Effect van medicatie die ACE-2 expressie beïnvloedt op uitkomst bij COVID-19 patiënten

Uitgangsvraag

What is the effect of medication that influence ACE-2 expression (ACEi, ARBs, NSAIDs and thiazolidinediones) on the outcomes of COVID-19?

Aanbeveling

Staak of ontraad ACEI/ARBs niet bij mensen die een COVID-19 infectie doormaken ongeacht ernst van de infectie, anders dan om acute hemodynamische redenen, acuut ernstig nierfunctieverlies of ernstige nierinsufficiëntie.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

De kwaliteit van het bewijs van de geïncludeerde studies is overwegend laag tot zeer laag. De GRADE systematiek is gevolgd om de kwaliteit van het bewijs te beoordelen. Deze is hier dan ook gevolgd. In een nieuwe situatie (zoals COVID) is het logisch dat de meeste studies nog niet kunnen voldoen aan de strenge eisen die aan studies van hoge kwaliteit worden gesteld. De GRADE methodiek zet de kwaliteit van het bewijs echter af tegen de best mogelijke kwaliteit en niet tegen de best mogelijke kwaliteit in de huidige situatie. De GRADE systematiek geeft het vertrouwen weer in de schatting van het effect van een interventie. Wanneer de modules en de search worden geüpdate zijn er hopelijk studies van betere kwaliteit beschikbaar en kan het niveau van de kwaliteit van het bewijs hierop worden aangepast.

In deze literatuursamenvatting is het effect van het gebruik van ACEI, ARBS, NSAIDS en thiazolidinediones van COVID-19 patiënten onderzocht op de uitkomstmaten mortaliteit, ic opname, ziekenhuisopname, verblijfsduur, ventilatie en tromboembolische complicaties. Mortaliteit was gedefinieerd als kritische uitkomstmaat. De literatuur laat zien dat er geen associatie is tussen gebruik van ACEI/ARBS (gecombineerd of los van elkaar) met mortaliteit voor zowel de overall groep (waarin gebruikers met niet gebruikers worden vergeleken) als de subgroep met alleen hypertensieve patiënten. De kwaliteit van het bewijs varieert van moderate (voor de overall groep waarin ACEI/ARBS gebruikers gecombineerd) tot zeer laag. Met betrekking tot NSAID gebruik is de kwaliteit van het wetenschappelijk bewijs zeer laag en kunnen geen conclusies voor de praktijk worden getrokken.

Voor de belangrijke uitkomstmaten was de kwaliteit van het bewijs laag tot zeer laag. Ook hier wijst het gebruik van het gebruik van ACEI, ARBS (zowel los als gecombineerd) en thiazolidinediones op geen of nauwelijks associatie met de belangrijke uitkomstmaten.

Er zijn nauwelijks studies waarin gebruik van ACEI, ARBs werd geassocieerd met hoger risico op slechte uitkomst, een van de weinige (Sulcuk et al) was een zeer kleine studie. Over het algemeen was er een zwakke associatie met betere uitkomsten bij gebruik van deze middelen (zie figuur 1 en 2) . Dit sluit nagenoeg uit dat deze middelen een negatief effect hebben op het beloop van een COVID-19 infectie. Het toont niet aan dat ze beschermend zijn, maar een beschermend effect kan niet worden uitgesloten. Herhaaldelijk uitsluiten van associatie met nadelige uitkomsten is wel in staat om de kans dat dat een dergelijk middel direct nadelige effecten heeft als zeer onwaarschijnlijk te beoordelen. Kortom, er is sterk bewijs voor de afwezigheid van een relatie tussen gebruik van ACEI, ARBs en slechtere uitkomsten. Er is geen sterk bewijs voor de beschermende effecten van deze middelen, maar dit kan ook niet worden uitgesloten.

CAPACITY

CAPACITY is een internationale registratie van patiënten met COVID-19 op basis van het ISARIC WHO CRF, aangevuld met informatie over specifieke cardiovasculaire parameters (https://capacity-covid.eu/). CAPACITY is in het voorjaar van 2020 gestart en bevat gegevens van 13034 patiënten uit 13 landen, afkomstig van 79 registrerende centra. CAPACITY bevat omvangrijke informatie over patiënten met COVID, omdat ongeveer 40% van de in Nederland opgenomen COVID19 patiënten in de registratie is opgenomen (n = 5524).

