Long-Term Oral Treatment with High Doses of Verapamil in Lone Atrial Fibrillation*

Transcription

1 Clin. Cardiol. 7, (1984) 0 Clinical Cardiology Publishing Co., Inc. LongTerm Oral Treatment with High Doses of Verapamil in Lone Atrial Fibrillation* P.A. JOHANSSON, M.D.,t s. BERTIL OLSSON, M.D. $ tdepartment of Medicine, Halmstad Central Hospital, Halmstad, and $Department of Cardiology, Medical Clinic I, Sahlgrenska Hospital, Goteborg, Sweden Summary: It has earlier been shown that verapamil given intravenously or orally in sufficiently high single doses, may result in regular ventricular rhythm in patients with atrial fibrillation. We have analyzed whether this effect of verapamil can be utilized in longterm oral treatment. Eleven patients with lone atrial fibrillation were studied. Veriipamil was given in gradually increasing doses from 40 mg three times a day to 30 mg three times a day, either alone or in combination with digoxin. Resting ECG was recorded and supine and standing blood pressures were measured on each dose level. When the patients were treated with verapamil alone, only a slight decrease in heart rate was noted, while during combined treatment with verapamil and digoxin a more marked heart rate decrease occurred with increasing doses of verapamil. The variation coefficient of the RR interval, a sign of ventricular regularity, decreased during verapamil treatment regardless of whether or not digoxin was also taken. A dosedependent blood pressure decrease was noted during verapamil treatment. Address for reprints: P.A. Johansson, M. D. Department of Medicine Halrnstad Central Hospital S Halmstad Sweden Received: September 6, 1983 Accepted: October 15, 1983 Side effects were common and led to discontinuation of the attempted protocol in all patients. Three patients were unexpectedly converted to stable sinus rhythm. Five patients improved subjectively, with a marked decrease in the sensation of palpitations during intake of increasing doses of verapamil. The study indicates that chronic oral treatment with vewpamil may sometimes relieve the subjective sensation of palpitations in patients with atrial fibrillation. Side effects do, however limit the value of this mode of treatment in the majority of patients. Key words: atrial fibrillation, verapamil, ventricularate Introduction One of the disadvantages of atrial fibrillation is a too high ventricular rate. Usually, this can be regulated to adequate levels with digitalis (Redfors, 1971), but in a minority of patients even high doses of digitalis are inadequate in this respect (Goldman et al., 1975). In such patients, beta blockers (Yahalom et al., 1977) or verapamil (Klein et al., 1979) may be used together with digitalis in order to decrease the ventricular rate. In addition to decreasing the ventricular rate, verapamil may induce regular ventricular rhythm in spite of persistence of atrial fibrillation (Khalsa and Olsson, 1979; Khalsa et al., 1979; Shamroth, 1971). Another drawback of atrial fibrillation, the subjective sensation of palpitation, may also be favorably affected by the regular rising effect of verapamil when the drug is given in a single oral dose.

