British Heartyournal, 1972, 34, 9II-9I4. Br Heart J: first published as 10.1136/hrt.34.9.911 on 1 September 1972. Downloaded from Combined treatment of atrial fibrillation with and beta-blockers

SG. F. Levi and C. Proto From the 4th Division of Medicine, Civil Hospitals, Brescia, Italy

43eta-blockers in combination with quinidine were given to 233 subjects with chronic atrial fibrillation. Conversion to sinus rhythm was obtained in 142 cases (6i%). was combined with quinidine in 122 subjects with a percentage of success of 64*8 per cent; in 32 with a conversion to sinus rhythm of 56.2 per cent; LB 46 in 44 patients who responded in 65 9 per cent of the cases, and practolol in 35 with a re-establishment of sinus irhythm in 45 7 per cent of the patients. In connexion with the duration of atrial fibrillation, the conversion to sinus rhythm was ob- lained in 76 4 per cent of the cases with a fibrillation of less than 6 months' duration and in 35 9 per cent with more than 6 months. Toxic effects and intolerance to treatment are clearly less than with quinidine alone, which is probably due to a synergism between the two drugs, and as a consequence of the beta-blocker ,depressant effects on ventricular excitability which avoids the onset of severe arrhythmias. copyright. e1he treatment of chronic atrial fibrillation Subsequently we have treated groups of with DC shock which initially met with great patients with an association of quinidine and enthusiasm, is now becoming less popular as a more recently beta-blockers, such as alpreno- consequence of the complications (Resnekov, lol, LB 46, and practolol (Levi and Proto, I970) and fatalities (2%, according to recent 1970a, I972).

data: Resnekov, 1970), connected with DC The chemical structure of these latest beta- http://heart.bmj.com/ conversion and the demonstration that most blockers differs from propranolol particularly subjects (72%, according to Szekely, Sideris, in the replacement of the naphtalenic nucleus and Batson, 1970) electrically converted to with the indolic one for LB 46 (Lubawski and sinus rhythm show a relapsing fibrillation by Wale, I969) and a benzenic one for alprenolol the end of 12 months. Blanchot et al. (I969) and practolol (Brandstrom et al., I966; Dol- discussed a return to quinidine therapy to lery, Paterson, and Conolly, I969). reduce atrial fibrillation in cases of failure of Pharmacologically, practolol differs from and 12 re- external shock, obtained positive propranolol by the absence of a membrane on September 25, 2021 by guest. Protected *sults with quinidine in 2I patients where DC activity or quinidine-like effect and by the shock had failed to convert to sinus rhythm. presence of obvious cardioselectivity (Dunlop s* In a recent paper (Levi and Proto, I970b), and Shanks, I968) and, like alprenolol and we reported our results obtained in I22 pa- LB 46, by an intrinsic sympathicomimetic ' tients with chronic atrial fibrillation with com- effect, lacking in propranolol (Hill and Turner, bined treatment with propranolol and quini- I969; Ablad, Brogard, and Ek, I967) (Table dine; 64-6 per cent of patients were converted I). -to sinus rhythm, and we came to the conclu- sion that this therapy 'is indicated in patients TABLE I Comparison of effects of different #,vith atrial fibrillation because of the incidence beta-blockers of successful outcome, because sinus rhythm s can be maintained, because it is excellently Beta-block Membrane Intrinsic sym- Cardioselectivity and because propranolol, with its effect pathicomimetic tolerated, effect depressant effect on ventricular myocardial excitability, provides a safeguard against the Propranolol + + - - possibility of quinidine-induced syncope due Alprenolol + + + + + + ventricular fibrillation'. LB 46 + + + + + +- ,to Practolol + + - + + + Received 29 November 197I. 912 Levi and Proto Br Heart J: first published as 10.1136/hrt.34.9.911 on 1 September 1972. Downloaded from