De peer-reviewed publicatie van CAPACITY over het onderwerp van deze module is momenteel in voorbereiding. De resultaten van CAPACITY kunnen daarom kunnen nog niet worden meegenomen bij het literatuuronderzoek, maar bij de overwegingen worden wel de voorlopige resultaten van CAPACITY meegenomen. De peer-reviewed publicatie over het onderwerp van deze module wordt binnenkort verwacht en bij een update van de module zal de publicatie in het literatuuronderzoek worden meegenomen.

De eerste analyses van de CAPACITY data zijn in lijn met bovengenoemde bevindingen. Daarbij lijken nog zeer voorlopige analyses te suggereren dat staken van juist meer krachtige ARBs geassocieerd is met slechtere uitkomsten ook na correctie voor confounders. Deze analyses moeten nog definitief worden bevestigd.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Patiënten die een behandeling met ACEI/ARBs krijgen vinden complete en eenduidige informatievoorziening belangrijk, o.a. over de veiligheid en risico’s van de behandeling.

Kosten (middelenbeslag)

De genoemde middelen zijn veelal reeds uit patent en daarmee generiek verkrijgbaar en zeer goedkoop (<1 euro per dag). De aanbevelingen die hier gedaan worden hebben vrijwel geen effect op kosten.

Aanvaardbaarheid, haalbaarheid en implementatie
Continueren van antihypertensiva bij patiënten met een ernstig verlopende infectieziekte zal in de dagelijkse praktijk discussie kunnen geven gezien de zorg voor te veel effect op de bedreigde bloeddrukregulatie. Daarom is uitdrukkelijk het advies om per geval te beoordelen of deze middelen doorgegeven kunnen worden, waarbij we hier herhalen dat indien klinisch wordt ingeschat dat deze worden verdragen het aanbeveling verdient ze niet te staken.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Er is geen relatie tussen gebruik ACEI en ARB en slechtere uitkomsten COVID-19 infectie. Dit is een sterk gegeven gezien meerdere studies deze associatie niet vinden op 1 kleine studie na. Eerder gebruik van ACE/ARBs lijkt geassocieerd met minder slechte uitkomsten van een ernstige COVID-19 infectie. Staken tijdens opname van ACE/ARBs in het kader van COVID-19 infectie is geassocieerd met slechtere uitkomsten. De gevonden associaties zijn zwak, echter met een redelijke effectgrootte. Het type bewijs is ook zwak (retrospectief).

Onderbouwing

Achtergrond

COVID-19 gebruikt het ACE-2 om de cel te infecteren. Dit ACE-2 breekt angiotensine II af. Angiotensine II verhoogt de bloeddruk. Medicijnen die worden gegeven tegen te hoge bloeddruk zoals ACE remmers of ARBs kunnen het niveau van ACE-2 verhogen. Er werd aanvankelijk gedacht dat veel ACE-2 gevoeliger zou maken voor COVID-19 omdat het immers de ‘poort’ is voor het virus. Echter, ACE-2 lijkt ook te beschermen tegen teveel angiotensine II, en teveel angiotensine II komt vaak voor in de long bij een door COVID-19 veroorzaakte longontsteking. Het is dus onduidelijk of medicijnen die ACE-2 verhogen of juist verlagen kwaad kunnen.

Conclusies

1. Mortality

1.1 Overall

Moderate GRADE

ACEI/ARBS use probably does not increase mortality.

Sources: Zhang (2020), Imam (2020), López-Otero (2020), Reynolds (2020)

Low

GRADE

The evidence suggests that ARBS use does not increase mortality.

Sources: Reynolds (2020), Mancia (2020) , Jung (2020) , Mehra (2020)

Low

GRADE

The evidence is uncertain about the effect of ACEI use on mortality.

Sources: Mancia (2020), Reynolds (2020), Bean (2020), Mehra (2020)

Low

GRADE

The evidence suggests that thiazolidinediones use does not increase mortality.

Sources: Reynolds (2020)

Very low GRADE

The evidence is very uncertain about the effect of NSAIDS use on mortality.