2 ~~ 164 Clin. Cardiol. Vol., March 1983 This study was designed to analyze the effect of longterm oral treatment with verapamil, alone or in combination with digitalis, upon the regularity of the ventricular rhythm during atrial fibrillation, as well as the subjective effects associated with the presumed influence upon ventricular regularity. Patients and Methods Eleven men with lone atrial fibrillation who had all undergone attempted DC conversion without stable sinus rhythm having been achieved were studied. Selected clinical details of the patients are given in Table I. Before admission to the study, the patients were subjected to a routine physical examination, resting ECG, x ray examination of the heart and lungs, and a bicycle ergometer test. No patient had any signs of heart disease, apart fmm the arrhythmia, at the time of the study. The patients were treated with a daily maintenance digoxin dose ranging between 0.5 and mg. One day after stopping digoxin treatment, the patients were given verapamil by mouth in a dose of 40 mg three times a day, gradually increasing, after not less than 3 days, by 40 mg three times a day, until either the final dose of 30 mg three times a day was reached or side effects necessitated discontinuation of the dose increment. All measurements were thus made on each verapamil dose after at least 3 days of treatment. Before each increase of the verapamil dose, the patient was subjected to a physical examination of the heart and lungs, resting ECG, and measurement of the supine and standing blood pressure with a sphygmomanometer. These measurements were made 4 h after the first or second verapamil dose of the day and after at least a 5min supine rest. Subjective side effects or improvements were analyzed by direct questioning. If slow heart rate (<45 beatslmin), dyspnea, vertigo, significant edema, or hypotension was reported or noted, the dose of verapamil was not increased. When side effects occurred, or a daily dose of 960 mg of verapamil had been reached, this treatment was discontinued and the patient was again given digoxin in the previously given dose. When the patient had been treated in this way for at least 4 days, verapamil was added to the digoxin treatment according to the principles already described. All individual RR intervals were measured from a 1530s long ECG tracing, using a paper speed of 50 mm/s. The mean value and standard deviation for RR interval lengths were then calculated for each recording. Heart rate values were calculated for each recording. Heart rate values were calculated from the mean RH intervals. Results Of the 11 patients originally included in the study, two had to be withdrawn. One patient (case 4) could not be analyzed during the second part of the study owing to having moved to Norway, but was given 40 mg verapamil daily in addition to digoxin due to a high resting ventricular rate. He was thereafter controlled at intervals of several months. Another patient (case ) was withdrawn after getting significant dyspnea on a dose of 10 mg verapamil three times a day, resulting in a desire to leave the study. The first part of the study (verapamil without digitalis) was not performed in two patients (cases 6 and 11) as these had had very high ventricular rates with severe symptoms before digoxin treatment was initiated. The individual results from all patients (heart rate, RR variation coefficients, and blood pressure) are given in Tables IIa and b. Heart Rate Heart rate decreased only slightly with increase of the daily dose of verapamil. When digoxin was added, a more pronounced heart rate decrease could be noted (Fig. 1). TABLE I Selected clinical data of patients participating in a study of high doses of vempamil by mouth Initial exercise test Case no. Heart size (total vlm BSA) Max work load (W) HR (beatslmin) / l I I I80 I

3 TABLE IIa Effect of verapamil upon heart rate (HR): variation coefficient of RR interval (VC) and blood pressure (BP)b Digoxin + Verapamil 40mg X 3 80mg x3 10 mg x 3 Case Age BP BP BP BP HR VC HR VC HR VC no. (years) Supine Standing Supine Standing Supine Standing HR vc Supine Standing ' Heart rate in beatsimin Blood pressure in mmhg 135/90 170/ /95 145/90 115/85 10/70 15/80 130/95 130/80 170/95 10/80 155/95 150/ /75 li5/65 135/85 150/ / / / / / / / / /75 135/90 160/ /70 15/ /75 15/75 130/75 115/ / / / / / / / /80 Missing data 10/80 150/100 15/75 140/ /70 100/75 10/70 10/ /85 15/ / / /75 10/75 a ? /80 100/80 c /65 115/65 e, 7 B =t e, /70 140/70 a? /70 110/70 a Q yl E il 3 HR VC. 160mg x 3 00 mg x 3 40 mg x3 80mg x 3 30 mg x 3 5' BP BP BP BP BP Eu HR VC HR VC HR VC HR VC Supine Standing Supine Standing Supine Standing Supine Standing Supine Standing u /90 110/ / /75 110/70 z. B / /85 110/ /70 105/ / /80 110/ /80 10/ /80 115/ i

4 TABLE IIb Effect of verapamil + digoxin upon heart rate (HR); variation coefficient of RR interval (VC) and blood pressure (BP)b Digoxin + Verapamil 40mg x 3 80mg x3 10 mg x 3 Case Age BP BP BP BP HR VC HR VC HR VC HR VC no. (years) Supine Standing Supine Standing Supine Standing Supine Standing / /80 130/ /85 135/ / / /80 10/ / /80 110/ / / /95 145/ /90 15/ / /80 15/ /80 110/ /65 110/ / /75 105/ / /75 105/ /85 135/ /85 15/ / /95 135/ /70 10/ /70 115/ / / / Heart rate in beatdmin Blood pressure in mmhg 160mg x 3 00mg x 3 40mg x3 80mg x 3 30 mg X 3 BP BP BP BP BP HR VC HR VC HR VC HR VC HR VC Supine Standing Supine Standing Supine Standing Supine Standing Supine Standing / 100/ / / 110/ /75 15/70 48 SR 130/ / 115/ / cl W a z d h)

