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Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations

Journal of Human Hypertension volume 36, pages 989–995 (2022)Cite this article

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Abstract

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: −0.03%[−0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[−1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

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Fig. 1: The correlation of observed hypokalemia and hyperkalemia event in 24 antihypertensive medication treatment arms from five randomized regulatory trials.
Fig. 2: Observed (circle) and model-estimated (vertical bar) hyper- and hypokalemia rates in 24 treatment arms.
Fig. 3: Simulated absolute risk of hypokalemia and hyperkalemia for the different FDCs observed in five randomized controlled trials.

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Funding

This study was supported by Resolve to Save Lives, which is funded by Bloomberg Philanthropies, the Bill & Melinda Gates Foundation, and Gates Philanthropy Partners, which is funded with support from the Chan Zuckerberg Foundation.

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Authors and Affiliations

  1. Quantitative Science, Certara, Princeton, NJ, USA

    Li Qin, Nancy Zhang, Marc Pfister & Eugène Cox

  2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Junichi Ishigami

  3. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Junichi Ishigami & Edgar R. Miller 3rd

  4. Pediatric Pharmacology and Pharmacometrics Research Center, University of Basel, Basel, Switzerland

    Marc Pfister

  5. Resolve to Save Lives, an initiative of Vital Strategies, New York, NY, USA

    Andrew E. Moran

  6. Columbia University Irving Medical Center, New York, NY, USA

    Andrew E. Moran

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  1. Li Qin
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Contributions

L.Q., N.Z., J.I., E.R.M., M.P., A.E.M., and E.C. wrote the manuscript; L.Q., N.Z., A.E.M., and E.C. designed the research; L.Q., N.Z., and E.C. performed the research; L.Q., and E.C. analyzed the data.

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Correspondence to Li Qin.

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Qin, L., Zhang, N., Ishigami, J. et al. Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations. J Hum Hypertens 36, 989–995 (2022). https://doi.org/10.1038/s41371-021-00600-w

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