, obstructive airways disease or severe peripheral vascular disease. Before entry into the study, all cardioactive medications apart from sublingual nitroglycerin

15E

16E A SYMPOSIUM: CURRENT ISSUES IN ANTIANGINAL THERAPY

were discontinued for at least 1 week, and fully informed consent was obtained from each patient. The study protocol was examined and approved by the hospital research ethics committee.

The study was open and crossover in design, and all patients received all treatments. Patients were assessed before entry into the study and at the end of each of the 3 active treatment phases. Assessment included clinical examination with heart rate and blood pressure recordings after 10 minutes supine and 2 minutes in the sitting position, an exercise test, a radionuclide angiogram and an adverse effect questionnaire. Patients exercised on a bicycle ergometer (Siemens-Elema), commencing at a workload of 50 W and progressively increasing by 25 W each minute to an endpoint of chest pain, dyspnea or fatigue. During each of the active treatment phases, patients performed at the same workload as that achieved during the control phase. Heart rate, systolic blood pressure and precordial maps? were recorded before, at each minute during, immediately after and at 1, 3, 5, 8 and 10 minutes after exercise. The PR interval was measured in lead Vi before exercise began,

Radionuclide angiography was performed after in vivo la- beling of red blood cells with 15 mCi of technetium-99m. Data were acquired from the left anterior oblique projection via a large-field-of-view scintillation camera (General Electric Maxi 409T) and fed to an online A2 multiterminal computer system (Medtronic MDS-Az). A single composite cardiac cycle was derived from 600 to 900 consecutive cycles and displayed in endless-loop format. A high temporal resolution time-activity curve was generated from the LV region of interest and from this various indexes were derived. The indexes used to describe global LV systolic function were the EF, peak ejection rate, time to peak ejection rate and time to end systole. In- dexes used to describe LV diastolic filling were the average filling rate, peak filling rate and time to peak filling rate, which were calculated according to our usual methods.17

After the control evaluation with patients on no medications, oral atenolol, 100 mg/day, was commenced and 2 weeks later assessment was repeated. If an inadequate dose of P-blocking drug had been administered (measured as >25% reduction in peak heart rate from control), the daily dosage

FIGURE 1. Changes in (A) supine and(B) sitting heart rate and (C) supine and (D) sitting blood pressure on no treatment (control), atenolol, atenolol plus nifedipine and nifedipine alone in 9 patients, and in subgroups of 6 patients who remained free of left ventricular failure (LVF) and 3 patients who developed LVF at some stage during the study. Bars represent mean f standard error of the mean.

of atenolol was doubled to 200 mg for an additional 3 days and the exercise test repeated. When adequate 6 blockade was achieved, cardiac catheterization was undertaken through percutaneous cannulation of the right femoral artery with diazepam, 10 mg orally, as premeditation, and coronary arteriography and left ventriculography performed. On completion of angiography, a long sheath was advanced to record ascending aortic pressure; simultaneously, a manometer- tipped (Millar) catheter was positioned to record LV pressure. The LV pressure was fed to a differential amplifier (Elec- tronics for Medicine) to provide the peak positive first de- rivative (dP/dt). All measurements were averaged over 25 cardiac cycles to compensate for respiratory variability.

Thirty minutes were allowed to elapse after completion of coronary arteriography and contrast ventriculography so that LV function could return to baseline. Then nifedipine was infused at 0.1, 0.2 and 0.4 pg/kg/min for 10 minutes each, representing 7, 14 and 28 ng/min, respectively, in a 70-kg patient, and recordings were made at the end of each infusion period. The infusion was discontinued immediately if an adverse reaction occurred, if the systolic blood pressure fell by >20% or if the left ventricular end-diastolic pressure (LVEDP) rose by >lO%. Nifedipine was drawn up under sodium light and administered with a syringe and cannula protected from the light.

After cardiac catheterization, patients continued on aten- 0101 and were given oral nifedipine, 30 mglday, for 3 days; if thii was tolerated without adverse reaction, the dosage was increased to 60 mg/day for an additional week. Full assessment was carried out on both drugs and again after the patients had been on nifedipine alone, 60 mg/day, for another 2 weeks.