5 P.A. Johansson and S. B. Olsson: Oral verapamil in atrial fibrillation 167 Verapamil dose (mg) 0 40x3 80x3 10x3 160x3 00x3 40x3 80x3 30x3 Verapamil dose (mg) FIG. 1 Effect of various daily doses of verapamil on the individual resting ventricular rates (A) without digitalis treatment (B) while digitalis has also been given to the patient. RR Variability (Signs and Symptoms) Gradually increasing doses of verapamil resulted in a slightly decreasing RR variation coefficient, regardless of whether or not digitalis was given in addition to verapamil (Fig. ). Three patients were converted from atrial fibrillation to sinus rhythm. This occurred in one patient (case 3) at a daily dose of 960 mg of verapamil, in the second patient (case 4) at a dose of 40 mg verapamil and 0.5 mg digoxin daily, and in the third patient (case 6) at a dose of 70 mg of verapamil and 0.5 mg digoxin daily. One

6 168 Clin. Cardiol. Vol.. March Y [r a: A. c A 0 40x3 80x3 10x3 160x3 00x3 40x3 80x3 30x3 Veraparnil dose (rng) I,. I30 40x3 80x3 10x3 160x3 00x3 40x3 80x3 30x3 Veraparnil dose (mg) FIG. Effect of different daily doses of verapamil on RR regularity in the individual patient with atrial fibrillation (A) without digitalis, (B) with digitalis administration. The RR regularity is expressed as the variation coefficient (VC). of these patients (case 3) experienced symptoms and signs indicating an arterial embolus in his right tibia1 artery, but recovered completely and was given chronic anticoagulant treatment. Five patients (cases 3,5,6, 10, and 11) reached an RR variation coefficient of less than 1% during atrial fibrillation, a value earlier used to indicate ventricular regularity (Khalsa and Olsson, 1979). Two of these (cases 10 and ll), as well as two more of the patients who stayed in chronic atrial fibrillation (cases 1 and 8), reported pronounced relief of their palpitation symptoms (Table III). Available data is not conclusive enough to

7 P.A. Johansson and S. B. Olsson: Oral verapamil in atrial fibrillation 169 TABLE 111 Daily oral verapamil doses at which desirable symptomatic effect upon cardiac regularity was noted and at which side effects developed, respectively Case Palpitation Verapamil Side effects Veraparnil no. symptoms dose (mg) dose (mg) Decreased Increased Regular (sinus rhythm) Regular (sinus rhythm) Not changed Regular (sinus rhythm) Not changed Decreased Not changed Decreased Decreased Peripheral edema Effort dyspnea, increased palpitation symptoms Peripheral edema, suspected arterial embolus Effort dyspnea Effort dyspnea, peripheral edema, constipation Slight tiredness Vertigo (vestibular origin) Effort dyspnea (peripheral edema) Peripheral edema Orthostatism, tiredness Flush, dry mouth, periorbital and peripheral edema ( 10) 70 say that a decreased RR variation coefficient developed more easily when verapamil was given in addition to digoxin than without this drug. Blood Pressure A gradual decrease in systolic and diastolic blood pressure could be noted in all patients (Tables IIa, b). Side Effects Side effects were common and necessitated discontinuation of the planned verapamil dose increment in 8 out of 9 patients when verapamil was not combined with digitalis and in 6 out of 8 patients during combined treatment (Table III). The dominant side effects were dyspnea and edema of the ankles, and in one patient also periorbitally. These side effects were dosedependent. When verapamil was given in doses below 10 mg three times a day, no side effects were noted. Discussion One of the aims of this study was to analyze the effect of verapamil on heart rate and ventricular regularity in atrial fibrillation with and without concomitant digitalis treatment. Ethical considerations forced us to abstain from a complete wash out of all digitalis effects before the patients were given verapamil only. For the same reason, two patients (cases 6 and 11) were not investigated with vempamil alone. Thus, the measurements during the initial phase of verapamil treatment (without concomitant digoxin) are presumably influenced by the digoxin treatment, which was stopped one day before verapamil was given. However, calculated with a mean halflife of 1 )/ days for digoxin, the value obtained in the study of doses of 10 mg verapamil or more three times a day alone may be assumed to be pure effects of verapamil. All recordings were made between and 4 hours after the last dose of verapamil was given. This was done intentionally, as our aim was not to study the peak effect of verapamil, but rather the average effect over a longer period. Both verapamil and digoxin have an AVblocking action, thereby decreasing heart rate during atrial fibrillation. This study indicates that the combination of verapamil and digoxin is superior to verapamil alone in this respect. Earlier studies have shown that verapamil may induce regular ventricular rhythm during atrial fibrillation when given intravenously or by mouth (Khalsa and Olsson, 1979; Khalsa el ul., 1979; Shamroth, 1971). This was also found in this study,

