key: cord-0896785-iqvmbs4z
authors: Mendez, Sean R.; Frank, Rachel C.; Stevenson, Elizabeth K.; Chung, Mabel; Silverman, Michael G.
title: Dihydropyridine Calcium Channel Blockers and the Risk of Severe COVID-19
date: 2021-02-03
journal: Chest
DOI: 10.1016/j.chest.2021.01.073
sha: 0819466d4797d09687490d1f65db5dac67872597
doc_id: 896785
cord_uid: iqvmbs4z

nan

There was no dedicated funding for this work. Michael G. Silverman receives support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. Mabel Chung receives support from the National Institutes of Health (5T32GM007592-40) and from Medtronic outside the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

Ventilation/perfusion (V/Q) mismatch and the loss of hypoxic pulmonary vasoconstriction play a pivotal role in the pathophysiology of COVID-19 respiratory distress. 1,2 Dihydropyridine calcium channel blockers (CCBs), frequently prescribed first-line antihypertensive agents, have the potential to disrupt hypoxic pulmonary vasoconstriction 3 and worsen V/Q mismatch leading to profound hypoxemia in patients with pulmonary pathology. 4 We hypothesized that CCBs would be associated with worse respiratory failure in patients with COVID-19.

Among 444 consecutively hospitalized patients with confirmed COVID-19 (admitted between March 13, and April 7, 2020 at a quaternary referral center and an affiliated community hospital in Massachusetts), 245 had hypertension and were included in the analysis. Data elements were retrospectively abstracted from the electronic health record by trained study personnel following standardized protocol. The study was approved by the Partners Healthcare Institutional Review Board with a waiver of informed consent.

Dihydropyridine CCB exposure status was based on confirmed home medication list at the time of hospital admission. The primary endpoint was a composite of intubation or death modeled as a time-to-event analysis. 5 For patients who died after intubation, the time of intubation was considered time of primary endpoint as with previous studies. 5 Cox models were used to evaluate the association between CCBs and the primary endpoint. Models were adjusted for age, sex, race/ethnicity, body mass index (BMI), diabetes, coronary artery disease (CAD), heart failure, pulmonary hypertension, chronic kidney disease (CKD), asthma/chronic obstructive pulmonary disease, peripheral arterial disease, Charlson comorbidity index, and the following medications: angiotensin-converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB), thiazide diuretic, loop diuretic, beta blocker, aspirin, and statin. To further J o u r n a l P r e -p r o o f account for potential confounding, an additional analysis was performed with propensity score matching. The propensity score for CCB use was estimated with a logistic regression model that incorporated the same covariates used in the multivariable Cox model.

Of 245 individuals with hypertension included in our analysis, 70 (29%) were taking CCBs and 175 (71%) were not. Baseline characteristics according to CCB use are shown in the Table for both the unmatched and matched samples. The propensity score matched cohort consisted of 116 individuals; 58 exposed to CCBs and 58 who were not. In both the matched and unmatched samples, slightly less than half the cohort was female, and nearly 50% of the cohort was non-white. Average time from symptom onset to hospital presentation was 7 (±5) days. At the time of hospital presentation, patients who had been taking CCBs were more likely to have an oxygen saturation less than 90% (Table) . 

Given that 37 patients (53%) in the CCB group had their CCBs discontinued on hospital admission, we performed a sensitivity analysis to evaluate the association between CCB use and the primary endpoint within 24 hours of admission, before the potential expected effect of drug discontinuation. CCB use was associated with a 2-fold increased risk of intubation and death (95% CI 1.1-3.9) p=0.03 within 24 hours of admission.

In the propensity score matched sample, 55 patients (47%) had a primary endpoint (45 were intubated, 10 died prior to intubation). Similar to the unmatched cohort, patients who had been taking CCBs had an increased risk of the primary endpoint: HR 1.9 (95% CI 1.1-3.2) p=0.02 (Figure) . Adjusting for the 5 covariates with standardized difference >0.1 (Table) revealed a HR of 1.9 (95% CI 1.1 -3.3) p=0.02. As a robustness check, an inverse probability treatment weighted Cox model yielded similar results: HR 1.6 (95% CI 1.1 -2.3) p=0.02. At time of censoring, 27 patients (23%) had died (CCB 29% no CCB 17%) and 89 survived to hospital discharge (CCB 71% no CCB 83%) p=0.12.

In our cohort of consecutive patients hospitalized with confirmed COVID-19, patients with a history of hypertension who had been taking dihydropyridine CCBs had a significantly increased risk of intubation or death compared to those not taking dihydropyridine CCBs. These findings support the pathophysiology-based hypothesis that in patients with COVID-19, dihydropyridine calcium channel blockers (medications that can disrupt hypoxic pulmonary vasoconstriction) are associated with an increased risk for respiratory failure. Our results are consistent with previously published data demonstrating a modestly increased likelihood of severe COVID-19 in patients with hypertension taking calcium channel blockers. 6 Additionally, prior research has demonstrated that in patients with ARDS, systemically administered J o u r n a l P r e -p r o o f pulmonary vasodilators can decrease regional hypoxic pulmonary vasoconstriction leading to worse hypoxemia, whereas selective pulmonary vasodilation using inhaled pulmonary vasodilators can attenuate hypoxemia through improving V/Q mismatch by acting in only wellventilated lung regions. 7 Limitations include small sample size, retrospective observational study design, and although we adjusted for likely confounders, we were unable to adjust for chronicity of hypertension and cannot rule out unmeasured confounding.

While we would not currently advocate for change in practice based on these results, we would urge caution against the suggestion to empirically transition patients from ACE-I/ARB to CCBs. 8 If our findings are confirmed, it may be reasonable to transition patients from dihydropyridine CCBs to alternative agents. Given the high prevalence of hypertension and its associated risk for COVID-19 coupled with the frequency of dihydropyridine CCB use, these findings may have significant public health implications and warrant further study. 

Management of COVID-19 Respiratory Distress

Acute respiratory distress syndrome

Inhibition of hypoxic pulmonary vasoconstriction by nifedipine

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Fifty Years of Research in ARDS. Gas Exchange in Acute Respiratory Distress Syndrome

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

COVID-19: Coronavirus Disease 2019 CCB: Calcium Channel Blocker BMI: Body Mass Index HR: Hazard Ratio CI: Confidence Interval J o u r n a l P r e

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