Methods TABLE 3 Patients converted to sinus rhythm All patients less than 70 years old with chronic No. of Converted Not Per cent atrial fibrillation of no more than 5 years' duration cases to sinus converted in sinus were included in the trial, with the following ex- rhythm rhythm ceptions: patients not well compensated, patients with severe cardiomegaly or with disturbances of Propranolol I22 79 43 64.8 atrioventricular conduction, patients with 'giant Alprenolol 32 i 8 14 56-2 4q left atrium', and those with severe pulmonary LB 46 44 29 15 65-9 hypertension revealed by haemodynamic analysis. Practolol 35 i6 I9 45 7 Subjects with bronchial asthma and obstructive Total 233 I42 9I 60-9 bronchopathies without respiratory insufficiency were treated with quinidine combined with al- prenolol, LB 46, or practolol, which, unlike pro- pranolol, and because of their intrinsic beta- stimulating effect, have poor activity on bronchial fibrillation, 6 thyrotoxic heart, and 2 congeni- A smooth muscle. tal heart disease, sinus rhythm was re-estab- We followed Stem's therapeutic schedule lished in 79 patients (64-8%). (Stem, I966) by administering a dose of beta- In 32 patients we tried to restore sinus blocker every 6 hours for two to four days to reach rhythm with the association of alprenolol- an average ventricular rate of 6o to 8o beats/min. At this time quinidine was added (hydroquinidine quinidine, with a favourable result in 56 2 per IS centigrammes with any single dose of beta- cent of the cases (i8 subjects). Of the 32 blocker). The combined treatment was carried on patients with chronic atrial fibrillation, IS had for another four to five days until atrial fibrillation coronary artery disease, I3 valvular heart was converted to sinus rhythm. To maintain sinus disease, and 4 thyrotoxic hearts. rhythm, treatment was continued indefinitely at Of 44 patients treated with LB 46 - quini- slightly reduced doses. dine combination, 20 had sclerotic heart dis- The combined treatment was withdrawn after ease, 17 valvular heart disease, 4 idiopathic five to seven days when sinus rhythm failed to be atrial fibrillation, 2 thyrotoxic hearts, and i achieved, or earlier in some rare cases of pharma- copyright. cological intolerance. luetic heart disease. Conversion to sinus Alprenolol, LB 46, and practolol were adminis- rhythm was obtained (65'9%) in 29 subjects. tered at a pharmacologically determined dosage, The combination ofpractolol-quinidine was corresponding to the beta-blocking effect obtained given to 35 patients, i8 of whom had sclerotic with propranolol, 20 mg. The doses were pro- heart disease and I7 valvular heart disease; i6 pranolol 20 mg; alprenolol 50 mg; practolol ioo responded (4517%). LB times a mg; 46 5 mg; 4 day. To provide evidence that the duration of http://heart.bmj.com/ The results of the trial confirmed that the atrial fibrillation is a key factor to the success therapeutic effects of these doses were the same. of In fact we were able to show the similar effect of the therapy, we divided the patients into 2 the 4 drugs by calculating the average reduction groups according to the duration of arrhyth- of heart rate in patients with re-established sinus mias (less or more than 6 months) (Table 4). rhythm (Table 2). In the first group we obtained conversion to sinus rhythm in 84-4 per cent of cases with

Results on September 25, 2021 by guest. Protected A combination of quinidine and beta-blockers TABLE 4 Duration offibrillation as factor in (Table 3) was administered to 233 patients determining success of conversion to sinus with chronic atrial fibrillation. Of I22 patients rhythm treated with propranolol and quinidine, of whom 59 had coronary artery disease, 48 Duration No. of Converted Not Per cent valvular heart disease, 8 idiopathic atrial of atrial cases to sinus converted fibrillation rhythm (mth) 4

TABLE 2 Propranolol < 6 66 56 Io 84-8 Per cent decrease of cardiac rate > 6 56 23 33 4I.I with different combinations Alprenolol < 6 2I 15 6 7I-4 > 6 II 3 8 27-2 Proprano- Alepreno- LB 46 Practo- LB 46 <6 3I 25 6 8o06 lol lol lol >6 I3 4 9 307 Practolol < 6 26 14 I2 53-8 Before 9I 97 94 95-8 > 6 9 2 7 22-2 After 59-2 62 60 63.6 Per cent Total < 6 144 II0 34 76 4 decrease 35 36 37 34 > 6 89 32 57 35.9 Quinidine beta-blockers treatment of atrial fibrillation 913 Br Heart J: first published as 10.1136/hrt.34.9.911 on 1 September 1972. Downloaded from

propranolol, 7I.4 per cent with alprenolol, (Proto et al., I969, I97I). No sudden death 8o06 per cent with LB 46, and 53-8 per cent due to cardiac arrest or ventricular fibrillation with practolol; in the other group (patients occurred in any of our subjects. We recorded with atrial fibrillation lasting more than 6 quinidine-induced toxic signs in 4-8 per cent months) conversion to sinus rhythm was (9 cases) but never of a severe type (5 cases in achieved in 4II per cent of cases with pro- the group treated with propranolol, 2 cases t pranolol, 27-2 per cent with alprenolol, 30-7 in the LB 46 group, i in the group treated per cent with LB 46, and 22-2 per cent with with alprenolol, and i with practolol). Cere- practolol. bral embolism occurred in 2 patients treated Of I42 cases converted to sinus rhythm, with quinidine and practolol on the second atrial fibrillation lasted for less than 6 months and the fifth day after conversion to sinus in IIO and for more than 6 months in 32; of rhythm. The treatment was continued with 9I subjects who failed to return to sinus quinidine alone 400 mg/day intramuscularly. W rhythm the atrial fibrillation lasted for over 6 The beta-blocker withdrawal caused serious months in 57. electrocardiographic abnormalities, particu- Of 79 patients treated with the propranolol- larly with reference to QT and the morph- quinidine combination with conversion to ology of the T wave (Fig.), confirming that sinus rhythm, 56 were controlled after 6 the beta-blockers probably provide a safe- months. 73-2 per cent maintained the sinus guard against some quinidine-induced electro- rhythm even when the combined treatment cardiographic abnormalities. X was not followed constantly; this result is For these reasons we think that treatment clearly better than those already reported for with quinidine-beta-blockers is a useful com- treatment with quinidine alone. bination for chronic atrial fibrillation, because With the exception of sporadic ventricular of the rapidity of response and its ability to extrasystoles, no electrocardiographic abnor- maintain sinus rhythm; in particular, these mality due to the drugs was observed during drugs are pharmacologically compatible, and

the trial either before or after conversion the depressant effect on ventricular excitability copyright.

