propafenone for malignant ventricular arrhythmia: an analysis of the literature

Propafenone for malignant ventricular arrhythmia: An analysis of the literature

Maribel Hernandez, MD, Robert F. Reder, MD, Roger A. Marinchak, MD, Seth J. Rials, MD, PhD, and Peter R. Kowey, MD. Philadelphia, Pa., and Whippany, N.J.

There are no really “safe” biologically active drugs. There are only “safe” physicians.

H. A. Kaminetzky

The Food and Drug Administration recently granted approval for the marketing of propafenone (trade name Rythmol), a new class I antiarrhythmic drug, for the treatment of patients with life-threatening ventricular arrhythmias. Although propafenone has been tested in long-term clinical trials in the United States since 1981, many potential prescribing physicians are not familiar with the drug, especially for its labeled use. In addition, no individual published experience has incorporated enough patients to draw firm conclusions regarding the efficacy of the drug for its approved indication. The purpose of this arti- cle is to report the results of our review of the literature regarding the usefulness of propafenone in the treatment of these most serious ventricular arrhythmias.

METHODS

We conducted a computer search of the literature including Bioquest, Medline, and Ringdoc for all ar- ticles and abstracts published between 1980 and 1989 that reported patients who were treated for malignant ventricular arrhythmias with oral or intravenous propafenone. To be included in our review, studies must have included patients with spontaneous sustained ventricular tachycardia (VT), ventricular fibrillation (VP) outside the setting of an acute infarction (including cardiac arrest victims), or nonsustained VT associated with presyncope or syncope. We excluded studies in which we could not be certain of the presenting arrhythmia or those that reported

From the Cardiac Arrhythmia Service, Medical College of Pennsylvania; and Knoll Pharmaceuticals, Whippany, N.J.

Received for publication June 26, 1990; accepted Aug. 6, 1990.

Reprint requests: Peter R. Kowey, MD, Cardiology Division, The Lankenau Hospital, Lancaster Ave. west of City Line, Philadelphia, PA 19151.

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only patients with asymptomatic or minimally symptomatic complex ventricular arrhythmia.

We identified 27 studies that incorporated a total of 684 patients with malignant ventricular arrhythmias treated with propafenone. Table I lists all of the publications utilized in the review. Table II summa- rizes the patient characteristics. The mean age was 57 years, with at least an 80% male preponderance. Since a minority of the studies did not specify the gender ratio of its cohort, an exact count was not possible. More than 69% of studied patients had coronary artery disease. Likewise, the majority had sustained VT as their presenting arrhythmia. In general, patients had failed two to four antiarrhythmic drugs prior to testing with propafenone.

Propafenone was administered only in its intravenous form in 23 patients and as an oral preparation in 661. Ninety-eight of the 661 also received the intravenous form at initial testing. The primary method of evaluation of drug efficacy was invasive programmed stimulation in 416 patients. In each of these cases, a sustained VT was induced at baseline such that an assessment of drug effect was possible.

Another 242 patients had sufficient ventricular ectopy at baseline to allow a noninvasive assessment of antiarrhythmic drug efficacy. Ambulatory monitoring and, in some cases, exercise testing were used to quantify the amount of baseline arrhythmia. Pro- pafenone was deemed effective if it caused a signif- icant reduction on follow-up testing. The criteria for efficacy during noninvasive testing was total elimi- nation of salvos of VT, >90% reduction in the frequency of ventricular couplets, and >50% reduction in the total number of ventricular premature depolarizations.

The remaining 26 patients did not have a paired assessment because propafenone was discontinued

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Table 1. Individual studies

Author No. of

patients VA Heart Daily

disease Form dose (mg) Test

1 mm ST

segment dev.