Sources: Imam (2020)

1.2 Hypertensive patients

Very low GRADE

ACEI/ARBS use may not increase mortality, but the evidence is very uncertain

Sources: Zhang (2020), Felice (2020), Gao (2020), Zhou (2020), Reynolds (2020), Selçuk (2020)

Low

GRADE

The evidence suggests that ARBS or thiazolidinediones use does not increase mortality.

Sources: Reynolds (2020), Mehra (2020)

Very low GRADE

The evidence is very uncertain about the effect of ACEI use on mortality.

Sources: Reynolds (2020), Mehra (2020)

2. IC admission

2.1 Overall

Very low

GRADE

The evidence is very uncertain about the effect of ACEI/ARBS or ACEI use on IC admission.

Sources: Reynolds (2020), López-Otero (2020), Bean (2020), Rentsch (2020)

Very low GRADE

ARBS use may have no effect on IC admission, but the evidence is very uncertain.

Sources: Reynolds (2020), López-Otero (2020

Low

GRADE

The evidence suggests that thiazolidinediones use does not increase IC admission.

Sources: Reynolds (2020)

2.2 Hypertensive patients

Very low GRADE

The evidence is very uncertain about the effect of ACEI/ARBS on IC admission

Sources: Reynolds (2020), Felice (2020), Selçuk (2020)

Low

GRADE

The evidence suggests that ARBS use, ACEI use, or thiazolidinediones use does not increase IC admission.

Sources: Reynolds (2020)

3. Hospital admission

3.1 Overall

Low

GRADE

The evidence suggests that ACEI/ARBS use, ARBS use, or ACEI use does not increase hospital admission.

Sources: López-Otero (2020), Rentsch (2020), Rossi (2020)

3.2 Hypertensive patients

Very Low GRADE

ACEI/ARBS use may have no effect on hospital admission, but the evidence is very uncertain.

Sources: Felice (2020)

4. Length of stay

4.2 Hypertensive patients

Very low GRADE

ACEI/ARBS may have no effect on length of stay, but the evidence is very uncertain.

Sources: Selçuk (2020), Zhou (2020)

5. Ventilation

5.1 Overall

Low

GRADE

The evidence suggests that ACEI/ARBS use, ACEI use or thiazolidinediones use does not increase ventilation.

Sources: Reynolds (2020), Jung (2020), Mancia (2020)

Very Low GRADE

ARBS use may have no effect on ventilation, but the evidence is very uncertain.

Sources: Reynolds (2020), Mancia (2020), Jung (2020)

5.2 Hypertensive patients

Very low GRADE

The evidence is very uncertain about the effect of ACEI/ARBS use on ventilation.

Sources: Gao (2020), Reynolds (2020), Felice (2020), Selçuk (2020)

Low GRADE

The evidence suggests that ARBS use, ACEI use or thiazolidinediones use does not increase ventilation.

Sources: Reynolds (2020)

6. Tromboembolic complications

6.1 Overall

Very low GRADE

ACE/ARBS use, ARBS use or ACEI use may have no effect on tromboembolic complications, but the evidence is very uncertain.

Sources: López-Otero, Jung

Samenvatting literatuur

Description of studies

Zhang (2020) assessed the relationship between ACEI/ARB use and COVID-19 infection in a systematic review. A comprehensive search of the PubMed, Embase, and Cochrane Library databases was performed to identify all relevant articles published between Jan 1, 2020 and May 9, 2020. Observational studies that met all the following criteria were included:

(1) study design: case-control, case-crossover, self-controlled case series (SCCS) or cohort study; (2) antihypertensive treatment: ACEI/ARB use versus non-ACEI/ARB use; (3) outcomes: the incidence of COVID-19, critical cases, or death; (4) adequate data were used to extract the risk estimates if the adjusted data were not provided in the publication. Editorials, correspondences, conference abstracts and commentary articles were excluded. Twelve articles (case-control and cohort studies) involving more than 19,000 COVID-19 cases were included. Information on follow-up duration or the number of patients for whom no complete outcome data was available was not mentioned.

Mackay (2020) evaluated whether use of ACEIs or ARBs either increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or was associated with worse COVID-19 disease outcomes, and the efficacy of these medications for COVID-19 treatment in a systematic review. MEDLINE (Ovid) and Cochrane Database of Systematic Reviews were searched from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality were included. Nineteen studies were included. Some of the included studies describe a composite outcome measure ‘severe COVID-19’.