Statistical analysis was performed using the Student t test for paired data, and a probability value of p <0.05 was considered significant. Values are given as mean f standard error of the mean. In all the figures, the mean data on all 9 patients are presented initially. This is followed by data on 2 subgroups-6 patients who were completely free of LV failure throughout the study and 3 patients who developed LV failure at some stage during treatment.

FIGURE 2. Effects of atenolol, atenolol plus nifedipine, and nifedipine alone on (A) heart rate, (8) systolic blood pressure and (C) rate-pressure product at peak exercise compared with control. Data presented as in Fig. 1. Bars represent mean f standard error of the mean.

May 17, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 17E

Results

Of the 9 patients included in the study, 6 tolerated the full treatment protocol uneventfully and 1 required 200 mg of atenolol to achieve adequate P blockade. Three patients suffered LV failure characterized by pulmonary edema at some stage during the study, and 2 of the 3 could nl tolerate chronic ,# blockade. Accordingly, these 2 pat tents were commenced on atenolol cautiously and under strict supervision in the hospital during the 48 hours before cardiac catheterization. Both achieved adequate and uneventful p blockade after receiving a total of atenolol, 200 mg, but when oral nifedipine was added both relapsed into LV failure. The third patient developed LV failure only while on atenolol plus nifedipine.

Resting heart rate, blood pressure and PR interval: In the group of 9 patients as a whole, the resting supine heart rate was significantly lower on atenolol alone (58 f 3 beats/min, p <O.OOl) and on atenolol plus nifedipine (66 f 4 beats/min, p <O.Ol) compared with the control value (75 f 4 beats/min) (Fig. 1). Similarly, the heart rate while sitting was significantly lower on atenolol alone (60 f 3 beatdmiti, p <O.OOl) and on atenolol plus nifedipine (70 f 4 beats/min, p KO.01) than during the control phase (80 f 5 beats/min), but the value on nifedipine alone (88 f 6 beats/min) was significantly faster (p <0.05). In the 3 patients who suffered LV failure, the control supine heart rate (78 f 3 beats/minj was faster than in those patients who remained free of LV failure (74 f 6 beats/min). In both groups the heart rate displayed a similar response tb each of the treatments.

Examination of the data from the 9 patients revealed that only the supine blood pressure on nifedipine alone (112/74 f 3/3 mm Hg) was significantly lower (p <0.05) than the control value (121/82 f 3/3 mm Hg). In the 3 patients who had LV failure at some stage during treatment, the control supine blood preseure (114/79 f 4/2 mm Hg) was lower than in those patients who remained free of this complication (124/84 f 4/4 mm Hg). As with the heart rate data, the blood pressure in the 2 groups displayed a similar response to each of the treatments. The mean PR intervals during the control phase, on atenolol, on atenolol plus nifedipine and on nifedipine alone were 156 f 7 nis, 164 f 8 ms, 160 f 8 ms and 161 f 9 ms, respectively; there was no significant difference between any of the values.

Exercise heart rate, blood pressure and rate- pressure ‘product: Compared with the control value (152 f 5 beats/min), the peak exercise heart rate was significantly lower on atenolol alone (105 f 4 beats/min, p <O.OOl), on atenolol plus nifedipine (108 f 7 beats/ min, p <O.OOl) and on nifedipine alone (144 f 7 beats/ min, p <0.05) (Fig. 2). The peak control exercise heart rate was slightly lower in those patients who developed LV failure compared with those who did not (148 f 9 vs 154 f 7 beatslmin), but in both groups the response to each of the treatments was identical. As with the exercise heart rate data, the peak exercise systolic blood pressure was significantly lower both on atenolol alone (130 f 4 mm Hg, p <O.OOl) and on atenolol plus ni-

fedipine (125 f 7 mm Hg, p cO.05) compared with control (161 f 8 mm Hg). The peak control exercise systolic blood pressure was also lower in those patients who had LV failure compared with those who did not (155 f 12 vs 164 f 10 mm Hg). In both groups the peak exercise systolic blood pressure showed a similar response to each of the treatments. The peak exercise rate-pressure product was significantly lower on aten- 0101 alone (13,600 f 800, p <O.OOl), on atenolol plus nifedipine (13,800 f 1,500, p <O.Ol) and on nifedipine alone (21,800 f 1,400, p <0.05) than control (24,400 f 1,500).