Efficacy long-term

Podrid (1982) Connolly35

Chilson36 (1983)

14 VT CAD, CM, none PO 450-900 HM/ETT 16 VT, VF, NSVT CAD, CM PO 450-900 EFW-IM

15 VT - PO 900

Katz37 Podrid31 (1984) Naccarella3s Kingha3s

Podridl* (1984)

7 60

9 28 VF 30

VT -

VT, VF, NSVT CAD, CM, V, none VT CAD VT CAD, none

14

2 29

26

28

VT CAD, CM, V, VF VT CAD, CM, V VF VT CAD VT, VF, NSVT CAD, CM, V

VT, VF, NSVT CAD PO 450-900 EPS

VT CAD, CM, V none IV

Raviele45 4 VT,VF CAD

Rabkin46 13 VT, VF CAD Chilson47 (1985) 25 VT, NSVT CAD, CM, V, none

Brodsky’ Minardo48

VT, VF, NSVT CAD, CM PO 900 VT, VF, NSVT CAD PO 779

Cueni4s Dugernierso

Klein13 (1987) KoweyS1

Fauchier5’

12 53

92 48

VT, VF, NSVT CAD, CM, V, none PO 900 VT, VF, NSVT - PO .470-664

Valero53

Klein54 (1988)

Kus~~

Haffajee56

11 27

16

28

20

17

40

VT CAD VT CAD

VT, NSVT CAD

VT CAD, CM

VT CAD PO 600-900 EPS

VT CAD PO 785 EPS

VT CAD PO 450-1200 EPS

9/13 4112 3 13/15 10*

l/7 30/57 6/9 2113 2117 16/30

719 11/14 10* l/2 la/29 12* 17126 12* 18127 14* 314 213 -

15/15 12,

- 2/5 8 mo

S/10 9 mo

-

11/20 16 mo 619 4 mo

25127 7 mo

lo/IO 10 mo

-

-

9/16 15 mo

7117 11 mo

617 11 mo

l/2 14 mo

12/13 12 mo 8110 11 mo

IV

PO PO IV

PO PO

2 mglkg EPS 450-900 HM/ETT 450-900 HM 900 EPS

450-900 HM/ETT, EPS

IV l-2 mg/kg EPS

IV 2 mg/kg EPS

PO 450-900 EPS

2 mg/min 600-1200 1.5 mg/kg

EPS

IV

PO PO PO

EPS

300-900 HM 900 EPS

EPS, HM/ETT EPS 31/53 HM/ETT EPS HM HM EPS, HM/ETT

5/S lo/12 717 14 mo 9131 34153 27 mo

49/93 7148 26148 g/11 7120 517 5116 2114 17128 7* 15115 7* 17117 11*

40140 36*

22135 23 mo 32/48 23 mo

450-900 450-900

PO

PO

IV

PO PO

- 14/15 9 mo

1.5 mg/kg 900 900

EPS 7/14 16 mo

EPS -

lo/14 20 mo

14/36 19 mo

CAD, Coronary artery disease; CM, cardiomyopathy; EPS, electrophysiology study; ETT, exercise treadmill test; HM, Holter monitor; IV, intravenous; mo, month; NSVT, nonsustained ventricular tachycardia; po, oral; V, valvular heart disease; VA, ventricular arrhythmia; VF, ventricular fibrillation; VT, ventricular tachycardia. *Number induced to VT, which was either slower or nonsustained.

during the initial oral dosing because of proarrhyth- Table III. Ninety-seven patients (25 % ) had their VT mia (15 patients) or noncardiac adverse effects (11 rendered noninducible after either intravenous pro- patients). pafenone (23 patients) or after a period of oral dos-

RESULTS ing lasting 2 to 5 days. An additional 125 patients (32%) were still inducible after the drug but had a

The results of electrophysiologic testing were sat- prolongation of the VT cycle length by at least 100 isfactorily reported in 394 patients and are shown in msec with better hemodynamic tolerance. Sixteen

1180 Hernandez et al. April 1991

American Heart Journal

Table II. Summary of patient characteristics

Number of studies 27 Number of patients 684 Mean age 57 (15-82) years Sex ratio (approximate) M:F 80:20 Structural heart disease

Coronary artery disease 414 Cardiomyopathy 51 Valvular 26 None 44 Not specified 89

Arrhythmia on presentation Sustained ventricular tachycardia 494 Ventricular fibrillation 79 Nonsustained ventricular tachycardia 111

Propafenone form and dose range Intravenous l-2 mg/kg 23 Oral 300-900/day 661 Intravenous and oral 98

Method of eualuation Electrophysiology study 416 Holter monitoring/exercise testing 242 Drug discontinued prior to testing 26

Table Ill. Summary of efficacy

Short-term l-5 days Electrophysiology Study n = 394

Non-inducible 97 (25:; 1 Slowed 125 (32%) Nonsustained 16 (4%)

Holterlewercise testing n = 242 Suppressed 171 (70.6 7; )

Long-term 14 (l-57) months n = 368 Free of recurrence 245 (67 5% )

patients (4%) who had sustained VT induced at baseline manifested only nonsustained VT after treatment with propafenone. The combined efficacy rate using all of these end points was 61%.