FIG. Electrocardiogram in the course of the treatment with practolol-quinidine (a) and after withdrawal (b) ofpractolol. http://heart.bmj.com/

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r *2 ' V6 914 Levi and Proto Br Heart J: first published as 10.1136/hrt.34.9.911 on 1 September 1972. Downloaded from of the beta-blockers protects from quinidine- Brandstrom, A., Corrodi, H., Junggren, U., and Jon- sson, T. E. (I966). Synthesis of some beta-adrener- induced syncopes due to ventricular fibrilla- gic blocking agents. Acta Pharmaceutica Suecica, tion. 3, 303. With regard to a pharmacological tolerance Dollery, C. T., Paterson, J. W., and Conolly, M. E. superior to propranolol, the second group of (i969). Clinical pharmacology of beta-receptor- treated with LB blocking drugs. Clinical Pharmacology and Thera- patients alprenolol, 46, and peutics, 10, 765. practolol cannot be perfectly compared with Dunlop, D., and Shanks, R. G. (i968). Selective block- the first one. In fact, the second series inclu- ade of adrenoceptive beta receptors in the heart. ded patients with chronic bronchopneumonia, British Journal of Pharmacology and Chemotherapy, who could not be treated with 32, 20I. certainly pro- Hill, R. C., and Turner, P. (i969). Preliminary investi- pranolol and, in particular in those treated gations of a new-adrenoceptive receptor blocking with practolol, the series included patients not drug, LB 46, in man. British Journal of Pharma- perfectly compensated. cology, 36, 368. This with the lack Levi, G. F., and Proto, C. (197oa). Associazione al- may explain, together of prenololo-chinidina per il trattamento della fibril- membrane effect of practolol, a lower percen- lazione atriale cronica. Le Clinica Terapeutica, 55, tage of conversions to sinus rhythm than with II5. the other beta-blockers. Levi, G. F., and Proto, C. (I97ob). Combined treat- In conclusion, the combination of beta- ment of atrial fibrillation with propranolol and quinidine. Cardiology, 55, 249. blockers and quinidine in the treatment of Levi, G. F., and Proto, C. (I972). Associazione di un chronic atrial fibrillation is valid for the nuovo beta-bloccante, LB 46 con idrochinidina per following three reasons. il trattamento della fibrillazione atriale cronica. Minerva Cardioangiologica, 20, 92. Lubawski, I., and Wale, J. (i969). Studies with LB 46, i) No harmful effects from therapy: pre- a new beta-receptor blocking drug. European Jour- treatment with beta-blockers allows the use of nal of Pharmacology, 6, 345. hydroquinidine in small doses (about 20% of Proto, C., Quadri, A., Rovetta, A., and Levi, G. F. those usually employed) for a possible syner- (i969). Trattamento combinato propranololo-chini- gism between the two drugs. dina della fibrillazione atriale cronica. Aspetti

elettrocardiografici nei soggetti in ritmo sinusale copyright. 2) The depressant effect of beta-blockers on ripristinato. Cardiologia Pratica, Suppl. 2-3, I29. ventricular excitability prevents the onset of Proto, C., Levi, G. P., Quadri, A., and Levi, G. F. severe arrhythmias. (I97i). Associazione LB 46-chinidina nel tratta- mento della fibrillazione atriale cronica. Aspetti 3) The percentage of subjects who remain in elettrocardiografici nei soggetti in ritmo sinusale sinus rhythm after 6 months is clearly higher ripristinato. Minerva Medica, 62, 2772. than after electrical conversion. Resnekov, L. (1970). Types of complications after DC shock. In Symposium Cardiac Arrhythmias, Elsinore, Denmark, p. 412. Astra, Sodentalze, Sweden. http://heart.bmj.com/ Stem, S. (i966). Synergistic action of propranolol with References quinidine. American Heart Journal, 72, 569. Ablad, B., Brogird, M., and Ek, L. (i967). Pharmaco- Szekely, P., Sideris, D. A., and Batson, G. A. (I970). logical properties of H. 56/28/a beta- Maintenance of sinus rhythm after atrial defibrilla- receptor antagonist. Acta Pharmacologica et Toxico- tion. British Heart Journal, 32, 741. logica, 25, Suppl. 2, 9. Blanchot, P., Fontanille, P., Coumau, P., and Tisne, J. (i969). Retour au traitement par la quinidine Requests for reprints to Dr. G. F. Levi, 4th apres echecs des chocs electriques pour fibrillation Division of Medicine, Civil Hospitals, Brescia, auriculaire. Bordeaux Medical, 2, 511. Italy. on September 25, 2021 by guest. Protected