Cardiotoxicity of Interferon*

Cardiotoxicity of Interferon* A Review of 44 Cases Moshe Sonnenblick~

M.D.; and Arnold Rosin~

M.B.

Cardiovascular complications have occurred in clinical trials of interferon. We review herein experience to date of cardiotoxicity with all types ofinterferons in cancer patients. The most common presentations of cardiotoxicity were cardiac arrhythmia, dilated ~rdiomyopathy, and symptoms of ischemic heart disease, including myocardial infarction and sudden death. The cardiac effects were not related to

the daily dose, cumulative total dose, or period of therapy. Some of the patients in whom interferon has caused cardiovascular sequelae have had a history of coronary heart disease or have previously been given chemotherapy with drugs known to be cardiotoxic. In most of the patients, cardiac toxicity was reversible following the cessation of the drug therapy.

trials with interferon have been carried out C linical in recent years in patients with various malignant

recombinant interferon alpha. The subtype recombinant interferon alpha-2 was used by 12 patients. Recombinant interferon gamma was used by eight patients. None of the patients received interferon beta.

diseases, but principally in patients with advanced nontreatable cancer. l The most common side effect is a fiulike syndrome. Various systems have been reported to be affected, including the central nervous, gastrointestinal, hematopoietic, musculoskeletal, and endocrine systems. Skin, adnexa and renal function are also affected. That interferon might be cardiotoxic in humans was first suggested following four deaths due to myocardial infarction in patients treated with that agent. Since that report, there have been a few additional reports concerning the possible cardiotoxic effects of interferon. Different manifestations of interferon-induced cardiotoxicity have been reported in some of the patients and were related to the febrile reaction induced by first exposure to interferon. It was also suggested that cardiovascular complications are superimposed on hearts with limited coronary or myocardial reserve. The purpose ofthe present report is to review the literature on interferon-related cardiotoxicity, to describe the various manifestations of cardiotoxicity, and to determine the risk factors possibly associated with interferon effects on the heart. DATA ON REpORTED CASES

There have been 15 reports on 44 patients with interferoninduced cardiotoxicity... us 'Dlble 1 summarizes the type of toxicity, the daily and cumulative total dose, the period of treatment, and the coexistence of underlying heart disease.

Sex and Age The sex and the age of 11 patients were reported. There was no correlation between cardiotoxicity and age or sex (Table 1). 7yPe of Interferon

Most patients with interferon-related cardiotoxicity received *From the Department ofGeriatrics, Sbaare Zedek Medical Center, Jerusalem, Israel. Manuscript received May 31; revision accepted September 4.

Doses and Duration of lreatment Low daily doses «9 x loa U/d) of interferon were administered in only seven patients, while ten of the patients were treated with high doses (>36 x loa U/d). The cardiotoxic effect of interferon was not related to the total amount of interferon nor to the duration of treatment. Toxic effects were documented from doses as low as 0.1 X loa U/d and sometimes after a period of only one day. On the other hand, some of the patients did not show signs of toxicity until after a period of treatment of more than six months, with a cumulative dose of 8,400 x loa U, and in one patient after the cumulative dose exceeded 8,400 X loa U (Table 1).

Underlying Heart Disease At least 12 of the patients had some evidence of preexisting heart disease; a few bad known coronary heart disease. However, while in almost aU of those with known heart disease the manifestations of interferon-induced cardiotoxicity were either arrhythmia or myocardial infarction, none of the patients with cardiomyopathy induced by interferon had known previous heart disease (Table 1).

Doxorubicin lreatment Previous as weD as concurrent treatment with doxorubicin (Adriamycin) was reported in at least eight of the patients. None of these patients had shown any evidence of cardiotoxic effects during the period of doxorubicin therapy (Table 1).