Felice (2020) investigated the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19 related outcomes in hypertensive patients. A single center study was conducted on 133 consecutive hypertensive subjects presenting to the Emergency Department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9th and 31st March 2020. All patients were grouped according to their chronic antihypertensive medications (ACEIs, N=40; ARBs, N=42; not on RAAS inhibitors, N=51).

Gao (2020) investigated if treatment of hypertension, especially with RAAS inhibitors, had an impact on the mortality of patients with COVID-19. Consecutive patients admitted to Huo

Shen Shan Hospital (solely to the treatment of COVID-19, in Wuhan, China) from 5 February to 15 March 2020 were included. In total, 2877 consecutive hospitalized patients with confirmed

COVID-19 were enrolled in the study. The median time from symptom onset to discharge (last follow-up) was 39 (30–50) days. There were 710/850 (83.5%) patients with hypertension taking

antihypertensive medications. There were 183 (25.7%) patients treated with RAAS inhibitors and 527

(74.2%) treated with beta-blockers, CCBs, or diuretics (non-RAAS inhibitors). For the outcome measures of interest the group of 710 patients was used, meaning that hypertensive patients treated with RAAS inhibitors were compared to hypertensive patients on taking antihypertensive medications other than RAAS inhibitors. The medical history and blood pressure at admission did not differ significantly between the RAAS inhibitor-treated [RAASi (+)] and non-RAAS inhibitor-

treated patients [RAASi (–)]. There were 14 patients who reported shivering at admission in the RAASi (–) cohort, compared with none in the RAASi (+) cohort. There were 183 (25.7%) patients treated with RAAS inhibitors and 527 (74.2%) with beta-blockers, CCBs, or diuretics (non-RAAS

inhibitors).

Jung (2020) aimed to assess the associations between prior use of RAAS inhibitors and clinical outcomes among Korean patients with coronavirus 2019 (COVID-19). Among 5179 confirmed COVID-19 cases, 762 patients were RAAS inhibitor users and 4417 patients were nonusers. Relative to nonusers, RAAS inhibitor users were more likely to be older, male, and have comorbidities. Among 1954 hospitalized patients with COVID-19, 377 patients were RAAS inhibitor users and 1577 patients were nonusers.

López-Otero (2020) performed a single-center, retrospective, observational cohort study on 965 patients diagnosed with COVID-19 from 10 March to 6 April 2020. In total, 210 patients were under ACEI or ARB treatment at the time of diagnosis. 165 (78.57%) were taking them for more than 1 year. During the study period, 38 patients died (3.94%), of whom 35 (3.6%) had heart failure. The cohort of patients under ACEI/ARB was older (72.1 ± 13.2 vs 56.0 ± 20.5; P<0.01) and had more cardiovascular risk factors (hypertension, diabetes, smoking, and dyslipidemia) and cardiovascular comorbidities (coronary artery diseases and ventricular dysfunction) than the cohort without ACEI/ARB. There were fewer women in the ACEI/ARB group (43.8% vs 59.5%; P<0.01). Renal impairment and peripheral vasculopathy were also more prevalent in patients taking ACEI/ARB.

Selçuk (2020) aimed to determine the relation between the use of angiotensin converting

enzyme inhibitors (ACE inh) and angiotensinogen receptor blockers (ARBs) and in-hospital

mortality of hypertensive patients diagnosed with COVID-19 pneumonia. All patients were on ACE inh/ARBs or other antihypertensive therapy. In total, 113 hypertensive COVID-19 patients were included, of them 74 patients were using ACE inh/ARBs. During in-hospital follow up, 30.9% (n = 35 patients) of patients died.

Imam (2020) evaluated mortality predictors of COVID-19 in a large cohort of hospitalized patients in the US. Retrospective, multicenter cohort of inpatients diagnosed with COVID-19 by RT-PCR from March 1-April 1,2020 was performed, and outcome data evaluated from March 1-April 17, 2020. Measures included demographics, comorbidities, clinical presentation, laboratory values, and imaging on admission. Primary outcome was mortality. Secondary outcomes

included length of stay, time to death, and development of acute kidney injury in the first 48-hours. 1305 patients were hospitalized during the evaluation period. Mean age was 61.0±16.3, 53.8% were male and 66.1% was African-American. Mean BMI was 33.2±8.8 kg/m². Median Charlson Comorbidity Index (CCI) was 2 (1-4), 72.6% of patients had at least one comorbidity, with hypertension (56.2%) and diabetes mellitus (30.1%) being the most prevalent. ACE-I/ARB use and NSAIDs use were widely prevalent (43.3% and 35.7% respectively). Mortality occurred in 200 (15.3%) of patients with median time of 10 (6-14) days.

