Abstract
Introduction
Sofosbuvir is a new direct-acting pyrimidine nucleotide analogue antiviral drug that has shown remarkable efficacy in the treatment of hepatitis C in clinical trials. However, observational anecdotal data have recently suggested an increased risk of serious bradycardia among patients treated with sofosbuvir and amiodarone.
Objective
We aimed to estimate and characterize the cardiac safety of sofosbuvir by performing a systematic review of randomized controlled trials (RCTs).
Methods
We conducted a systematic review of RCTs (PROSPERO 2016: CRD42016033109) comparing sofosbuvir and non-sofosbuvir regimens in patients with chronic hepatitis C by searching the MEDLINE, Embase, and Cochrane Library databases up to January 2017. Non-published data were obtained from the sofosbuvir marketing authorization holder. Random-effects meta-analysis was performed to derive pooled estimates of relative risks (RRs) and corresponding 95% confidence intervals (CIs).
Results
Six trials, enrolling 2346 patients (1625 treated with sofosbuvir), were included. The overall risk of bias across studies was moderate. The risk of reported cardiac events (RR 0.87; 95% CI 0.41–1.85), arrhythmias (RR 0.93; 95% CI 0.34–2.51), bradycardia (RR 0.47; 95% CI 0.04–5.20), and tachycardia (RR 0.91; 95% CI 0.20–4.20) were not significantly different between sofosbuvir and non-sofosbuvir regimens. The risks of reported syncope, presyncope, loss of consciousness, or palpitations were similar among those receiving sofosbuvir regimens and controls.
Conclusions
The pooled data from RCTs did not show an increased risk of cardiac outcomes, including arrhythmias (and bradycardia), among sofosbuvir-treated patients, although the overall quality of the evidence supporting this conclusion was very low.
Registration: PROSPERO 2016:CRD42016033109 at http://www.crd.york.ac.uk/PROSPERO/.
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References
Yang HJ, Ryoo JY, Yoo BK. Meta-analysis of the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection. Int J Clin Pharm. 2015;37(5):698–708.
US Department of Health and Human Services. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir (Harvoni) or Sovaldi in combination with another Direct Acting Antiviral drug. Silver Spring, MD: 2015; US FDA. http://www.fda.gov/Drugs/DrugSafety/ucm439484.htm. Accessed Mar 2017.
Renet S, Chaumais MC, Antonini T, et al. Extreme bradycardia after first doses of sofosbuvir and daclatasvir in patients receiving amiodarone: 2 cases including a rechallenge. Gastroenterology. 2015;149(6):1378.e1–1380.e1.
Brainard DM, McHutchison JG. Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med. 2015;373(19):1888.
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65–94.
Zorzela L, Loke YK, Ioannidis JP, et al. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.
Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med. 2015;373(19):1886–8.
White VJ, Glanville JM, Lefebvre C, et al. A statistical approach to designing search filters to find systematic reviews: objectivity enhances accuracy. J Inf Sci. 2001;27(6):357–70.
Glanville JM, Lefebvre C, Miles JN, et al. How to identify randomized controlled trials in MEDLINE: ten years on. J Med Libr Assoc. 2006;94(2):130–6.
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions. 5.1.0 ed. New York: Wiley; 2011.
Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002;21(11):1575–600.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351–75.
Bradburn MJ, Deeks JJ, Berlin JA, et al. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26(1):53–77.
Bhaumik DK, Amatya A, Normand SL, et al. Meta-analysis of rare binary adverse event data. J Am Stat Assoc. 2012;107(498):555–67.
Caldeira D, David C, Santos AT, et al. Efficacy and safety of low molecular weight heparin in patients with mechanical heart valves: systematic review and meta-analysis. J Thromb Haemost. 2014;12(5):650–9.
Cai T, Parast L, Ryan L. Meta-analysis for rare events. Stat Med. 2010;29(20):2078–89.
Friedrich JO, Adhikari NK, Beyene J. Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol. 2007;23(7):5.
Alonso-Coello P, Oxman AD, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016;30(353):i2089.
Alonso-Coello P, Schunemann HJ, Moberg J, et al. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016;28(353):i2016.
Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–6.
Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867–77.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–87.
Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med. 2014;370(21):1993–2001.
Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir–sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015;15(4):397–404.
Feld JJ, Jacobson IM, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599–607.
Sperl J, Horvath G, Halota W, et al. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: a phase III randomized controlled trial. J Hepatol. 2016;65(6):1112–9.
Josefsson A, Fu M, Bjornsson E, et al. Prevalence of pre-transplant electrocardiographic abnormalities and post-transplant cardiac events in patients with liver cirrhosis. BMC Gastroenterol. 2014;05(14):65.
Mozos I. Arrhythmia risk in liver cirrhosis. World J Hepatol. 2015;7(4):662–72.
Karajamaki AJ, Patsi OP, Savolainen M, et al. Non-alcoholic fatty liver disease as a predictor of atrial fibrillation in middle-aged population (OPERA Study). PLoS One. 2015;10(11):e0142937.
Mantovani A, Ballestri S, Lonardo A, et al. Cardiovascular disease and myocardial abnormalities in nonalcoholic fatty liver disease. Dig Dis Sci. 2016;61(5):1246–67.
Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol. 2014;60(3):643–53.
Back DJ, Burger DM. Interaction between amiodarone and sofosbuvir-based treatment for hepatitis C virus infection: potential mechanisms and lessons to be learned. Gastroenterology. 2015;149(6):1315–7.
US Department of Health and Human Services. US Food and Drug Administration. FDA Hepatitis Update—Important safety information: Harvoni, and Sovaldi. Silver Spring, MD: US FDA; 2015. http://content.govdelivery.com/accounts/USFDA/bulletins/f97c71. Accessed Mar 2017.
Regan CP, Morissette P, Regan HK, et al. Assessment of the clinical cardiac drug–drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys. Hepatology. 2016;64(5):1430–41.
Millard DC, Strock CJ, Carlson CB, et al. Identification of drug–drug interactions in vitro: a case study evaluating the effects of sofosbuvir and amiodarone on hiPSC-derived cardiomyocytes. Toxicol Sci. 2016;154(1):174–82.
Higgins J, Deeks JJ, Altman DG. Special topics in statistics. Cochrane handbook for systematic reviews of interventions. Cochrane book series. New York: Wiley; 2008, p. 481–529.
Acknowledgements
The authors thank the manufacturer of sofosbuvir and Dr. Diana Brainard for providing unpublished safety data from sofosbuvir trials.
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DC contributed to the concept and design and wrote the first draft of the manuscript; DC, FBR, MMD, CS, MB, and NG contributed to data acquisition and data analysis. DC, FBR, MMD, CS, MB, NG, FJP, JJF, and JC contributed to interpretation of the data, critically revised the manuscript, and gave final approval of the submitted manuscript. DC is the guarantor.
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This was an academic project not funded by any government or non-government grant.
Conflict of interest
Daniel Caldeira, Filipe B. Rodrigues, Marta M. Duarte, Carmelo Sterrantino, Márcio Barra, Nilza Gonçalves, Fausto J. Pinto, Joaquim J. Ferreira, and João Costa have no conflicts of interest that are directly relevant to the content of this study.
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Caldeira, D., Rodrigues, F.B., Duarte, M.M. et al. Cardiac Harms of Sofosbuvir: Systematic Review and Meta-Analysis. Drug Saf 41, 77–86 (2018). https://doi.org/10.1007/s40264-017-0586-2
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DOI: https://doi.org/10.1007/s40264-017-0586-2