Manifestations of Toxicity Table 2 summarizes the various ways in which interferon-induced cardiotoxicity presented. Most ofthe patients suffered from arrhythmia. Ten suffered a myocardial infarction or sudden death, and cardiomyopathy occurred in five patients. In nine patients the cardiotoxic effect ofinterferon was the direct cause oftheir death. w.e The various manifestations of the cardiotoxicity were not related to the duration of treatment, to the single daily dose, or to the total amount of interferon. Arrhythmia: Supraventricular and ventricular arrhythmias, which were the most common manifestations of cardiotoxicity, were reported in 25 patients. 1.5.7.8.11.15.18 Most had underlying heart disease. Atrial arrhythmias did not represent life-threatening events. Three patients with supraventricular arrhythmia continued treatment without further arrhythmia while receiving treatment with antiarrhythmic drugs. II One patient had fatal ventricular 6brillation ll and CHEST I 99 I 3 I MARCH. 1991

557

Table 1- Summary of Reported CGrdiotoDcity of InterferonNo. of Patients

Ref. No.

2 I

3

4 I I

I

2 I

Type of Interferon

Single Interferon Dose (U)

Total Interferon Dose (Period)

ND

ND

Ralpha

ND

ND

5

ND

None

NR alpha

15 x 1()6

75 x loa

7

ND

Arrhythmia

R alpha-2

ND

ND

8

ND

None

Ralpha

50 x 1()6/ml

8 II

ND F/67

None Left axis

R alpha R alpha-2

50x 1()6 30x 1()6/mt

II

F/67

IO-AVB

R alpha-2

50 x 1()6/mt

15

ND

None

Rgamma

0.6-20 x loa/m t

15

ND

IO-AVB

Rgamma

ND

16 II

ND F/64

None AF

Rgamma R alpha-2

0.1 x IOS/m l 30x 1()6/ml

II

MfTI

None

R alpha-2

lOx IOS/ml

150 x loa/ml (I wk) 50 x loa 150 x loa/ml «Iwk) 1000 x loa/ml «12wk) ND «2wk) ND (2wk) ND 300 x loa/ml «5wk) 60x IOS/ml «2wk)

2 3 6

ND ND ND

ND MI IHD

Alpha Ralpha Ralpha

ND ND SOx IOS/m t

8

ND

AP

R alpha

SOx IOS/m t

9

ND

IHD

R alpha-2

5 x 1()6/ml

16

ND

AP

Rgamma

I x 1()6/ml

4

MI56

None

NRalpba

3xl()6

9

ND

None

R alpha-2

lOx IOS/m t

9

ND

LVH

R alpha-2

I x 1()6/ml

10 II

ND MI58

ND None

Rgamma R alpha-2

ND 30x IOS/m l

9

2

Sex!Age (yr)

Previous Cardiac Disease

1 I

12 13

F/62 M/42

None None

R alpha-2 Ralpha

3-9xl()6 3-35 x loa

1

13

MfJ5

None

Ralpha

35x 1()6

13

MfJ7

None

R alpha

11.8xloa

14

MfT4

None

R alpha-2

3xlOS

ND ND SOx IOS/mt (I d) SOx IOS/ml (I d) 65 x loa/ml (8wk) 2 x loa/m t (2 d) 3xl()6 (I d) ND

6x IOS/m t (3.5 wk) ND 300 x IOS/m t «5 wk)

27 x lOS 5,SOOx lOS (57 wk) 2,700 x 1()6 «II wk) 8,400 x loa (102wk) 540 x loa

Interferoninduced Cardiotoxicity ARRHYTHMIA Atrial and ventricular arrhythmia Fatal VF (I wk) Atrial arrhythmia VF

Comments Mostpreexistent heart disease or doxorubicin

VPBs SVf

Doxorubicin

AF

Doxorubicin

AFland VPBs AFI APBs AF

Doxorubicin

AF

Doxorubicin

ISCHEMIA Fatal MI Fatal MI Fatal MI MI MI Ischemia CHF COMPLICATION Cardiac arrest Left heart failure Sudden death IO-AVB 8R 168Im

Concurrent doxorubicin therapy

Doxorubicin

CARDIOMYOPATHY Cardiomyopathy Cardiomyopathy Cardiomyopathy Cardiomyopathy Cardiomyopathy

-Ref =reference; ND = no data; R = recombinant; NR = nonrecombinant; VF = ventricular fibrillation; VPBs = ventricular premature beats; SVf= supraventricular tachycardia; IO-AVB = lst-degree atrioventricular block; AF = atrial fibrillation; AFI = atrial flutter; APBs = atrial premature beats; MI = myocardial infarction; AP = angina pectoris; IHD = ischemic heart disease; CHF = congestive heart failure; LVH = left ventricular hypertrophy; HR = heart rate.