Zhou (2020) aimed to explore the clinical characteristics of COVID-19 complicated by hypertension. A retrospective, single-center study was conducted in which 110 discharged patients with COVID-19 at Wuhan Fourth Hospital in Wuhan, China, from January 25 to February 20, 2020 were included. All study cases were grouped according to whether they had a history of

hypertension. Then, a subgroup analysis for all hypertensive patients was carried out based on whether to take ACEI or ARB drugs. The mean age of 110 patients was 57.7 years (range, 25–86 years), of which 60 (54.5%) were male patients. The main underlying diseases included hypertension [36 (32.7%)] and diabetes [11 (10.0%)].

Table 1 General study characteristics

Author (year)	Study type	Comments	N	Country	Outcome
Zhang (2020)	Systematic review and meta-analysis			Multiple	Mortality
Mackay (2020)	Systematic review	There is overlap between studies included in Zhang and Mackay. Mackay included two studies for mortality that are not included in Zhang. One of those papers is not peer-reviewed and the other is in Chinese so both cannot be used.		Multiple	Mortality was assessed but not used, see comments, IC admission Hospital admission
Felice, (2020)	Observational study		133	Italy	Mortality, IC admission, Hospital admission, Ventilation
Gao (2020)	Observational study		2877	China	Mortality, Ventilation
Imam (2020)	Observational study		1305	US	Mortality
Jung (2020)	Observational study		5179	Korea	Mortality, Ventilation, Thromboembolic complications
López-Otero (2020)	Observational study		965	Spain	Mortality, IC admission, Hospital admission, Thromboembolic complications
Selçuk (2020)	Observational study		113	Turkey	Mortality, IC admission, Hospital admission, Ventilation, Length of stay
Zhou (2020)	Observational study		110 (36 of which were used for the analysis of interest)	China	Mortality, length of stay

Results

The results were described for two different groups, an overall group in which all users were compared with non-users and a group in which only hypertensive patients were included. Within each group a distinction was made between results for ACEi/ARBS use, ACEi use, ARBS use or NSAID use.

1. Mortality

1.1 Overall

1.1.1ACEI/ARBS

We were unable to provide a pooled estimate for mortality since some studies did not provide the absolute number of events or used a composite outcome measure. Therefore, the results of each of the studies were described separately.

Zhang (2020) performed a meta-analysis to study the relation between ACEI/ARBS use and mortality. In this meta-analysis, all studies that assessed this relation were included, irrespective of the type of patients in the intervention (all patients using ACEI/ARBS or only hypertensive patients) and control group (all COVID-19 patients not on ACEI/ARBS, hypertensive patients not on ACEI/ARBS but on other or no blood pressure lowering medication). Overall, the risk of mortality in ACEI/ARB-exposed was similar to non-ACEI/ARB exposed COVID-19 patients (pooled OR 0.73; 95% CI 0.5-1.07; P=0.11) (figure 3.1).

Imam (2020) and López-Otero (2020) also studied the relation between ACEI/ARBS use and mortality between users of ACEI/ARBS) and non-users. In a multivariate analysis both Imam and López-Otero reported no statistical significant difference in mortality between users of ACEI/ARBS and non-users (López-Otero (8 out of 78 ACEI/ARBS users died): OR, 0.62; 95%CI, 0.17-2.26; P =0.486, Imam: adjusted OR 1.20; 95%CI 0.86-1.68; P=0.278). López-Otero found that the absence of an impact on mortality remained both in the multivariate analysis and in the propensity score model, including in the evaluation of treatment taken for more than 1 year.

Reynolds (2020) (included in the review of Mackay) studied the relation between ACEi or ARBS use and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −0.1 (95%CI −3.7 to 3.5) meaning that there was no statistically significant difference between both groups.

