Combined hydroxychloroquine, azithromycin use increases cardiovascular risk in RA
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The combination of hydroxychloroquine and azithromycin significantly increased risk for heart failure and cardiovascular mortality among patients with rheumatoid arthritis, according to data published in The Lancet Rheumatology.
“European guidelines for the treatment of patients with rheumatoid arthritis contain little high-level evidence for the safety of hydroxychloroquine, and most systematic reviews of rheumatoid arthritis treatments have focused on biological therapies,” Jennifer C.E. Lane, MRCS, of the University of Oxford, in the United Kingdom, and colleagues wrote. “Before the COVID-19 pandemic, evidence for hydroxychloroquine safety was largely found in retrospective case series and case reports, or within pharmaceutical adverse events registers.”
“Azithromycin and macrolides in general are also known to induce cardiotoxicity and to interact with other drugs that prolong QT [interval],” they added. “The combination of minimal large-scale hydroxychloroquine safety studies before this pandemic, and the extensive research suggesting risks associated with hydroxychloroquine use that has been produced during 2020 is of great concern to both patients and clinicians.”
To analyze the safety of hydroxychloroquine, both as monotherapy and in combination with azithromycin, as part of routine care for rheumatoid arthritis, Lane and colleagues conducted a multinational, retrospective study of new-user cohort trials. The researchers compared adult patients with RA who initiated hydroxychloroquine with those who began treatment with sulfasalazine over a period of 30 days. In addition, self-controlled case series, including all patients treated with hydroxychloroquine regardless of RA status or indication, were used to further determine safety in larger populations.
The researchers also separately examined severe adverse events linked to combination therapy with hydroxychloroquine and azithromycin, compared with hydroxychloroquine plus amoxicillin. Analyzed data included 14 sources of claims data and electronic medical records from Germany, Japan, the Netherlands, Spain, the United Kingdom and the United States. Lane and colleagues used propensity score stratification and calibration, with negative control outcomes, to address confounding. They then employed Cox models to estimate calibrated hazard ratios according to drug use. Estimates were pooled when the I2 value was less than 0.4.
In all, the researchers included 956,374 patients treated with hydroxychloroquine, 310,350 patients treated with sulfasalazine, 323,122 treated with hydroxychloroquine plus azithromycin, and 351,956 participants who received hydroxychloroquine plus amoxicillin.
According to the researchers, there was no excess risk for severe adverse events over a period of 30 days among patients who initiated hydroxychloroquine, compared with those who started sulfasalazine. This finding was later confirmed by self-controlled case series. However, long-term hydroxychloroquine use was associated with increased cardiovascular mortality (calibrated HR = 1.65; 95% CI, 1.12-2.44).
Meanwhile, adding azithromycin to a regimen of hydroxychloroquine was associated with an increased risk for not only 30-day cardiovascular mortality (calibrated HR = 2.19; 95% CI, 1.22-3.95), but also chest pain or angina (HR = 1.15; 95% CI, 1.05-1.26]) and heart failure (HR = 1.22; 95% CI, 1.02-1.45).
“In this large-scale, international, real-world data network study, hydroxychloroquine appears to be largely safe for short-term use in patients with rheumatoid arthritis compared with sulfasalazine, but when used in combination with azithromycin, this therapy carries a relative risk of 2.19 for cardiovascular death compared with hydroxychloroquine combined with amoxicillin,” Lane and colleagues wrote.
“The collective experience of almost a million patients builds our confidence in the evidence around the safety profile of hydroxychloroquine,” they added. “In line with consensus expert guidance, our findings suggest that a cautious assessment of cardiovascular risk is needed before initiating high-dose hydroxychloroquine or hydroxychloroquine plus azithromycin combination therapy, and in long-term monitoring of patients with rheumatoid arthritis, especially those with cardiovascular risk factors.”
Perspective
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J. Nicholas Manwaring, MSN, APRN, FNP-C
This multinational retrospective study that included over a million participants from multiple developed countries by Lane and colleagues offers much needed insight into an area previously largely unstudied. It further overcomes some of the prevailing limits all too often found in small population data sets contained within relatively small geographical and limited genetic populations. Of further value, this study highlights an area of study largely unstudied in a large-scale contemporary analysis such as this.
Up to this point, there has not been any previous large-scale current study such as this one that has looked at the safety of hydroxychloroquine (HCQ) compared to other synthetic DMARDs, specifically when used concurrently with other potentially QT prolonging medications. It would seem this study shows there may be at least one silver lining in the otherwise dark cloud of the COVID-19 pandemic.
HCQ has long been used as a first-line DMARD therapy namely in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Until now there has been limited large-scale evidence as to its safety compared to other first-line DMARDs. One of the benefits of the use of HCQ as a first-line therapy for RA patients has been its minimal monitoring and minimal adverse effects compared to many of the other DMARDs.
This study helps to remind the prescriber of one potential risk of HCQ treatment that may be present even in patients without previously known cardiovascular risks and also allow prescribers to provide their patients with valuable current research-based information to aid in the shared decision-making process. It further helps to remind prescribers to consider the patients other QT prolonging risk factors before initiating HCQ.
Extending beyond HCQ, it is an important reminder of the need to consider all drug to drug interactions before prescribing a new medication. Many of the RA patients seen in our clinic are also seen regularly by other prescribers, whether it be their PCP or other specialists. By nature of the disease, patients with RA often have other comorbidities that warrant the regular prescribing of various QT prolonging medications. Azithromycin is a commonly used antibiotic in the primary care providers arsenal, and many of them see patients with RA and SLE who are already on HCQ.
Many PCPs also prescribe other QT prolonging medications, such as selective serotonin reuptake inhibitors, that could potentially have the same combined adverse effect as azithromycin when prescribed in patients who are already taking HCQ for SLE or RA. This brings home the importance of any practitioner working in rheumatology to educate their patients about the potential drug interaction between HCQ and other potentially QT prolonging medications.
This can further help to empower patients, when they are prescribed any new medications, to ask their primary provider, specialty prescriber and/or pharmacist about drug interactions before taking any additional medication that may increase their risk of QT prolongation. The COVID-19 pandemic may yet offer other serendipitous findings in many areas of medicine.
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