key: cord-0841808-dsr3h8bv
authors: Rezel‐Potts, Emma; Douiri, Abdel; Chowienczyk, Phil J.; Gulliford, Martin C.
title: Antihypertensive medications and COVID‐19 diagnosis and mortality: Population‐based case‐control analysis in the United Kingdom
date: 2021-05-10
journal: Br J Clin Pharmacol
DOI: 10.1111/bcp.14873
sha: 1c548c40b5d904a46fb834a711b0eeb05bd36738
doc_id: 841808
cord_uid: dsr3h8bv

AIMS: Antihypertensive drugs have been implicated in coronavirus disease 2019 (COVID‐19) susceptibility and severity, but estimated associations may be susceptible to bias. We aimed to evaluate antihypertensive medications and COVID‐19 diagnosis and mortality, accounting for healthcare‐seeking behaviour. METHODS: A population‐based case‐control study was conducted including 16 866 COVID‐19 cases and 70 137 matched controls from the UK Clinical Practice Research Datalink. We evaluated all‐cause mortality among COVID‐19 cases. Exposures were angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta‐blockers (B), calcium‐channel blockers (C), thiazide diuretics (D) and other antihypertensive drugs (O). Analyses were adjusted for covariates and consultation frequency. RESULTS: ACEIs were associated with lower odds of COVID‐19 diagnosis (adjusted odds ratio [AOR] 0.82, 95% confidence interval [CI] 0.77‐0.88) as were ARBs (AOR 0.87, 95% CI 0.80‐0.95) with little attenuation from adjustment for consultation frequency. C and D were also associated with lower odds of COVID‐19 diagnosis. Increased odds of COVID‐19 for B (AOR 1.19, 95% CI 1.12‐1.26) were attenuated after adjustment for consultation frequency (AOR 1.01, 95% CI 0.95‐1.08). Patients treated with ACEIs or ARBs had similar odds of mortality (AOR 1.00, 95% CI 0.83‐1.20) to patients treated with classes B, C, D or O or patients receiving no antihypertensive therapy (AOR 0.99, 95% CI 0.83‐1.18). CONCLUSIONS: There was no evidence that antihypertensive therapy is associated with increased risk of COVID‐19 diagnosis or mortality; most classes of antihypertensive therapy showed negative associations with COVID‐19 diagnosis.

Coronavirus disease 2019 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. The World Health Organization's 9 February 2021 epidemiological update reported 105.4 million cumulative cases and 2.3 million cumulative deaths of COVID-19 globally. 1 The UK is among the countries with the highest COVID-19 incidence and death rates in the world, with figures from 14 February 2021 indicating that among those first testing positive for the virus, 117 166 died within 28 days. 2 Biomedical scientific evidence suggests a role of the renin-angiotensin-aldosterone system (RAAS) in COVID-19. SARS-CoV-2 enters host cells via interaction with the angiotensin-converting enzyme 2 (ACE2) receptor, which is part of the RAAS. [3] [4] [5] [6] Angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) modulate the RAAS, and treatment with ACEIs and ARBs may enhance ACE2 activity, thereby increasing SARS-CoV-2 susceptibility and COVID-19 severity. 7, 8 Conversely, increased ACE2 might have a protective effect by competitive inhibition of SARS-CoV-2 entry into the respiratory epithelium or via negative regulation of the RAAS for anti-inflammatory, antioxidative and vasodilatory effects. 7, 9 Antihypertensive drugs represent the most frequently prescribed medicines in the UK, used by 15% of adults with long-term conditions including diabetes, hypertension and cardiovascular diseases. 10 These pre-existing conditions are frequent among those receiving healthcare for COVID-19 6, 11 and have also been associated with high COVID-19 case fatality rates, [12] [13] [14] raising concerns about possible associations with antihypertensive treatment (AHT). There have been conflicting results from several observational studies exploring the relationship between AHT and COVID-19 susceptibility and severity since the start of the pandemic. 15, 16 A living systematic review, updated to 3 August 2020, included three studies with 8766 COVID-19 patients and found no evidence of association between either ACEI or ARB treatment and positive COVID-19 test results. 15 Two of the studies drew on patients attending hospital in the United States, 17, 18 while the third study was populationbased, including both primary care and hospital attendances in the Lombardy region in Italy. 19 A large international study which was initially included in the review has since been retracted by the journal in which it was published. A retrospective cohort study using Danish national disease registries which found no evidence of association of prior treatment with ACEIs/ARBs with COVID-19 diagnosis, severity or death. 20 In contrast, a systematic review and meta-analysis of 28 872 patients found that treatment with RAAS inhibiting (RAASi) drugs was associated with lower risk of death or critical events. 16 

