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Bradyarrhythmias Associated with Sofosbuvir Treatment - Correspondence
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Download the PDF here
Download the PDF here
N Engl J Med November 5 2015; 373:1886-1888
Bradycardia, also known as bradyarrhythmia, is a slow heart rate, namely, a resting heart rate of under 60 beats per minute (BPM) in adults. It is a type of cardiac arrhythmia. It seldom results in symptoms until the rate drops below 50 BPM......https://en.wikipedia.org/wiki/Bradycardia
To the Editor:
Treatment with sofosbuvir-based regimens is associated with a sustained virologic response in more than 90% of patients with chronic hepatitis C virus (HCV) infection, with a rate of serious adverse events of less than 5%.1 Here, we report three cases of severe bradyarrhythmia that occurred during treatment with sofosbuvir plus daclatasvir, simeprevir, or ribavirin among 415 patients treated in our unit from January 2 to December 31, 2014.
The characteristics of the patients at baseline are provided in Table 1, and electrocardiograms for Patients 1 and 3 are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org. Symptomatic bradycardia, with syncope in two cases (Patients 2 and 3), occurred within the first 10 days of treatment with sofosbuvir. The bradycardia was due to sinus-node dysfunction in Patients 1 and 2 and to intermittent third-degree atrioventricular block in Patient 3. In Patient 1, sinus-node dysfunction persisted after treatment with propranolol was discontinued. In Patient 2, sinus-node dysfunction resolved after discontinuation of treatment with sofosbuvir, simeprevir, and amiodarone. However, the reintroduction of sofosbuvir (with ribavirin), 46 days later, was followed by recurrence of the conduction abnormality at day 6. Pacemakers were implanted in all three patients. In Patient 1, interrogation of the pacemaker (performed by a cardiologist who was unaware of the patient's identity) during sofosbuvir treatment revealed atrial pacing during 26% of the exposure time. Three months after the discontinuation of sofosbuvir treatment, atrial pacing was observed for 4% of the exposure time.
Common causes of bradyarrhythmia (electrolyte disorders, renal insufficiency, thyroid dysfunction, and cardiac ischemia) were ruled out. In Patient 2, a known drug interaction between amiodarone and simeprevir could have been a factor in the initial occurrence of bradyarrhythmia. Simeprevir could not have contributed to the recurrence 46 days later. Given the long half-life of amiodarone, we cannot exclude the possibility that residual levels of this agent contributed to the recurrence when sofosbuvir treatment was reintroduced.
In January 2015, after four arrhythmias in 1337 patients were found in a safety investigation of the compassionate use of daclatasvir given with sofosbuvir in France, the French National Agency for Medicines and Health Products Safety published an online warning.2 In March 2015, the Food and Drug Administration warned that serious slowing of the heart rate can occur when HCV treatments, including sofosbuvir plus another antiviral drug, are taken together with amiodarone.3
The pathophysiological mechanism underlying this potential adverse event is not clear. However, the potential cardiac toxicity of sofosbuvir-containing regimens suggests the need for caution with the use of such regimens, including review of other medications, consideration of risk factors for bradyarrhythmias, and possibly monitoring of cardiac rhythm during the initiation of therapy.
Helene Fontaine, M.D.
Arnaud Lazarus, M.D.
Caroline Pecriaux, M.D.
Francois Bagate, M.D.
Philippe Sultanik, M.D.
Estelle Boueyre, M.D.
Marion Corouge, M.D.
Vincent Mallet, Ph.D.
Anais Vallet-Pichard, M.D.
Philippe Sogni, Ph.D.
Denis Duboc, Ph.D.
Stanislas Pol, Ph.D.
Hopital Cochin, Paris, France
helene.fontaine@cch.aphp.fr
for the Cochin Hepatology and Cardiology Group
Gilead Sciences, the manufacturer of sofosbuvir, replies: The three cases of bradyarrhythmia described by Fontaine and colleagues, in addition to other cases, were promptly reported by Gilead Sciences to the Food and Drug Administration and to the European Pharmacovigilance Risk Assessment Committee as we became aware of them earlier this year. To date, according to data on file at Gilead Sciences, more than 13,000 clinical trial participants have received a sofosbuvir-containing regimen, and more than 470,000 patients have been treated with sofosbuvir or ledipasvir-sofosbuvir since their approvals in 2013 and 2014, respectively. To put this in a broader context, postmarketing pharmacovigilance identified nine cases of symptomatic bradycardia worldwide in patients who were taking amiodarone and sofosbuvir, in combination with another direct-acting antiviral agent. These cases resulted in "Dear Health Care Provider" letters and label updates to sofosbuvir, ledipasvir-sofosbuvir, simeprevir, and daclatasvir. Efforts are under way to elucidate the potential mechanism of the interaction with amiodarone and the combination of direct-acting antivirals. Symptomatic bradycardia has not previously been associated with sofosbuvir treatment in the absence of amiodarone and another direct-acting antiviral (e.g., sofosbuvir with ribavirin or pegylated interferon and ribavirin).
In their case report, Patient 2 was receiving amiodarone. Although treatment with amiodarone was discontinued, its mean plasma half-life of 58 days1 suggests that substantial drug levels may have been present at the time HCV treatment was reintroduced, 46 days later.
The report also suggests that the reduction in atrial pacing from 26% during HCV treatment to 4% at 3 months after treatment suggests a causal relationship between treatment and a requirement for pacing in Patient 1. This patient had decompensated cirrhosis (Child-Pugh class C with a MELD [Model for End-Stage Liver Disease] score of 23, on a scale from 6 to 40, with higher scores indicating more severe disease) at the time of treatment, and after sustained virologic response, the patient had substantial clinical improvement, with a reduction in MELD score to 13. This clinical improvement could also potentially account for the change in the need for atrial pacing, given the well-described effects of end-stage liver disease on cardiac function, including bradyarrhythmias.2,3
According to data on file at the Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET), amiodarone use is uncommon among HCV-infected patients who are treated with sofosbuvir in combination with another direct-acting antiviral agent. Per the recent label updates, cardiac monitoring is recommended in the rare instance in which coadministration of amiodarone and sofosbuvir with another direct-acting antiviral is necessary to avoid these rare events. However, making generalized recommendations on the basis of these isolated case reports - such as routine monitoring of cardiac rhythm during the initiation of sofosbuvir therapy, as suggested by Fontaine et al. - seems premature.
Diana M. Brainard, M.D.
John G. McHutchison, M.D.
Gilead Sciences, Foster City, CA
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