None of the studies showed a statistically significant difference between ACEI or ARBS use and non-users with regard to mortality (or a composite outcome including mortality).

1.1.2 ARBS

Reynolds (2020) (included in the review of Mackay) studied the relation between ARBS and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −1.4 (95%CI −6.1 to 3.3) meaning that there was no statistically significant difference between both groups.

Mancia (2020) (included in the review of Mackay) studied the relation between ARBS and the composite outcome ‘severe COVID-19’ defined as assisted ventilation or death. The adjusted OR was 0.83 (95% CI 0.63–1.10).

Jung (2020) studied the relation between ACEI/ARBS use (N=377) and mortality. Since most of the included patients only used ARBS the results of this paper are used for the ARBS only category. In a multivariate analysis (adjusted for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type) Jung found no statistical significant difference in mortality between users and non-users (adjusted OR, 0.88 ; 95% CI 0.53–1.44; p=0.60).

In the study of López-Otero (2020) 6 out of 50 ACEI users died. López-Otero found no statistically significant difference in a multivariate analysis (analysis adjusted for arterial oxygen saturation <95%, diabetes mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin, ferritin, C-reactive protein, interleukin-6))(OR 1.54; 95%CI 0.42-5.59).

Mehra (2020) (included in the review of Zhang) studied the relation between ARBS use and mortality and found an OR of 1.23 (95%CI 0.87-1.74).

None of the studies showed a statistically significant difference between ARBS use and non-users with regard to mortality (or a composite outcome including mortality).

1.1.3 ACEI

Bean (2020) (included in the review of Mackay) found and adjusted OR for the composite outcome ‘mortality and transfer to critical care within 7 days of symptom onset’ of 0.29 (95%CI: 0.10–0.75) for ACEi use vs non-users. This paper was not peer-reviewed.

Mancia (2020) (included in the review of Mackay) studied the relation between ACEI and the composite outcome ‘severe COVID-19’ defined as assisted ventilation or death. The adjusted OR was 0.91 (95% CI 0.69–1.21).

In the study of López-Otero (2020) 2 out of 29 ACEI users died. López-Otero found no statistically significant difference in a multivariate analysis adjusted for arterial oxygen saturation <95%, diabetes mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin, ferritin, C-reactive protein, interleukin-6) (OR 0.14; 95% CI 0.01-1.57).

Mehra (2020) (included in the review of Zhang) studied the relation between ACEI use and mortality and found an OR of 0.33 (95% CI 0.20-0.54).

Three studies showed no statistically significant difference between ACEI use and non-users with regard to mortality (or a composite outcome including mortality). Two studies (one not peer reviewed and assessed mortality within 7 days of symptom onset) showed a statically significant difference.

1.1.4 NSAID

For NSAID use, Imam (2020) found that NSAID users had a statistical significant lower risk of mortality compared to non NSAID users in a multivariate analysis (adjusted for age, Initial Serum Creatinine, CCI, NSAID, HTN, ACE-I/ARB use, CKD) (OR 0.57; 95%CI 0.40-0.82; P=0.002).

1.1.5 Thiazolidinediones

Reynolds (2020) studied the relation between thiazide diuretics and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −3.4 (95% CI −8.3 to 1.6).

1.2 Hypertensive patients

1.2.1 ACEI/ARBS

Zhang (2020) performed a meta-analysis of seven studies in which hypertensive ACEI/ARB users were compared with hypertensive patients on other blood pressure lowering medication or no medication. In this meta-analysis Zhang observed no statistically significant difference in risk of mortality among those who used ACEI/ARB (OR 0.62; 95% CI 0.38-1.02; P=0.059, I²=74.8%) (figure 3.2).

Zhang (2020) found in meta-analysis of four studies that ACEI/ARB use in hypertensive patients was associated with a lower risk of mortality compared to those on non-ACEI/ARB antihypertensive drugs (OR 0.48, 95% CI 0.29-0.81; P=0.006; I² 0%).

Selçuk (2020) found that ACEI/ARBs use was associated with a higher risk of mortality (adjusted OR 3.66; 95%CI 1.11-18.18; P=0.032). The Kaplan-Meir curve analysis displayed that patients on ACE inh/ ARBs therapy had a higher incidence of in-hospital death than those who were not (log rank test p value <.001).