Cardiac catheterization and nifedipine infusion: Coronary arteriography revealed that 3 patients had l-vessel disease (>70% luminal stenosis of a major coronary artery), 4 patients had 2-vessel disease and 2 patients had 3-vessel disease. All patients displayed extensive LV dyskinesia; in addition, 1 patient had an LV aneurysm. The mean LVEDP for the group as a whole was 30 f 3 mm Hg (range 20 to 42), but in the 6 patients who tolerated the full treatment protocol, the mean LVEDP was 26.5 f 2.0 mm Hg (range 20 to 35) (Fig. 3). In the 3 patients who developed LV failure at some stage during the study, the mean LVEDP was 38 f 3 mm Hg (range 33 to 42).

Two of the 9 patients did not undergo infusion of nifedipine. In 1 of these 2 patients, the LVEDP was prohibitively elevated at 42 mm Hg, while in the other technical diffjculties with the recording equipment prevented accurate measurements. The remaining 7 patients encountered no adverse reactions, and no patient developed LV failure during the course of the

LVF NO LVF LVF

n=7 n=5 n=2 No LVF. LVF NO LVF LVF

0 Control q N,fed,p,ne q N,fed,p,ne w N,fed,p,ne ‘P<O.O5 ‘PCO.01 0.1 @kg/mm 0 2 @g/kg/mln Od~glkglmm 1P<OOOl

FIGURE 3. Changes in (A) heart rate, (B) left ventricu!ar (LV) systolic pressure, (C) Left ventricular end-diastolic pressure (LVEDP) and (D) peak positive dP/dt after intravenous nifedipine in groups of 7, 5 and 2 patients receiving atenolol. Bars represent mean f standard error of the mean for control and nifedipine at 3 infusion rates. LVF = left ventricular failure present at some stage during the study; no LVF = patients remained free of left ventricular failure throughout the study.


TABLE I Radionuclide Indexes of Left Ventricular Function

Control Atenolol

Atenolol + No. of

Nifedipine Nifedipine Significance Patients

PER (EDV/s) 1.63f0.14 1.43f0.15 1.49f0.17 1.66f0.19 9

TPER (ms) 186 f 16 209 f 14 213 f 8 198 f 19 Ii: PFR (EDVh) 1.59 f 0.19 1.32 f 0.13 1.56 f 0.20 1:45 f 0.16

: TPFR (ms) 541 f 40 509 f 14 520 f 13 487 f 19 t: 9

EDV/s = enddiastolic volume/second; NS = not significant; PER = peak ejection rate; PFR = peak filling rate; TPER = time to peak ejection rate; TPFR = time to peak filling rate.

infusion. The mean total dosage of intravenous (IV) nifedipine that each patient received was 518.2 f 25.0 pg. Although the difference was small, the heart rate was significantly faster (62 f 5 beats/min, p <0.05) for the group as a whole after the highest nifedipine infusion rate of 0.4 pglkglmin compared with the preceding rate of 0.2 pg/kg/min, (60 f 5 beats/min). Five of the subgroup of 7 patients who received IV nifedipine remained free of LV failure on the oral drugs. In these 5, there was a tendency for the heart rate to fall as the infusion progressed, whereas in the other 2 patients there was a tendency for the reverse to occur. In the group of 5 patients without LV failure, the mean LV systolic pressure declined from a control value of 123 f 11 to 113 f 9 mm Hg at the end of the infusion (8% decrease). The corresponding values for the 2 patients who suffered LV failure were 114 f 2 and 100 f 2 mm Hg, respectively (12% decrease). For the complete group, the LV systolic pressure was significantly lower after 0.2 (114 f mm Hg, p <O.Ol) and 0.4 pg/kg/min (109 f 7 mm Hg, p <O.OOl) of IV nifedipine compared with the control value (120 f 8 mm Hg).

