Evidence for risk of cardiomyopathy with hydroxychloroquine

Abstract

Sir,

Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic drug used in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).^1–3 SLE and RA carry an increased cardiovascular morbidity and mortality risk because of the inflammatory nature of these diseases.^4–6 While HCQ has been shown to lessen the cardiovascular risk associated with SLE and RA,⁷ we believe direct cardiotoxic effects can occur with prolonged HCQ therapy.

A literature search found 17 reports of cardiomyopathy (four fatal) associated with HCQ therapy.^8–11 Among these 17 HCQ cardiomyopathy reports, 13 had a diagnosis of SLE; the remainder had RA. Patient ages ranged from 31 to 88 years. Dosage levels before hospitalization were generally ≤400 mg per day. The total dose collected from 10 of the 17 reports ranged from 290 to 4380 g, with a median dosage of 1825 g, or 12.5 years of continuous therapy at 400 mg per day. Figure 1 shows the duration of HCQ treatment at the time cardiotoxicity was detected, with only two of 16 cases occurring before three years. All patients who survived had improvement of cardiomyopathy upon HCQ discontinuation.

Figure 1

Duration of hydroxychloroquine (HCQ) treatment before cardiotoxicity detected, 16 patients (treatment duration information missing for one patient).

HCQ is fifth among drugs generating cardiomyopathy signals in MedWatch

The reports of HCQ-associated cardiomyopathy motivated an investigation of cases reported to MedWatch, the U.S. Food and Drug Administration’s (FDA) Adverse Event Reporting System (AERS). MedWatch is a voluntary reporting system for serious adverse events associated with FDA-regulated drugs and biologics. Information submitted by healthcare professionals and consumers through MedWatch is publicly disseminated via the AERS database. AERS reports are reviewed by the Center for Drug Evaluation and Research and the Center for Biologics Evaluation to monitor product safety. The AERS data are limited by the voluntary submission requirements, the ability of non-healthcare professionals to submit adverse event reports, and permitting reports without causality proven between the product and the adverse event. These attributes constitute many of the weaknesses in this study. More than 600,000 reports were submitted to the FDA MedWatch system in 2010, with healthcare professionals and consumers each constituting roughly half of the reporters (51.4% vs. 48.6%, respectively).¹² These data allow calculation of the proportional reporting ratio¹³ (PRR) as a signal for association of cardiomyopathy with a given drug, measuring the disproportionality of a particular adverse event (AE) occurring for a drug with respect to the same AE occurring in all drugs. The PRR is calculated as:

\frac{\frac{Reports AE with Drug of Interest}{Reports of All AEs with Drug of Interest} [HCQ]}{\frac{Reports of AE with All Drugs}{Reports of All AEs with All Drugs} [All Drugs]}

The PRR for cardiomyopathy and corresponding Pearson χ² statistic was calculated for all MedWatch cases from 2004 to 2010 inclusive. Data mining techniques, similar to those of Moore et al.,¹⁴ selected all AERS reports from 2004 to 2010 where cardiomyopathy was the adverse event, then tabulated those reports where HCQ was the primary suspect; this total provided the HCQ numerator above. Reports of cardiomyopathy for all drugs in the database were collected to provide the equivalent total for all drugs in the PRR denominator. Table 1 lists the primary suspect drugs with the highest PRR values, signifying a higher rate of cardiomyopathy incidence when compared to other drugs within the database. Table 1 lists the drugs with the highest PRR values, signifying a higher rate of cardiomyopathy reported with HCQ than all but four drugs in the AERS database. Most drugs in this table are either antineoplastic/immunomodulating drugs or have known cardiac toxicity, such as digoxin and clozapine. Cardiac myocytes have limited ability to regenerate or otherwise overcome oxidative stress because of antimetabolites and other intracellular stress. Specific mechanisms, summarized by Figueredo,¹⁵ are shown.

Table 1

Drugs with proportional reporting ratios greater than 10 calculated from MedWatch database

Drug name	Proportional reporting ratio (PRR)	χ²	Potential cardiomyopathy mechanism
Digoxin	77.4	24,712.2	Higher digoxin levels toxic to myocardium
Ondansetron	54.8	792.8	Unknown
Alglucosidase alfa	45.7	1224.8	Unknown
Trastuzumab	36.7	2847.6	HER2 receptors in myocardium
Hydroxychloroquine	28.2	262.4	Inhibition of lysosomal hydrolases (7)
Doxorubicin	27.3	1088.9	Anthracycline oxidative stress in myocytes (7)
Rosiglitazone	23.2	7635.1	PPAR-γ-deficiency in myocytes
Propofol	22.8	2802.6	Unknown
Pamidronate	16.9	806.9	Unknown
Nilotinib	15.6	309.4	Tyrosine kinase inhibitor myocyte toxicity (7)
Clozapine	15.6	388.9	Direct myocyte toxicity, unknown mechanism
Cytarabine	14.3	156.9	Antimetabolite
Fluorouracil	12.6	148.9	Coronary ischemia and vasospasm
Bortezomib	12.2	619.8	Ubiquitin-proteasome inhibition
Nevirapine	12.2	227.5	Unknown
Cyclophosphamide	11.8	259	Antimetabolite (alkylating agent) myocyte death
Betaseron	11.2	427.9	Myocarditis by immune overstimulation
Rituximab	10.2	391.7	Cytokine release cardiomyopathy
Imatinib	10	391.6	Tyrosine kinase inhibitor myocyte toxicity (7)

Measures to prevent HCQ toxicity: Cardiac screening and drug holidays

First, greater awareness of HCQ cardiotoxicity is needed. Early detection may be lifesaving, since our 17-case review showed cardiac status improved in all cases where HCQ was discontinued. There are currently no screening guidelines for HCQ cardiotoxicity. Newton-Cheh et al. suggested an annual electrocardiogram (ECG).¹¹ Cotroneo et al. observed that abnormalities detectable by ECG such as atrioventricular block and bundle branch block precede HCQ cardiomyopathy.¹⁰ Our data show HCQ cardiomyopathy mostly occurs after three years of therapy. Questioning patients on HCQ regarding symptoms suggesting cardiac compromise including dyspnea on exertion should be a component of management, especially for patients on HCQ doses >400 mg/day. The safety of HCQ may be increased by therapeutic holidays for some patients on HCQ therapy, for example, those patients with cutaneous lupus erythematosus who may not need HCQ therapy during the winter months.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors have no conflicts of interest to declare.

Note

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