8 170 Clin. Cardiol. Vol. 7, March 1984 although permanent ventricular regularity during rest could only be achieved in a few patients. Most of the patients experienced a subjective improvement in their sensations of palpitations although only at a dose level which was not accompanied by side effects. Three patients were unexpectedly converted to sinus rhythm, although earlier attempts at DC conversion had failed, even with concomitant prophylactic treatment to prevent relapse to atrial fibrillation. The present observations concerning conversion to sinus rhythm by combined treatment with verapamil and digoxin warrant further investigation. Blood pressure decreased in a seemingly dosedependent manner. Vertigo was precipitated at a daily dose of mg verapamil in one case, prompting a dose reduction, after which the symptoms disappeared. In the other patient complaining of vertigo, this symptom proved to be of vestibular origin. None of the patients reported fainting. The edema, which appeared to be a common side effect, is presumably caused by the effect of verapamil on peripheral vessels and is a side effect also noted with other calcium antagonists (Pepine and Conti, 1981). This side effect was noted at a daily dose of mg of verapamil or more and was thereafter dose dependent. The edema disappeared in all patients after reduction of the dose of verapamil. We have not been able to find any report in the literature concerning effects of verapamil in maintenance doses above mg daily. Therefore, although our material is small, it demonstrates that blood pressure and heart rate do not drop to levels that may cause serious side effects, provided that no other drug than digoxin is given together with verapamil. Side effects made us abstain from analyzing the effects of high doses of verapamil as intended in the original protocol in all patients who were included in the study. The high frequency of side effects made us also abstain from including more patients in the study. Using a verapamil dose of mg daily, a study on 1 patients with unstable angina in a coronary care unit disclosed side effects in only three patients and none of these had edema (Parodi et al., 1979). However, the patients in that study may have been bedridden, thereby preventing edema from developing in the ankles. Constipation was reported by only one patient in our study. In a larger series of patients, this symptom was present in more than onethird of all cases and was considered severe in 10 out of the 94 patients (Raftos, 1980). It is obvious that the side effects of verapamil in the doses used in this study need to be further evaluated. An interaction has recently been reported between digoxin and verapamil, leading to increasing digoxin concentrations after administration of verapamil (Mein et al., 1980). Neither the digoxin nor the verapamil concentration was measured in this study. If we disregard the effects upon the AV nodal conduction (e.g., RR rate and regularity during atrial fibrillation), however, no patient reported symptoms or exhibited signs which could be attributed to digoxin intoxication. This study indicates that longterm oral treatment with verapamil, alone or preferably in combination with digoxin, may have a beneficial effect on the subjective palpitation symptoms in selected patients with lone atrial fibrillation. Side effects are, however, common with the verapamil doses necessary for documentation of this beneficial effect, thereby reducing the number of patients suitable for this mode of therapy. This treatment should therefore be initiated by stepwise increases of the dose of verapamil under careful observation for any side effects. 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