key: cord-0804279-zhbw09pg authors: Trifirò, Gianluca; Crisafulli, Salvatore; Andò, Giuseppe; Racagni, Giorgio; Drago, Filippo title: Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)? date: 2020-04-17 journal: Drug Saf DOI: 10.1007/s40264-020-00935-2 sha: a723fbd68f4a132a621a72a29f79a0f99bd68001 doc_id: 804279 cord_uid: zhbw09pg nan (ARBs) and direct renin inhibitors (DRIs). ACEIs enact their blood pressure-lowering effects by blocking the peptidyldipeptidase that hydrolyzes angiotensin I (A-I) to angiotensin II (A-II). In addition, it inactivates bradykinin, a vasodilating peptide promoting the release of nitrogen monoxide and prostacyclin. ARBs have no effect on bradykinin metabolism and block the effects of A-II more selectively than ACEIs. In detail, ARBs determine their antihypertensive effect by preventing the binding of A-II to the A-II receptor type 1 (AT 1 ). Finally, DRIs exert blood pressure-lowering effects by decreasing plasma renin activity and inhibiting the conversion of angiotensinogen to A-I [5] . In vitro studies demonstrated that ACEIs and ARBs can significantly increase the expression and activity of angiotensin-conversion enzyme 2 (ACE2), highly expressed in the heart and lungs [6] . Coincidentally, ACE2 is the receptor-binding site for the spike protein of SARS-CoV-2 at the target cell [7] . Hence, Fang et al. [4] recently hypothesized in The Lancet Respiratory Medicine that patients with cardiac diseases, hypertension, or diabetes mellitus treated with ACE2-increasing drugs might be at higher risk for severe SARS-CoV-2 infection. Accordingly, the authors suggested that calcium channel blockers (CCBs) may be a more suitable alternative antihypertensive treatment than ARBs/ ACEIs because of their lack of increased ACE2 expression or activity. On the other hand, recently published commentaries outlined the mechanisms by which RAAS inhibitors may be beneficial in patients with COVID-19 and discussed the unclear effects of these drugs on ACE2 levels and activity in humans, recommending against the suspension or withdrawal of RAAS blockers [8, 9] . We present here our contribution to the scientific debate, highlighting the importance of continuing ACEI/ARB treatments and reporting several arguments against switching from ACEIs or ARBs to other antihypertensive drugs and specifically to CCBs. Italian Society of Pharmacology members are listed in acknowlegements. First, to date, there is no sound evidence from clinical studies that replacing ACEIs/ARBs with other antihypertensive drugs, including CCBs, is associated with beneficial effects on either the prevention of COVID-19 or the prognosis for infected patients. The scant available data are mostly derived from in vitro studies. For this reason, in Nature Cardiology, Zheng et al. [2] reported, "Whether patients with COVID-19 and hypertension who are taking [an] ACE inhibitor/ARB should switch to another antihypertensive drug remains controversial, and further evidence is required" [2] . Second, other studies carried out in SARS-CoV and probably generalizable to SARS-CoV-2 suggested, paradoxically, a protective effect of ARBs against COVID-19 [1] . The interaction of the coronavirus spike protein with ACE2, its cellular-binding site, leads to ACE2 downregulation. In turn, this results in excessive production of angiotensin by ACE, whereas less ACE2 is capable of converting it to angiotensin (1-7), an heptapeptide with vasodilator activity [1, 10] . It has been suggested that exaggerated stimulation of AT 1 by A-II determines increased pulmonary vascular permeability, thereby mediating increased lung pathology when the expression of ACE2 is decreased [11, 12] . Thus, higher ACE2 expression following chronic treatment with ARBs may protect patients infected with SARS-CoV-2 against acute lung injury rather than increasing the risk of developing COVID-19. Third, switching among different antihypertensive drugs in older patients with relevant comorbidities may put this very frail population at risk of developing adverse cardiovascular events such as uncontrolled hypertension/symptomatic hypotension or even deterioration of other chronic diseases. Moreover, considering the proven effects of ACEIs and ARBs in reducing mortality in cardiovascular diseases, the discontinuation of these therapies could increase the occurrence of negative outcomes in patients affected by cardiovascular diseases and COVID-19 [13] . Fourth, ACEIs and ARBs are currently approved (with differences across various compounds) for the treatment of hypertension, heart failure and diabetic nephropathy and for secondary prevention after acute myocardial infarction, whereas CCBs and other antihypertensive drugs are not approved for all the same indications. Finally, none of the drug regulatory agencies worldwide recommend switching from ACEIs/ARBs to other antihypertensive drugs or vice versa during the COVID-19 outbreak. Instead, on 17 March 2020, the Italian Drug Agency issued a warning against any change of antihypertensive therapies in patients with well-controlled hypertension, irrespective of the agents being used, because of the lack of clinical data [14] . Ten days later, the European Medicines Agency advised that, since there is no clinical evidence that these drugs can worsen SARS-CoV-2 infections, it is important that patients do not discontinue their treatment with ACEIs or ARBs and there is no need to switch to other medicines [15] . These recommendations are in line with the position statements of national/international scientific societies (e.g., European Society of Cardiology [16] , Italian Society of Pharmacology [17], Heart Failure Society of America, American College of Cardiology and American Heart Association [18] , International Society of Hypertension [19] , European Society of Hypertension [20] ) that recommend continuing RAAS inhibitor therapy for patients who are currently prescribed such agents for indications for which it is known that these agents are safe and effective, such as acute and chronic heart failure [21] , acute myocardial infarction [22] and hypertension [23] . Regarding the postulated protective effect, ACEIs/ARBs should never be used in healthy people or patients who are not affected by diseases that are not approved indications as reported in the summary of product characteristics. No specific information has been described for DRIs. Nevertheless, all the recommendations reported above can be extended to this class of RAAS inhibitors. In a scenario in which experimental clinical studies cannot rapidly shed light on the association between COVID-19 and ACEI/ARB use, real-world studies based on dedicated COVID-19 patient registries, whenever available, or claims databases from countries with a high incidence of SARS-CoV-2 infection are urgently needed. In the absence of clinical evidence supporting any change in patients treated with ACEIs/ARBs, clinicians should still follow the old principle "primum non nocere." Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics COVID-19 and the cardiovascular system Preventing a COVID-19 pandemic Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Renin angiotensin aldosterone system inhibitors in hypertension: Is there evidence for benefit independent of blood pressure reduction? Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensinconverting enzyme 2 Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19 Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy. Vasc Health Risk Manag Angiotensin-converting enzyme 2 protects from severe acute lung failure SARS and MERS: recent insights into emerging coronaviruses SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers state ment-addre ssesconce rns-re-using -raas-antag onist s-in-COVID -19 19. International Society of Hypertension. A statement from the International Society of Hypertension on COVID-19 Statement of the European Society of Hypertension (ESH) on hypertension, Renin Angiotensin System blockers and COVID-19 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation ESC/ESH guidelines for the management of arterial hypertension The authors are grateful for the help and sup-ACE-Inhibitors or Angiotensin Receptor Blockers in COVID-19: To Switch or Not To Switch? gelheim; personal fees from Daiichi Sankyo, Menarini, AstraZeneca, Chiesi and Biosensors; and non-financial support from Terumo, all outside the submitted work. Salvatore Crisafulli, Giorgio Racagni and Filippo Drago have no conflicts of interest that are directly relevant to the content of this commentary.