Felice (2020) found no statistically significant association between ACEI/ARB use in hypertensive patients in a multivariate analysis (OR 0.56; 95% CI 0.17-1.83; P=0.341).

Gao (2020) found no statistically significant association between ACEI/ARB use in hypertensive patients in a multivariate analysis (adjusted OR 0.85;95% CI 0.28-2.58; P=0.774).

Zhou (2020) found no statistically significant difference in mortality between ACEI/ARB use (N= in hypertensive patients using Student’s unpaired t-test. We calculated the OR which was 0.49 (95% CI 0.082-2.966).

Most of the studies showed no statistically significant difference between ACEI/ARBS use in hypertensive patients and non-users with regard to mortality (or a composite outcome including mortality). In the sub-analysis of Zhang (included only hypertensive patients on other than ACEI/ARBS drugs in the control group, so did not include hypertensive patients on no medication) and Selçuk a significant difference was found.

1.2.2 ARBS

Reynolds (2020) (included in the review of Mackay) studied the relation between ARBS use in hypertensive patients and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was 0.1 (95% CI −4.8 to 4.9).

Jung (2020) studied the relation between hypertensive ACEI/ARB users and hypertensive patients on other blood pressure lowering medication or no medication. Since most of the included patients only used ARBS the results of this paper are used for the ARBS only category. Jung found that RAAS inhibitor use was not independently associated with a higher risk of mortality among hypertensive COVID-19 patients (adjusted OR 0.71; 95% CI 0.40-1.26; P=0.25) adjusted for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type.

Mehra (included in the review of Zhang) studied the relation between ARBS use and mortality. Mehra found an OR of 1.233 (95% CI 0.87-1.74).

None of the studies showed a statistically significant difference between ARBS use in hypertensive patients and non-users with regard to mortality (or a composite outcome including mortality).

1.2.3 ACEI

Reynolds (2020) (included in the review of Mackay) studied the relation between ACEI use in hypertensive patients and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −3.3 (−8.2 to 1.7).

Mehra (included in the review of Zhang) studied the relation between ACEI use and mortality. Mehra found an OR of 0.33 (95% CI 0.20-0.54).

The study showed no statistically significant difference between ACEI use in hypertensive patients and non-users with regard to mortality (or a composite outcome including mortality) and one study found a statistically significant difference.

1.2.4 Thiazolidinediones

2. IC-admission

2.1 Overall

2.1.1 ACEI/ARBS

In the review of Mackay (2020) two studies assessed the relationship between ACEI/ARBs use and IC-admission (Rentsch and Reynolds). Rentsch (2020) found that admission to the IC was more likely to occur in patients using ACEI/ARBS compared to non-users (adjusted OR 1.69; 95% CI 1.01-2.84). This study was not peer-reviewed.

Reynolds (2020) studied the relation between ACEi or ARBS use and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −0.1 (95%CI −3.7 to 3.5) meaning that there was no statistically significant difference between both groups.

López-Otero (2020) found no statistically significant difference in a multivariate analysis (adjusted for arterial oxygen saturation <95%, diabetes mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin, ferritin, C-reactive protein, interleukin-6)(OR 0.87; 95% CI 0.30-2.50; P=0.798).

Two studies showed no statistically significant difference and one study that was not peer reviewed showed a statistically significant difference.

2.1.2 ARBS

López-Otero (2020) found that 7 ARBS users were admitted to the intensive care unit. López-Otero (2020) found no statistically significant difference in a multivariate analysis (adjusted for arterial oxygen saturation <95%, diabetes mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin, ferritin, C-reactive protein, interleukin-6)(OR 0.84; 95% CI 0.25-2.87 P=0.786).

2.1.3 ACEI

Reynolds (2020) (included in the review of Mackay) studied the relation between ACEI and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −1.9 (95%CI −6.6 to 2.8) meaning that there was no statistical significant difference between both groups.
López-Otero (2020) found that 6 ACEI users were admitted to the intensive care unit. López-Otero (2020) found no statistically significant difference between ACEI users and non-users in a multivariate analysis (adjusted for arterial oxygen saturation <95%, diabetes mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin, ferritin, C-reactive protein, interleukin-6)(OR 0.97; 95% CI 0.22-4.16 P=0.962).