• Associations were sensitive to adjustment for confounding and healthcare-seeking, but there was no evidence that antihypertensive therapy is associated with increased risk of COVID-19 diagnosis or mortality.

• Most classes of antihypertensive therapy showed negative associations with COVID-19 diagnosis.

• This study adds to the evidence that antihypertensive therapy may be safely continued during the COVID-19

pandemic.

AHT and COVID-19 susceptibility. We examined associations between AHT classes and COVID-19 mortality using date of death in the CPRD within 30 days as the outcome. Analyses were adjusted for covariates and consultation frequency.

The CPRD GOLD is among the world's largest databases of anonymised electronic health records from primary care. It is estimated that 7% of UK general practices contribute to CPRD GOLD, enabling the database to have extensive coverage and good sociodemographic and geographic representativeness of the UK population. 25 The high quality of the CPRD GOLD data has been verified by several studies. 26 The protocol was approved by the CPRD Independent Scientific Advisory Committee (ISAC protocol 20_081RA).

Patients recorded with COVID-19 were identified from the July 2020 release of CPRD GOLD. COVID-19 events were identified from Read codes recorded into patients' clinical, referral and test records: 

The exposure was defined as prescription of AHT in the 6 months before the index date of the following classes: ACEIs, ARBs, beta blockers (B), calcium channel blockers (C), thiazide diuretics (D) and other antihypertensive drugs (O). Each class of AHT was coded as either prescribed or not prescribed.

Covariates were defined using data recorded in the 5-year period before date of diagnosis. These included smoking status (nonsmoker, current smoker, exsmoker), body mass index (BMI; underweight, normal weight, overweight, obese and missing), systolic blood pressure (SBP) and diastolic blood pressure (DBP) in categories of 10 mmHg.

Ethnicity was classified as 'white', 'black', 'Asian', 'mixed', 'other'

and 'not known'. We used Clegg's electronic Frailty Index (eFI) to evaluate frailty into categories of nonfrail, mild, moderate and severe frailty. 27 We also evaluated the 15 comorbidities of the Charlson comorbidity index as present or absent, following the recommendations of Khan et al. 28, 29 We evaluated healthcare-seeking behaviour by calculating the rate of events in each patient's clinical record file, including consultations and other contacts with the practice, in the year preceding the index date. This rate per patient year was entered as a continuous variable.

A conditional logistic regression model was employed for the casecontrol analysis. Unadjusted odds ratios (ORs) were compared with covariate adjusted odds ratios (AORs) including ethnicity, BMI, blood pressure, smoking status, frailty level, comorbidities and treatment with each class of AHT. Finally, additional adjustment was made for consultation frequency. As a sensitivity analysis we repeated the analysis only including patients with confirmed COVID-19 diagnoses, excluding patients recorded to have 'suspected' COVID-19. We also explored evidence of an interaction between age group and each class of AHT, conducting a subgroup analysis to examine age as an effect modifier. We conducted subgroup analyses by BMI and frailty category.

