Hypertension is the single largest global contributor to disability-adjusted life
years lost [1]. The majority of the population aged over 60 years have hypertension
[2], and it has been suggested that they may be at increased risk from the effects
of COVID-19. Despite this, and perhaps due to its ubiquity in the older population,
current UK Government guidance does not identify people with hypertension as ʻat risk’
[3], however, other bodies such as the British Heart Foundation and the Health Service
Executive in Ireland do [4, 5]. This article seeks to summarise and interpret the
current evidence for and against an increase in COVID-19 risk and severity for those
with raised blood pressure, and discusses the implications for the choice of anti-hypertensive
treatment.
Early small case series did not indicate an excess of hypertension in people admitted
to hospital with COVID-19 [6]. The Novel Coronavirus Pneumonia Emergency Response
Epidemiology Team published a large case series from China; they found an overall
case fatality rate of 2.3% (1023 of 44,672 confirmed cases), which increased to 6.0%
for people with hypertension [7]. These data were reported without adjustment for
age. Both COVID-19 case fatality rates and hypertension prevalence increase with age,
reaching 8.0% and over 50% respectively for the 70–79 year age group [2]. New emerging
evidence from the largest epidemiological study to date, examining over 17 million
health records in England suggests that hypertension or a recorded blood pressure
≥140/90 mmHg taken together are not associated with COVID-19 in-hospital mortality
after full adjustment: Hazard Ratio (HR) 0.95, (95% confidence interval (CI) 0.89–1.01).
In sensitivity analyses, diagnosed hypertension alone was associated with slightly
increased risk (HR 1.07, 95% CI 1.00–1.15) which might reflect residual confounding
due to the strong age-related association [8].
Several other small case series that examine hypertension prevalence with and without
severe COVID-19 have appeared in the literature [9]. In March 2020, a study-level
meta-analysis of 2552 confirmed COVID-19 patients reported a pooled odds ratio (OR)
of 2.49 (CI: 1.98–3.12; 11 studies) for severe disease in the presence of hypertension,
with low heterogeneity between studies (I
2 = 24%). The OR for death was similar and weak evidence from meta-regression suggested
that hypertension might be a clinical predictor of COVID-19 severity in people aged
over 60 [10]. Likewise, a retrospective cohort analysis of 191 patients treated in
hospital in China (not included in the meta-analysis) confirmed apparent high mortality
in patients presenting with hypertension: 48% versus 23% of survivors [11].
Similar findings were reported with previous coronavirus infections, such as severe
acute respiratory syndrome and Middle East Respiratory Syndrome [12, 13]. The mechanism
by which hypertension leads to increased risk from COVID-19 is undoubtedly complex
and may well relate to underlying co-morbidity. The prognosis for people with hypertension
is markedly worse when COVID-19 infection is complicated by myocardial injury and
in the presence of cardiovascular disease [8, 14]. End organ damage and cardiovascular
events are associated with poorer control of high blood pressure, and mean blood pressure
rises with age [15, 16]. It seems plausible, therefore, that older age, poorer blood
pressure control and cardiovascular disease can explain the observed associations
between age, hypertension and severity of COVID-19 infection.
Are anti-hypertensive medications a risk for severity of COVID-19?
The viral structural spike (S) protein binds to the angiotensin-converting enzyme
2 (ACE2) receptor to gain entry to cells; this has led to suggestions that use of
ACE inhibitors and angiotensin II type-I receptor blockers (ARBs) may be implicated
in poorer outcomes with COVID-19 [17, 18]. Whilst gaining much publicity, with attendant
worry for patients and clinicians, this theory has been debated and ACE inhibitor
and ARB treatment has also been associated with improved outcomes in some reports
[19, 20]. Polymorphism in expression of the ACE2 receptor gene in association with
hypertension and excess cardiovascular risk in ethnic minority groups has also been
suggested as a partial explanation for observed excess mortality from COVID-19 in
these populations [21, 22]. The National Institute for Health and Care Excellence
are currently undertaking a rapid review of this topic [23]. Recent observational
studies of confirmed COVID-19 patients have increased confidence that these drugs
are not harmful: a case-control study of 6272 COVID-19 patients in Lombardy, Italy,
matched to 30,759 controls, confirmed higher use of ACE inhibitors and ARBs in patients
than controls, but after adjustment for greater prevalence of underlying cardiovascular
disease, there was no evidence that ACE inhibitors (OR 0.96; 95% CI 0.87–1.07) or
ARBs (OR 0.95; 95% CI 0.86–1.05) were associated with different risks of COVID-19
[24]. Two large retrospective cohort studies have also been published; one found no
association between ACE inhibitor or ARB use and a positive coronavirus test in 18,472
people from Ohio and Florida (weighted OR 0.97; 95% CI 0.81–1.15), whist another study
of 12,594 electronic health records from New York, found no association between any
anti-hypertensive medication (ACE inhibitors, ARBs, beta-blockers, calcium-channel
blockers, or thiazide diuretics) and increased likelihood of either a positive coronavirus
test or an increased risk of severe COVID-19 illness [25, 26].