The LVEDP showed a different response following the infusion of nifedipine in the 2 groups of patients with and without LV failure. Thus, in those patients who remained free of this complication, the value was consistently lower after each of the infusion rates compared with control; in contrast, in those with LV failure the reverse was the case, although the difference was not significant. The peak dP/dt was significantly lower after 0.2 pg/kg/min (1,108 f 59 mm Hg/s, p X0.05) and 0.4 pg/kg/min (1,072 f 60 mm Hg/s, p <O.Ol) of IV nifedipine than control (1,158 f 58 mm Hg/s); both subgroups displayed a similar response.

Radionuclide indexes of left ventricular function: The EF, average ejection rate, time to end systole and average filling rate displayed the only significant changes among the various treatments (Fig. 4). The values of the other indexes are presented in Table I.

The mean control EF (%) for the group as a whole, for the group of 6 patients without LV failure and for the group of 3 patients who suffered LV failure at some stage during the study were 28.5 f 2.4%, 31.5 f 2.8% and 22.6 f 2.7%, respectively. In the group of 6 patients without LV failure, the EF rose significantly from 31.5 f 2.8% to 33.5 f 2.5% (p <0.05) on atenolol alone, whereas in the 3 patients who suffered LV failure it fell significantly from 22.6 f 2.7% to 20.0 f 3.0% (p <0.05). In both groups the EF rose slightly when nifedipine was added, but this effect was greater in those patients

without LV failure. The individual EF and peak ejection rates for each patient on each treatment are plotted in Fig. 5. Five episodes of LV failure occurred in 3 patients during the study; the mean EF and peak ejection rate for the 5 episodes were 19.6 f 2.5% and 1.16 f 0.13 end-diastolic volumes per second (EDV/s), respectively.

Compared with the control average ejection rate for the whole group (0.79 f 0.1 EDV/s), there was a small decline on atenolol alone (0.7 f 0.1 EDV/s, difference not significant) but a rise on atenolol plus nifedipine and on nifedipine alone (0.9 f 0.1 EDV/s). The value on atenolol alone was significantly shorter than that on nifedipine alone (p <0.05), and the patients without LV failure displayed a response similar to that described for the group as a whole. However, in those patients who suffered LV failure at some point during treatment, the average ejection rate was lower on each of the treatments compared with the control value. A similar response was evident with the average filling rate.

The mean time to end systole (Fig. 4) in the 8 patients in whom it could be measured was significantly longer (p <0.05) on atenolol plus nifedipine (414 f 20 ms) than the control (346 f 16 ms) and nifedipine alone (343 f 17 ms) values. For the 6 patients without LV failure, the value on atenolol plus nifedipine (417 f 21 ms) was significantly longer (p <0.05) than that on nifedipine alone (334 f 22 ms). However, in the 2 patients with LV failure, the value on atenolol alone (360 f 12 ms) was significantly longer (p X0.05) than the control value (333 f 11 ms).

Discussion Calcium antagonists and /3-adrenoceptor blocking

drugs have complementary action in the treatment of angina pectoris, and the combination is frequently su- perior to either drug used separately.*15 Most studies that have examined the effect of separate and concur- rent administration of /I-adrenoceptor blockers and calcium antagonists on LV performance and hemody- namics have included patients with well-preserved ventricular functionil-l5 or, alternatively, patients with reversible exercise-induced LV dysfunction.ls The results have indicated that these drugs are generally safe in such situations. However, many patients who com- plain of angina have moderate or severe fixed LV dysfunction, and legitimate concern exists about the possible risks of combining these drugs in this setting.6 We carefully investigated the effect of nifedipine and atenolol given separately and together, both acutely and

May 17, 1985 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 55 ISE

chronically, to patients with significantly impaired LV function. Our patient population was different in that the majority had moderate-to-severe irreversible ventricular impairment and relatively little exercise-induced &hernia.