A Cox proportional hazards model was employed to examine the association of AHT with patient survival. Survival time in days from the date of first COVID-19 diagnosis to date of death or end of record was the outcome. Patients who were still alive at the end of the study period were censored. Covariates were month of COVID-19 diagnosis, gender, age (0-4, 5-9 and 10-14, then 10 years age groups up to 85 years and over), smoking status, BMI, blood pressure, ethnic group, eFI category comorbidities and treatment with each class of AHT. A secondary analysis also adjusted for region of practice. We did not adjust for consultation frequency because all patients in this analysis had already accessed care from their general practice. We also evalu- Figure S3 ).

Adding an interaction term for age within logistic regression models for each class of AHT improved the model goodness of fit, therefore we conducted a subgroup analysis for cases and controls by AHT and age (Supporting Information Table S3 ). AHT was more strongly associated with higher odds of COVID-19 diagnosis at younger ages but this pattern of association was accounted for by adjusting for covariates, including consultation frequency. We conducted subgroup analyses for cases and controls by AHT and BMI category (Supporting Information Table S4 ) and by AHT and frailty category (Supporting Information Table S5 ). These analyses did not reveal any consistent difference in association between AHT and COVID-19 diagnosis across categories of BMI or frailty in either unadjusted or adjusted analyses.

Among the 16 866 COVID-19 cases, 921 (5%) died within 30 days.

The age and gender distribution of these fatal COVID-19 cases showed a higher frequency of males compared to females across most age categories, with cases peaking in the highest age categories (Supporting Information Figure S2 ). Patients treated with antihypertensive drugs were more highly represented among deceased patients than the overall sample and this was true for each class of AHT drugs ( Table 2 and Supporting Information Table S2 ). there was no evidence that any of the classes of AHT drugs might be associated with mortality after COVID-19 diagnosis (Table 2) .

Additional adjustment for practice region did not influence associations ( Figure 2 ). There was no evidence that treatment with RAASi drugs, including ACEI and ARB drugs, might be associated with higher mortality than other classes of AHT drugs (BCDO) with adjusted hazard ratio (AHR) 1.00 (0.83 to 1.20) (Figure 3) outcomes in patients treated with these medications. [33] [34] [35] [36] [37] [38] Some studies suggest ACEIs and ARBs could be associated with reduced risks of indicators of severe COVID-19 disease. 21, 39 However, systematic reviews also highlight limitations of the evidence presented to date. 36 A high proportion of studies has been based on data from patients admitted to hospital with COVID-19, sometimes with small samples.

Many studies failed to include adequate adjustment for confounding.

Few studies have directly addressed the question of collider bias, which distorts associations when data are gathered from patients conditional on their attendance for healthcare. COVID-19 has been evaluated in an ongoing randomised controlled trial of ramipril treatment. 40 The analysis found no evidence for an effect of ramipril on COVID-19

incidence or severity but the analysis comprised 102 patients with 11 cases of COVID-19. 40 A larger trial in Brazil recruited patients who were hospitalised with mild to moderate COVID-19 and taking ACEIs or ARBs and randomly allocated them to either discontinuation (n = 334) or continuation (n = 325) of their AHT. There was no difference in the mean number of days patients were alive and out of the hospital between the two groups (21.9 days versus 22.9 days) and

other secondary outcomes measuring disease severity. 41 Further trials are ongoing. 15 

Drawing on data for a large population-based sample and using rigorous analytical methods, this study adds to the evidence that antihypertensive therapy may be safely continued during the SARS-CoV-2 pandemic. While previous studies have largely evaluated drugs acting on the RAAS, the study found no evidence that any class of antihypertensive therapy might be associated with greater risk of COVID-19 diagnosis or mortality. There was evidence that, after adjusting for covariates including blood pressure, several classes of AHT might be associated with lower risk of a clinical COVID-19

diagnosis, but this pattern of association was not apparent for COVID-19 mortality. While this might be interpreted as evidence of a protective effect, in this observational study it is not possible to exclude the possibility that this pattern of association may be caused by bias.

The study is based in part on data from the Clinical Practice Research

Datalink obtained under license from the UK Medicines and

Healthcare products Regulatory Agency. However, the interpretation and conclusions contained in this report are those of the authors alone.

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The funder of the study had no role in study design, data collection,