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Dihydropyridine Calcium Channel Blockers and the Risk of Severe COVID-19

2021; Elsevier BV; Volume: 160; Issue: 1 Linguagem: Inglês

10.1016/j.chest.2021.01.073

1931-3543

Sean R. Mendez, R Frank, Elizabeth K. Stevenson, Mabel Chung, Michael G. Silverman,

Cardiac Arrest and Resuscitation

V˙/Q˙ mismatch and the loss of hypoxic pulmonary vasoconstriction play a pivotal role in the pathophysiology of COVID-19 respiratory distress.1Marini J.J. Gattinoni L. Management of COVID-19 respiratory distress.JAMA. 2020; (;323(22):2329-2330)Crossref PubMed Scopus (733) Google Scholar,2Sweeney R.M. Mcauley D.F. Acute respiratory distress syndrome.Lancet. 2016; 388: 2416-2430Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar Dihydropyridine calcium channel blockers (CCBs), frequently prescribed first-line antihypertensive agents, have the potential to disrupt hypoxic pulmonary vasoconstriction3Simonneau G. Escourrou P. Duroux P. Lockhart A. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine.N Engl J Med. 1981; 304: 1582-1585Crossref PubMed Scopus (199) Google Scholar and worsen V̇/Q̇ mismatch that leads to profound hypoxemia in patients with pulmonary disease.4Mishra A. Reed R.M. Eberlein M. Severe, rapidly reversible hypoxemia in the early period after bilateral lung transplantation.Ann Am Thorac Soc. 2016; 13(6): 979-985Crossref Scopus (6) Google Scholar 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 patients had hypertension and were included in the analysis. Data elements were abstracted retrospectively from the electronic health record by trained study personnel who followed 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 end point was a composite of intubation or death modeled as a time-to-event analysis.5Geleris J. Sun Y. Platt J. et al.Observational study of hydroxychloroquine in hospitalized patients with Covid-19.N Engl J Med. 2020; 382(25): 2411-2418Crossref Scopus (1199) Google Scholar For patients who died after intubation, the time of intubation was considered time of primary end point as with previous studies.5Geleris J. Sun Y. Platt J. et al.Observational study of hydroxychloroquine in hospitalized patients with Covid-19.N Engl J Med. 2020; 382(25): 2411-2418Crossref Scopus (1199) Google Scholar Cox models were used to evaluate the association between CCBs and the primary end point. Models were adjusted for age, sex, race/ethnicity, BMI, diabetes mellitus, coronary artery disease, heart failure, pulmonary hypertension, chronic kidney disease, asthma/COPD, peripheral arterial disease, Charlson Comorbidity Index, and the following medications: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, thiazide diuretic, loop diuretic, beta blocker, aspirin, and statin. To further 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 the 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 Table 1 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 one-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 3 mg/dL), No. (%)10 (6)3 (4)0.071 (2)3 (5)0.19 Pulmonary hypertension, No. (%)7 (4)1 (1)0.161 (1)1 (1)0 Peripheral arterial disease, No. (%)18 (10)9 (13)0.087 (12)9 (16)0.10 Charlson Comorbidity Index, mean±SD2.1 ± 2.02.0 ± 1.70.071.8 ± 1.72.1 ± 1.60.18Baseline medications, No. (%) Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker88 (50)37 (53)0.0529 (50)30 (52)0.03 Thiazide diuretic34 (19)16 (23)0.0814 (24)14 (24)0 Loop diuretic29 (17)11 (16)0.028 (14)8 (14)0 Beta blocker66 (38)31 (44)0.1323 (40)24 (41)0.04 Statins96 (55)46 (66)0.2234 (59)36 (62)0.07 Aspirin76 (43)29 (41)0.0422 (38)26 (45)0.14Clinical presentation SpO2 % in ED, median (interquartile range)96 (94-97)94 (92-97)0.4296 (94-97)94.5 (91 -97)0.40 SpO2 in ED 0.1 (Table 1) revealed an HR of 1.9 (95% CI, 1.1-3.3; P = .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 = .02). At time of censoring, 27 patients (23%) had died (CCB, 29%; no CCB, 17%), and 89 patients survived to hospital discharge (CCB, 71%; no CCB, 83%; P = .12). In our cohort of consecutive patients who were 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 with those not taking dihydropyridine CCBs. These findings support the pathophysiologic-based hypothesis that, in patients with COVID-19, dihydropyridine CCBs (medications that can disrupt hypoxic pulmonary vasoconstriction) are associated with an increased risk for respiratory failure. Our results are consistent with previously published data that showed a modestly increased likelihood of severe COVID-19 in patients with hypertension who were taking CCBs.6Reynolds H.R. Adhikari S. Pulgarin C. et al.Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19.N Engl J Med. 2020; 382(25): 2441-2448Crossref Scopus (831) Google Scholar Additionally, previous research has demonstrated that, in patients with ARDS, systemically administered pulmonary vasodilators can decrease regional hypoxic pulmonary vasoconstriction leading to worse hypoxemia, whereas selective pulmonary vasodilation with the use of inhaled pulmonary vasodilators can attenuate hypoxemia through improving V˙/Q˙ mismatch by acting in only well-ventilated lung regions.7Radermacher P. Maggiore S.M. Mercat A. Fifty years of research in ARDS: gas exchange in acute respiratory distress syndrome.Am J Respir Crit Care Med. 2017; 196(8): 964-984Crossref Scopus (97) Google Scholar Limitations include small sample size, retrospective observational study design; although we adjusted for likely confounders, we were unable to adjust for chronicity of hypertension and cannot rule out unmeasured confounding. Although we would not advocate currently for a change in practice based on these results, we would urge caution against the suggestion to transition patients empirically from angiotensin-converting enzyme inhibitor/angiotensin receptor blocker to CCBs.8Fang L. Karakiulakis G. Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; 8: e21Abstract Full Text Full Text PDF PubMed Scopus (2068) Google Scholar 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. Other contributions: 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.