It is important to recognise that, to date, no randomised trial evidence exists to
demonstrate either benefits or risks of continuing ACE inhibitors or ARBs on the incidence
or outcomes of COVID-19. It must also be acknowledged that these observational data
carry risks of residual confounding [27]. One retrospective cohort study found a positive
association between ACE inhibitor or ARB use and admission to hospital (OR 1.93; 95%
CI 1.38–2.71) or intensive care (OR 1.64; 95% CI 1.07–2.51) in small subgroup analyses
(N = 421 and 161, respectively) [26]. These secondary outcomes are rightly viewed
with caution due to the potential for residual confounding by co-morbidity and also
imprecision (as evidenced by wide confidence intervals) due to small sample sizes
[28]. Nevertheless, these studies taken together convey a consistent message of absence
of harm associated with anti-hypertensive medications during infection with coronavirus,
and clinical equipoise should therefore apply. Whilst these drugs appear increasingly
unlikely to worsen COVID-19 severity, the consequences of poor blood pressure control,
under normal circumstances, are well documented [16]. Consequently, the British and
Irish Hypertension Society (BIHS), and our European and International partner societies,
have issued clear position statements advising against cessation of anti-hypertensive
therapy on the grounds of concern over risks with COVID-19 (available at: https://bihsoc.org/bihs-statement-on-acei-arb-and-covid19/)
[29]. Current evidence does not support published opinions that doctors may consider
stopping treatment with ACE inhibitors and ARBs in well-controlled patients with mild
(Stage 1) hypertension and coronavirus infection [30]. The unintended consequences
of discontinuing effective treatments for hypertension, without a suitable replacement
titrated against appropriate blood pressure measurements and under direct medical
supervision, could put patients at increased cardiovascular risk. In addition, managing
such titration at a time when primary care is prioritising acute illness over routine
contacts (including surgery blood pressure checks), makes the proposed strategy impractical
and risks further diluting access to care.
So, what can we say to hypertensive patients who may be anxious about taking anti-hypertensive
medication and about their risks from infection during the COVID-19 pandemic?
The evidence base remains incomplete, so strong recommendations are difficult. However,
people with complications of hypertension, such as ischaemic heart disease, are already
regarded as being at high risk from COVID-19. It seems reasonable to advise those
with poorly controlled hypertension (i.e. blood pressure above guideline targets),
particularly if prolonged, to also consider themselves to be at elevated risk, and,
therefore, to follow appropriate social distancing advice [3]. For younger individuals
with hypertension, there is an association of obesity with COVID-19 severity among
Western populations [2, 8, 31, 32]. Generally, for people with good control of blood
pressure, risks of undiagnosed cardiovascular disease are low, and they could therefore
be reassured. All hypertensive patients should be strongly reassured that continuing
their current medications is both safe and desirable.
We should support all our hypertensive patients in continuing to strive for, and maintain,
good blood pressure control by continuing to take their medications as prescribed,
and by endeavouring to follow and maintain sensible lifestyle choices, including regular
exercise [3].
Large numbers of people are being affected by COVID-19 with potentially profound consequences,
however, their continued surveillance will also provide further data that will help
us to understand the true risk from elevated blood pressure, its treatment and co-morbidities,
on outcomes of the disease. Careful and continuous research is vital for an understanding
of the mechanisms underlying any additional risk from hypertension with COVID-19,
and to determine the best and safest ways to treat those with severe manifestations
of disease. Our patients are best served when their treatment is based on available
evidence rather than speculation, and the growing body of evidence suggests that continuation
of ACE inhibitors and ARBs during the current COVID-19 pandemic is safe.