558

Cardiotoxicity of Interferon (Sonnenbllclc, RosIn)

Table 2- Various PraentationB of Interferon-induced CardiotoDcity No. of Patients

Type of Toxicity Arrhythmia Myocardial infarction/ischemia Cardiomyopathy Sudden death Atrioventricular block Congestive heart failure·

25 9

5 2 2

1

• Another patient with ischemia had, in addition, congestive heart failure. another experienced ventricular tachycardia, 8 both without a history of heart disease. The ventricular tachycardia resolved after the dose of interferon was reduced. Ischemia: Myocardial infarction was reported in eight patients,l1.3.6,8,9 six of whom died.2.3 •6 One additional patient had development of chest pain associated with ST segment elevation on electrocardiogram that was complicated by pulmonary edema. 6 All five patients who were questioned concerning previous heart disease indeed had underlying coronary artery disease.3,8.8.16 Three of the five experienced the ischemic event within the first two days of interferon therapy.6,8,16 Therapy was restarted in one patient after the single dose was reduced significantly, without further cardiac toxicity. Cardiomyopathy: The first case of interferon-induced cardiomyopathy was reported in 1988 by Cohen et a1. 12 Since then cardiomyopathy has been described in another four patients who were treated with interferon. 13,14 In four of the five patients, myocardial dysfunction significantly improved after interferon therapy was suspended. All four patients were treated for a relatively long period, but the average daily dose appeared to be high in only one of the four. Two of the patients were retreated with lower doses of interferon but did not demonstrate a change in the ejection fraction during the rechallenge. DISCUSSION

Three different types of cardiovascular sequelae attributed to interferon treatment have been reported: arrhythmia, manifestations of ischemic heart disease, In most of the cases, the cardioand cardiomyopath~ toxic effect of interferon consisted primarily of arrhythmias. In one study, however, 20 patients receiving recombinant DNA gene interferon were prospectively assessed for cardiac rhythm disturbances; no significant changes in average heart rate and in the frequency of ventricular or supraventricular ectopic beats were documented when comparing monitoring at baseline and during therapy}7 It seems, therefore, that even arrhythmia is a very uncommon side effect of interferon administration. Moreover, from 15 phase 1 trials involving a total of 432 patients, most of whom were given recombinant interferon alphal 8-25 or interferon gamma,26-30 and a few interferon beta,31.32 no significant cardiotoxic adverse effects of interferon were reported. In some of these studies, however, acute effects of interferon in the cardiovascular system consisted mainly of tachycardia, hypertension, and distal cyanosis. Since these side effects were described during the first exposure to interferon, it was suggested

that they were related to the fiulike reaction. Predisposing factors for interferon-related cardiotoxicity are not clear. It appears that in most of the cases, toxicity was not necessarily related to a long period of interferon therap~ Of those on whom data were available, cardiotoxicity occurred in 18 of 24 within five weeks. Similarly, cardiotoxicity occurred in patients receiving low and high daily doses and in patients receiving accumulating doses. Some of the patients died of a cardiac event following the administration of a very low total dose and within one to seven days of initiating the drug treatment. Toxicity was also not related to age. The only possible risk factor for cardiotoxicity was previous cardiac disease, as reported in 12 ofthe patients. An interesting finding is that none of the patients with toxic cardiomyopathy had known previous heart disease. It seems, therefore, that the presence of underlying heart disease can be considered a risk factor for interferon-induced arrhythmia or ischemic manifestations. The importance of previous or concurrent administration of doxorubicin is also not clear. One might speculate that some of the cases of interferon-induced cardiotoxicity were not reported because the toxicity was ascribed to the administration of doxorubicin. More data on cardiotoxicity in patients receiving treatment with interferon who had been previously treated with doxorubicin might clarify the importance of doxorubicin as a contributing risk factor for interferon-induced cardiotoxicity. Although some ofthe adverse effects ofthe different types of interferon might differ from one another, they are, in general, similar. 33 Most of the patients with interferon-related cardiotoxicity received recombinant interferon alpha or recombinant interferon alpha-2. A few received recombinant interferon gamma, while none received interferon beta. Since a great majority of trials with interferon therapy were carried out with the recombinant alpha type, we have to assume that this is the reason that most reports on interferonrelated cardiotoxicity were from patients who had been treated with recombinant interferon alpha. The various presentations of interferon-related cardiotoxicity as shown in the present review indicate more than one mechanism. The most common doselimiting toxicity of interferon is a 8ulike syndrome. Febrile responses are generally noted in all patients and always most severely after the first dose. Increased oxygen demand caused by fever, chills, and tachycardia may therefore precipitate infarction or arrhythmia in compromised myocardium. Another possibility is that interferon induced coronary spasm in these patients. It seems, therefore, that the cardiotoxic effect may be principally due to peripheral vascular effects ofinterferon which reflexly stress the heart. A different mechanism has to be considered to explain the reversCHEST I 99 I 3 I MARCH, 1991

