Introduction
Soon after the report of first clusters of COVID-19 cases in China in December 2019, concerns were raised among clinicians and investigators that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) might increase susceptibility to COVID-19 infection and the likelihood of severe and fatal COVID-19 illness (1). These concerns are based on the concept that angiotensin-converting enzyme 2 (ACE2), an enzyme potentially up-regulated by ACEIs/ARBs use, is the viral entry receptor that COVID-19 uses to enter lung cell (2), coupled with the observation of high prevalence of hypertension and other cardiovascular comorbidities among COVID-19 patients who have poor outcomes (3) . Consequently, it was speculated that due to considerable prescribing of ACEIs/ARBs to treat cardiovascular diseases (CVD), this would adversely affect outcomes from COVID-19 (4) with underlying cardiac and kidney diseases already associated with poorer outcomes (3, 5, 6). Consequently, care to avoid treatments that well add to this.
Unsurprisingly, discussions regarding the potential impact of ACEIs/ ARBs has resulted in anxiety, which might cause patients and clinicians to discontinue or stop these medications (7) . This should be avoided as there will be harm from the indiscriminate withdrawal of ACEIs/ARBs (8). This concern is complicated by uncertainty surrounding the up-regulation of ACE2 by ACEIs/ARBs (9). Furthermore, the paradoxical protective role of ACEIs/ARBs in COVID-19 patients is also being proposed (10). Due to these controversial findings, and despite consistent and reassuring recommendations for the continued use of ACEIs/ARBs in COVID-19 patients issued by International Societies (11), these concerns remain. We wish to address this as we have already seen the impact that inappropriate endorsement of treatments can have on morbidity and mortality. Early endorsement of hydroxychloroquine resulted in drug shortages for other indications, price hikes, increased adverse drug reactions and deaths from suicides (12, 13). However, subsequent studies failed to show clinical benefit resulting in the World Health Organisation (WHO) and the National Institute of Health (NIH) in the USA stopping the hydroxychloroquine arm in their studies (14-16). A similar situation has been seen with lopinavir/ritonavir(15). Consequently it is imperative that any considerations regarding management are evidenced based.
We are aware that several observational studies have been conducted to address these concerns. However, these studies have reported conflicting findings which is a concern given the controversies with hydroxychloroquine and lopinavir/ritonavir. For instance, some studies (17-22) have reported a lower risk of severe COVID-19 outcomes with ACEIs/ARBs whilst another study (23) found a higher risk. Similarly, ACEIs/ARBs have been associated with lower mortality rates in some studies (17, 20, 24-27) whilst others (23, 28) reported higher mortality rates. We are also aware that two recently published systematic reviews (29, 30) containing 16 studies reported no evidence of any association between ACEIs/ARBs and mortality, severe COVID-19 outcomes, or acquiring COVID-19 infection; however, these studies only analysed a limited range of outcomes, and did not report the effects of ACEIs and ARBs individually. The authors also did not undertake any sub-group analysis to explore the effect of potential confounders such as study’s quality and there are concerns that the findings may now be out-dated. Furthermore, one of these studies (30) only used narrative synthesis of the data. Consequently, we sought to undertake an updated and comprehensive evaluation of effect of ACEIs/ARBs use on all reported COVID-19 related outcomes, including exploration of any class differences, through a systematic review of the literature coupled with a meta-analysis.