Several studies have examined the effect of acutely administered nifedipine in patients with impaired LV function. Ludbrook et all9 administered nifedipine, 20 mg sublingually, to 19 patients stratified according to baseline LV performance. In those with impaired cardiac function (LVEDP >20 mm Hg), nifedipine had a signficant and substantial beneficial effect on LVEDP and EF (34% increase), which was more conspicuous than in patients with normal baseline LV function (LVEDP <20 mm Hg) who also displayed an improve- ment. Nelson et a120 examined the effect of nifedipine in 2 similar groups of patients and concluded that the drug did not further impair cardiac pumping activity even in patients with severe LV dysfunction (LVEDP >20 mm Hg). Klugmann,21 Magorien22 and their co- workers treated patients suffering from chronic heart failure with nifedipine, 20 mg sublingually. They showed significant decreases in systemic arterial pressure and pulmonary capillary wedge pressure with ap- preciable enhancement of cardiac index and afterload reduction. In contrast, Brooks et a123 administered a similar dose of nifedipine sublingually to 6 patients with severe cardiac failure; in 2 patients there was a dramatic decrease in systemic arterial pressure, peripheral re- sistance and cardiac output. Thus, they expressed res- ervations about using the drug in patients with LV failure and urged caution about using the drug in patients with poor LV function.

Patients in our study had moderate-to-severe LV dysfunction; those with the greater impairment of LV

NO LiF LVF

C

500 1 ,i,i rihT

‘P < 0.05

‘P < 0.01

FIGURE 4. Effects of atenolol, atenolol plus nifedipine and nifedipine alone on cardiac function indexes as assessed by technetium-99m radionuclide angiography compared with control. Data presented as in Fig. 1. Bars represent mean f standard error of the mean. AVER = average ejection rate; AVFR = average filling rate: EDV/s = enddiastolic volume/second; EF = ejection fraction; TES = time to end systole.

function developed hemodynamic deterioration and LV failure while taking atenolol. Extensive anterior myocardial infarction frequently complicated by LV failure at the time of infarction was an association, as was control LVEDP at cardiac catheterization >32 mm Hg (with the patient taking atenolol) and EF on radionu- elide angiography <30% while on no treatment. Control supine heart rate at rest was slightly higher and blood pressure was slightly lower in patients who developed hemodynamic deterioration. Further, peak exercise heart rate, systolic blood pressure and rate-pressure product were all lower compared with patients who tolerated the full treatment protocol. Other, albeit less important, predictors in clinical practice were the responses of the LV systolic pressure, LV peak positive dP/dt and LVEDP to IV nifedipine; the first 2 variables showed a greater decrease in patients who were intol- erant of treatment and LVEDP tended to increase.

The addition of atenolol precipitated hemodynamic deterioration in 2 patients; this deterioration persisted when oral nifedipine was added. In the third patient, decompensation occurred only during atenolol plus nifedipine treatment. These facts, when considered with the hemodynamic data, support the hypothesis that patients with the lowest EF and highest LVEDP are critically dependent on increased sympathetic stimu- lation to maintain cardiac compensation. In keeping with this finding is the fact that no patient had an adverse reaction to oral nifedipine alone, although a negative inotropic effect was evident from the IV infusion. The negative inotropic effect of oral nifedipine was more than offset by the baroreflex-mediated tachycardia induced by the fall in blood pressure.

This study thus demonstrates that in patients with less severe impairment of LV function, atenolol, alone or in combination with nifedipine, did not further impair cardiac performance. However, in patients with more severe myocardial dysfunction, hemodynamic deterioration occurred with atenolol alone and persisted despite the addition of nifedipine. The decisive factor

A.

5ol

e F 40-

s ‘G 0

30-

li 6 20- .- P iii lo-

0. 2.5-

B 2 2.0- w,

g 1.5- a: El ‘G g l.O-

ii i

s 0.5- h

FIGURE 5. Changes in (A) individual ejection fractions and (B) peak ejection rates as assessed by technetium99m radionuclide angiography in patients on atenolol, atenolol plus nifedipine and nifedipine alone compared with control. The mean for each group is given at each assessment, and open circles (0) denote presence of left ventricular failure. EDV/s = enddiastolic volume/second.


in precipitating cardiac decompensation may have been the removal of the critical supportive function of the sympathetic nervous system in these seriously ill patients.

Acknowledgment: We gratefully acknowledge the technical assistance of S. Dickie, S. Krikler and J. Powell.

1.

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3.

4.

5.

6.

7.

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