Short-term efficacy using the noninvasive approach is also presented in Table III. Propafenone was administered from 1 to 5 days after baseline testing. Of 242 patients so evaluated, 171 (71%) met suppression criteria. The range of efficacy in these studies was from 53 % to 92 % .

Of the 409 patients who met either an invasive or noninvasive criterion for efficacy, 368 were discharged from the hospital taking the drug. The mean duration of reported follow-up was 14 months, with a range of 1 to 57 months. Efficacy in the long-term phase of the trials was defined as the absence of symptomatic recurrences of the presenting arrhythmia. Propafenone was judged effective in 245 of the 368 patients (67 % ) who were released taking the drug. If judged by the total number of patients who entered the trials (6841, the long-term efficacy rate was 36%.

Long-term efficacy was further analyzed according to whether or not the patient had been tested inva- sively or noninvasively. Two hundred eighty-one patients in the invasive group were released on long- term therapy and 184 (65 % ) were found to be free of recurrences. Likewise, patients who were tested using noninvasive testing and who were followed for the long term had a similarly good outcome. Of the 87 patients released taking the drug after noninvasive testing, 26 (30 % 1 had a recurrence. However, insufficient information was provided to determine if patients who were rendered noninducible had fewer recurrences than those who achieved the less desirable end points of slowing of VT rate or induction of nonsustained VT.

Table IV lists the adverse experiences that oc- curred either during the short-term or long-term phases. Noncardiac adverse effects forced discontinuation of the drug in 42 patients (6.1% of the total cohort). Cardiac adverse effects are divided into three categories including proarrhythmia, conduction ab- normalities, and congestive heart failure. Definite proarrhythmia was reported in 31 patients (4.5% ), which in 25 patients consisted of an increase in the frequency of ventricular premature depolarizations, couplets, or runs of nonsustained VT, and could be described as nonserious. In six, VT was incessant or was tolerated less well than at baseline. Another 18 patients died suddenly during the follow-up period. These cases may have represented a loss of efficacy of the drug or noncompliance, or may have been caused by a proarrhythmic event. If they are included in the “worst case” assessment of serious proarrhythmia, the incidence of proarrhythmia could be as high as 7.2%) with a serious proarrhythmia frequency of 3.5%.

Ten patients (1.5% ) developed conduction abnor- malities, of which the most common form was sinus arrest. Congestive heart failure of new onset or requiring discontinuation of therapy was reported in 18 patients (2.6% 1. Four of these patients had a left ventricular ejection fraction of 22 % or less measured before propafenone was administered.

DISCUSSION General information. Propafenone, like many new

antiarrhythmic drugs, defies definitive classification according to the Vaughan Williams scheme. It has many properties akin to the class IC compounds, including prolongation of conduction in the atrium, ventricle, atrioventricular node, and accessory connections27 3 In addition, propafenone has been shown to prolong refractoriness in specialized conduction tissue, and to block both p-adrenergic recep- tors and calcium channels.4 The P-blocking property

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of the drug is particularly intriguing, since it may impact on the drug’s efficacy, and may explain some of its adverse effects such as congestive heart failure and exacerbation of bronchospastic lung disease.5 The calcium channel blocking effects are weak and probably not clinically relevant.

The pharmacokinetics of the drug are relatively complex.6 It is almost completely absorbed orally. It undergoes hepatic hydroxylation to 5-hydroxy propafenone, an active metabolite. The extent of metabolism is genetically determined using the same enzyme system as debrisoquine.7 The drug and its metabolite are renally excreted, with a plasma half- life of 5 to 6 hours. The recommended interdosing interval is 8 hours. Some studies in patients with less serious ventricular arrhythmias have used a twice- daily dosing scheme, but this regimen is not recommended for life-threatening arrhythmias. The usual daily starting dose is 450 mg, which may be escalated to 600, 775, or 900 mg daily in three divided doses. Although there is some experience with doses up to 1200 mg per day, the package insert lists 900 mg per day as the maximum recommended daily dose. Be- cause of nonlinear kinetics and the potential for ac- cumulation of the drug and its metabolite, 72 hours should elapse before the dose is escalated.8

