Hydroxychloroquine tied to increased CV risk

While hydroxychloroquine (HCQ) alone seems to have no increased cardiovascular (CV) risk when used in the short-term (up to 30 days) for rheumatoid arthritis (RA), combining it with azithromycin (AZM) led to increased risks of CV mortality, angina, and heart failure (HF). Moreover, long-term use conferred excess CV mortality, a retrospective study suggests.

“In line with consensus expert guidance, our findings suggest that a cautious assessment of CV risk is needed before initiating high-dose HCQ or HCQ-AZM combination therapy, and in long-term monitoring of patients with RA, especially those with CV risk factors,” said the researchers.

Under the COVID-19 spotlight

The current COVID-19* pandemic has propelled the RA drug HCQ under the spotlight, owing to its reported antiviral potential against SARS-CoV-2**, the causative agent of COVID-19. [Int J Antimicrob Agents 2020;55:105932; Int J Antimicrob Agents 2020;55:105938; Cell Res 2020;30:269-271] In one study, high-dose HCQ and AZM led to viral load reduction and faster recovery, leading to the extensive use of high-dose HCQ, either alone or with AZM, in COVID-19 patients. [Int J Antimicrob Agents 2020;56:105949]

However, the widespread attention on HCQ took a detour – not only for its safety implications in COVID-19 patients but also for its traditional indications – when reports about serious cardiac adverse events (AEs) that could trigger potentially fatal outcomes came out. [JAMA Cardiol 2020;5:1036-1041; Nat Med 2020;26:808-809; JAMA Netw Open 2020;3:e208857] The negative publicity drove authorities to withdraw the emergency authorization of HCQ¹, circulate statements cautioning against its use^2-4, and put randomized trials to a halt, the researchers stressed.

Large-scale, real-world data

Using 14 databases, the investigators amassed data of nearly a million patients on HCQ (n=956,374). Data on these patients were compared against data on individuals on sulfasalazine (SSZ; n=310,350). They also compared the HCQ-AZM regimen (n=323,122) against a combination of HCQ and amoxicillin (HCQ-AMX; n=351,956). [Lancet Rheumatol 2020;2:e698-711]

Although short-term HCQ use did not confer increased CV mortality compared with SSZ (calibrated hazard ratio [cHR], 1.36), long-term use appeared to show otherwise (cHR, 1.65).

The increased risks of chest pain or angina (cHR, 1.15), HF (cHR, 1.22), and CV mortality (cHR, 2.19) with short-term use of HCQ-AZM vs HCQ-AMX is, according to the researchers, “more worrying … [HCQ-AZM] doubled the risk of CV mortality in the first month of treatment … probably [due to] their synergistic effects on QT length and subsequent induction of lethal arrhythmia.”

As HCQ and AZM are contraindicated for patients with cardiac arrhythmias, it is presumed that these were prescribed ‘as per existing labelling advice’. “It is therefore concerning that CV effects were still seen in our study populations, possibly indicating that the true risks of these drugs are understated in the analysis,” the researchers noted.

“[A]s we do not know the baseline risk of serious AEs within this population, we cannot report absolute risk of these events in patients with RA, and this limitation must be acknowledged,” they explained. Another limitation is the odds of US patients being included in more than one dataset. While the team ran meta-analyses, underestimating variance is possible, they noted. Also, mortality analysis was confined only to databases with good assessments of the outcome.

“[Nonetheless,] the combination of minimal large-scale HCQ safety studies before the pandemic, and the extensive research suggesting risks associated with HCQ use that has been produced during 2020, is of great concern to both patients and clinicians … [T]he collective experience of almost a million patients builds our confidence in the evidence around the safety profile of HCQ,” they said.

Although long-term use of HCQ is unlikely for COVID-19 management, the higher doses required for COVID-19 compared with doses required for RA may lead to equivalent AEs, even in the short term, due to its long half-life. [Drug Saf 2018;41:919-931] “[As such,] we call for careful consideration of the benefit-risk trade-off when counselling those on HCQ treatment,” the researchers concluded.