559

ible cardiomyopathy that occurred in patients with no known previous ischemic heart disease. Since three of the patients with interferon-induced myocardial depression were patients with acquired immunode6ciency syndrome, it was suggested that cardiomyopathy resulted from a synergy between human immunode6ciency virus infection and interferon. However, a recent report in interferon-induced reversible cardiomyopathy in a patient with hairy cell leukemia points to a different mechanism. 14 A complex of interferon and cardiac tissue stimulating an autoimmune or inflammatory reaction is a possibility. However, an endomyocardial biopsy carried out in a patient with reversible cardiomyopathy did not demonstrate the characteristics of myocardial damage such as my06brillar loss, sacrotubular swelling, interstitial 6brosis, or inflammation. The only 6ndings were of mild focal vacuolization of the myocytes. 13 Different in vitro studies have been carried out to investigate the effect of interferon on cardiac cells. Lampidis and Brouty-Boye34 studied steadily pulsating rat cardiac cells in culture that were continuously exposed to rat interferon for 24 h and showed a decrease in the beating rate. Although in that study the mechanism for the action of interferon on cardiac cell function was not investigated, it was thought that adenosine triphosphate (ATP) levels are significantly altered in interferon-treated cells. Another possibility suggested is the interchange shown between the action of interferon and noradrenaline in cultured cells. 35 The long-standing stimulation of noradrenaline may cause some eventual impairment of myocyte contractile function. However, another in vitro study investigating the effect of interferon on neonatal rat heart myocytes failed to show any adverse effect on beating rate or any reduction in the ATP/protein ratio. It is therefore not clear from the different in vitro studies whether interferon-induced myocardial depression is by a direct effect or is indirectly mediated by changes in functional cellular elements in response to interferon administration. Since interferon has been introduced principally as antineoplastic therapy and has been administered to patients in a debilitated state, it is possible that some of the cardiovascular sequelae of interferon have been overlooked. From the cases ofcardiotoxicity reviewed, one can point to several possible predisposing conditions. Patients with documented or symptomatic heart disease may show aggravation of ischemic symptoms. Therefore, interferon should not be given in the presence ofunstable angina. Patients with effort angina or previous ischemic events should be under careful cardiac observation following the 6rst dose of interferon until the cessation of the flulike reaction. It is advisable to commence treatment with small doses Arrhythmias, should they and increase them graduall~ 580

occur, must be treated symptomatically, the interferon treatment may be continued, usually without risk. Awareness of the possibility of cardiomyopath~ even in patients without previous cardiac disease, should focus attention on the cardiovascular tolerance of a patient receiving prolonged interferon treatment. If symptoms develop, tests of myocardial function and ejection fraction should be carried out. In older subjects, a routine electrocardiogram should be done before commencing treatment. The present review emphasizes the importance of recognizing the different adverse cardiotoxic consequences of interferon, especially in view ofreported evidence ofthe potential reversibility following the discontinuation of the drug therap~ REFERENCES

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