Risk of QT prolongation through drug interactions between hydroxychloroquine and concomitant drugs prescribed in real world practice

Abstract

Hydroxychloroquine has recently received attention as a treatment for COVID-19. However, it may prolong the QTc interval. Furthermore, when hydroxychloroquine is administered concomitantly with other drugs, it can exacerbate the risk of QT prolongation. Nevertheless, the risk of QT prolongation due to drug-drug interactions (DDIs) between hydroxychloroquine and concomitant medications has not yet been identified. To evaluate the risk of QT prolongation due to DDIs between hydroxychloroquine and 118 concurrent drugs frequently used in real-world practice, we analyzed the electrocardiogram results obtained for 447,632 patients and their relevant electronic health records in a tertiary teaching hospital in Korea from 1996 to 2018. We repeated the case-control analysis for each drug. In each analysis, we performed multiple logistic regression and calculated the odds ratio (OR) for each target drug, hydroxychloroquine, and the interaction terms between those two drugs. The DDIs were observed in 12 drugs (trimebutine, tacrolimus, tramadol, rosuvastatin, cyclosporin, sulfasalazine, rofecoxib, diltiazem, piperacillin/tazobactam, isoniazid, clarithromycin, and furosemide), all with a p value of < 0.05 (OR 1.70-17.85). In conclusion, we found 12 drugs that showed DDIs with hydroxychloroquine in the direction of increasing QT prolongation.

Figure 1

Overview of the study process. Among 1,040,752 ECG results, 992,968 ECGs that have no duplicated or repeated measurements were extracted and selected one ECG for one patient with sex and age information with no age outlier. Total of 444,475 ECG results were enrolled and divided into QT prolongation case (n = 58,258) vs. control (n = 386,317). Multiple logistic regression analysis was repeated iteratively for each target drugs.

Figure 2

Interaction plots for 12 drugs that showed significant DDI with hydroxychloroquine. These plots show how the logit value (Y-axis) changes when the target drug (X-axis) is used alone and in combination with hydroxychloroquine. The 12 drugs plotted were drugs with statistically significant drug-drug interaction (DDI) in the iterative multiple logistic regression analysis. If there is a DDI, the two graphs have non-parallel slopes. In particular, when the interval between slopes increases, DDI exists in the direction of increasing QT prolongation. The interval between slopes increases in all 12 drugs.