The pharmacodynamic effects of the drug have been well explored. In the basic and clinical electrophysiology laboratories, it exerts a powerful effect on conduction velocity in a concentration-related manner.” It exhibits use-dependent properties, as do other drugs of its class. Many of its pharmacologic properties have been described in experiments using the intravenous formulation (which will not be available in the United States). These results may be ex- trapolated to the oral form only with caution, since metabolite concentrations are higher with the use of the peroral preparation.8

A number of potentially important drug interactions have been discovered. Propafenone levels are raised by the concurrent use of cimetidine, and propafenone increases serum digoxin levels and prolongs prothrombin time by interfering with the excretion of warfarin.‘O-l2 Propafenone also interacts with p- blockers and other antiarrhythmic drugs, either pharmacokinetically or pharmacodynamically, and these interactions have important clinical implica- tions.l%I5

Previous studies. Propafenone has been studied in a variety of patient populations for many kinds of arrhythmias. Early studies emphasized ventricular ectopy suppression. The drug was found to suppress ambient ventricular arrhythmia in a number of disease states in the recommended dose range.16* lT This included abolition of simple and complex ventricular

Table IV. Summary of adverse experiences

“0 of cohort

Drug discontinuations 119 17.4 7, Noncardiac adverse effects 42 6.lr,. Proarrhythmia 31 4.5%

Non-serious 25 3.6 ‘L> Serious 6 0.8*;,

Sudden death 18 2.6 5, Congestive heart failure 18 2.6”;, Conduction abnormality 10 1.5%

Sinus arrest 4 0.5 “h Complete heart block 3 0.4 c;, Bundle branch block 1 0.2% Unspecified 2 0.3%

arrhythmias, as well as suppression of VT.18 The drug also suppresses ventricular arrhythmia provoked by exercise.18T lg

Although not approved for these indications, propafenone has demonstrable efficacy for a variety of supraventricular arrhythmias including atria1 fibrillation, atria1 flutter, and reentrant supraventricular tachycardia, either confined to the atrioventricular node or utilizing an accessory pathway.20-22 This efficacy has been substantiated both in the electrophysiology laboratory as well as in extended clinical trials.23t 24

The adverse effects of propafenone have been well described after a substantial European experience and large clinical trials in the United States and Canada.25 The most important of these are cardiac and include ventricular proarrhythmia, heart block, and congestive heart failure.25 The noncardiac adverse effects include nausea, vomiting, dizziness, dysgeusia, fatigue, headache, and blurred vision.25 Fortunately, organ toxic side effects are not common, and when they do occur, usually do not force discontinuation of the drug.

Some of the most comprehensive information regarding the drug has come from a company-spon- sored long-term trial carried out at 85 US centers in which 1175 patients were enrolled.26 The major inclusion criterion was ventricular arrhythmia, which was sustained VT or VF in 59% of patients. Since criteria for entry and judgments concerning efficacy were diverse, the principal value of the study is in the safety information it provides, especially with re- spect to cardiovascular adverse effects. Proarrhyth- mia was reported in 51 patients (4.3 % ), sudden death was reported in 30 (2.6% 1, bradycardia was reported in 11 (0.9%), and congestive heart failure was described in 49 (4.2%). The incidence figures are similar to those obtained in our literature-based report and to those listed in the manufacturer’s package in-



sert from a separate cohort of 2127 patients. The number of patients who were discontinued for any adverse effect was 282 (24.0%)) which is not signifi- cantly different from our overall discontinuation computation of 17 % nor from the 20 % discontinuation rate noted in the package insert.

The present review. Despite a surfeit of information regarding propafenone and the large number of patient-years of experience (estimated at nearly 900,000 patient-years as of December 1989), there has never been a large clinical trial that incorporated only patients with malignant ventricular arrhythmias, the only approved indication for the drug in the United States. The present study was an attempt to review the literature and to report on the cumulative experience in this patient group. We tabulated nearly 700 cases in which there was sufficient information to judge the drug’s efficacy and safety, not only in the acute situation, but also over the long term. We found an efficacy that is similar to that seen in smaller clinical trials and to the reported efficacy of other class I drugs that have a potent effect on conduction.27 As in other published experience, short-term efficacy defined by invasive techniques is substantially less than that defined by noninvasive testing.28 The long-term experience indicates that the drug main- tains its efficacy over a reasonable period of follow- up. The follow-up was favorable, whether the judg- ment of efficacy was made using invasive or noninvasive techniques, perhaps suggesting that the difference in efficacy rates reported using these two techniques is caused by an overprediction of non-re- sponse by the invasive methods.2g Perhaps some clarification of this point will be forthcoming from clinical trials in progress that will study the relative value of invasive and noninvasive testing in predicting the long-term prognosis of patients treated with a number of antiarrhythmic drugs.

The safety data are also informative. Discontinu- ations for noncardiac adverse effects were relatively infrequent, which is consistent with a relatively low risk of organ toxicity with the newer class I drugs.30 Despite the fact that the drug is a negative inotrope, congestive heart failure was relatively infrequent and was seen almost exclusively in patients with poor left ventricular function or a history of heart failure prior to testing. 31 This also undoubtedly represents a strong bias in terms of patient selection, since investigators usually excluded patients with the very worst left ventricular function or uncontrolled heart failure symptoms.

Patients who have a history of sustained ventricular arrhythmia have been shown to be at highest risk of serious proarrhythmia. Nevertheless, proar-

rhythmia was infrequent in our study. Even assum- ing that the patients who died suddenly during out- patient therapy did so because of proarrhythmia, the incidence of serious proarrhythmia is less than that reported for other drugs with similar electrophysiologic properties such as encainide or flecainide.27 We would again add the caution that these data may be biased by the exclusion of patients who have the greatest likelihood of proarrhythmia, those with the worst left ventricular function.

Limitations. This study has a number of limitations, many of which are common to literature-based meta- analyses. Investigators are more prone to report pos- itive rather than negative results, which would se- verely bias reports of this type. Although we took pains to exclude inadequate studies, the amount of clinical information generated may be insufficient to make completely valid judgments regarding safety and efficacy. The methods of evaluation and follow- up are never uniform. In addition, patients studied had a variety of forms and severity of heart disease, the only common thread being the occurrence of a malignant ventricular arrhythmia. Finally, there may be overlap in the patients reported in the literature and those accumulated in the large-scale safety trials. As detailed by Yusuf, Peto, and others, the compen- sation for these flaws is the power of the study whereby the myriad of variables may be offset by the large number of patients analyzed.3”

This study can not be used to make any definitive statement regarding the comparative safety or efficacy of antiarrhythmic drugs. Such pronouncements can only come after large, well-controlled trials in which drugs are compared against each other, opti- mally in the same patients, but at least in cohorts that have similar clinical profiles and presenting arrhythmias. Consequently, analyses such as this provide only some general reassurance that the rates of com- plications and efficacy are reasonable in a defined patient population. In essence, the clinician can be reassured by this kind of experience, even though it does not offer data such as one would obtain from blinded, controlled trials.

Finally, this study has no value in making the decision to use this drug for any other indication or for any other patient group. Although propafenone has been used with reasonable success for supraventricular arrhythmias, including atria1 fibrillation,2” the sponsor never presented information to the Food and Drug Administration (FDA) to gain approval to label the drug for these indications. The decision to use the drug for off-label purposes belongs to the physician after she/he has carried out a careful assessment of the risk versus the benefit.

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CONCLUSIONS

No antiarrhythmic drug is universally safe or effective, but better physician awareness of how antiarrhythmic drugs should be used will improve the chances of therapeutic success. Consequently, physician familiarity with these drugs will be the most important factor in guaranteeing that they will be used properly. Propafenone is the newest addition to the list of drugs available for the treatment of life- threatening ventricular arrhythmia. The information available in the published literature suggests that it has reasonable efficacy and safety, at least compara- ble to and perhaps superior to agents previously released and marketed in the United States. This information should help the physician make proper use of this new antiarrhythmic drug.

The authors thank Ms. Donna Simonds for her patient and ex- cellent help in the preparation of the manuscript.

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propafenone for malignant ventricular arrhythmia: an analysis of the literature

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