One study showed no statistically significant difference and one study that was not peer reviewed showed a statistically significant difference

Thiazolidinediones

2.2 Hypertensive patients

2.2.1 ACEI/ARBS

Felice (2020) found that admission to semi-intensive/intensive care units was less likely to occur in hypertensive patients using ARB or ACEI (adjusted OR 0.25 95% CI 0.09-0.66; P=0.006).

Selçuk (2020) found a statistically significant difference (P=0.001) between IC-admission for hypertensive ACEI/ARB users (50%) compared to hypertensive non-users (17.9%). No correction for confounders was applied.

Reynolds (2020) (included in the review of Mackay) studied the relation between ACEi or ARBS use in hypertensive patients and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −0.5 (95%CI −4.3 to 3.2).
One study found no statistically significant difference, one study found a statistically significant difference in favour of ARB/ACEI users and one study found a statistically significant difference in favour of non-users.

2.2.2 ARBS

2.2.3 ACEI

2.2.4 Thiazolidinediones

3. Hospital admission

3.1 Overall

3.1.1 ACEI/ARBS

López-Otero (2020) reported 731 patients admitted to the hospital (75.8%), of which 210 were ACEI/ARBS users. López-Otero concluded in a multivariate analysis (adjusted for days with symptoms, fever, arterial oxygen saturation, <95%, age, sex, health personnel, institutionalized, dependency status, dementia, hypertension, dyslipidemia, ventricular dysfunction, lung disease, previous cancer, hypothyroidism, antiplatelet therapy) that there was no statistically significant difference in hospital admission in ACEI/ARBS users vs non-users (OR 0.85; 95% CI 0.45-1.64; P=0.638.

Rentsch (2020) (included in the review of Mackay) found in a multivariate analysis that there was no statistically significant difference between hospital admission in ACEI/ARBS users vs non-users (adjusted OR 1.24; 95% CI 0.79-1.95). This study was not peer-reviewed.

Two studies found no statistically significant difference (one of those studies was not peer-reviewed).

3.1.2 ARBS

López-Otero (2020) concluded in a multivariate analysis (adjusted for days with symptoms, fever, arterial oxygen saturation <95%, age, sex, health personnel, institutionalized, dependency status, dementia, hypertension, dyslipidemia, ventricular dysfunction, lung disease, previous cancer, hypothyroidism, antiplatelet therapy) that there was no statistically significant difference in hospital admission in ARBS users (n=50) vs non-users (n=134) (OR 1.10; 95% CI 0.59-2.04 P=0.757).

3.1.3 ACEI

Rossi (2020) (included in the review of Mackay) performed a multivariate analysis and found an adjusted HR with ACEI (adjusted for age, sex, and Charlson comorbidity score) of 1.13 (95%CI 1.1–1.5). When the analysis was restricted to patients with cardiovascular disease the aHR was 1.12 (95%CI 0.82–1.54; (adjusted for age, sex, and Charlson comorbidity score).

López-Otero (2020) concluded in a multivariate analysis (adjusted for days with symptoms, fever, arterial oxygen saturation <95%, age, sex, health personnel, institutionalized, dependency status, dementia, hypertension, dyslipidemia, ventricular dysfunction, lung disease, previous cancer, hypothyroidism, antiplatelet therapy) that there was no statistically significant difference in hospital admission in ACEI users (N=20) vs non-users (N=77) (OR 0.78; 95% CI 0.38-1.60 P=0.505).

3.2 Hypertensive patients

3.2.1 ACEI/ARBS

Felice (2020) concluded in a multivariate analysis (adjusted for gender, BMI, days with symptoms prior to admission, previous cardiovascular events, diabetes and cancer) that there was no statistically significant difference in hospital admission in hypertensive ACEI/ARBS users vs non-users OR 0.39 (95% CI 0.05-2.94; P=0.365).

4. Length of stay

4.2 Hypertensive patients

4.2.1 ACEI/ARBS

Selçuk (2020) assessed length of stay for hypertensive patients on ACEI/ARBS and hypertensive patients on other medication. There was no statistically significant difference between both groups ACE inh/ARBs users: 9 days ± 6, Non-user 8 days ± 4 (P=0.524).

Zhou (2020) found no statistically significant difference (P=0.405) in hospital length of stay in hypertensive patients using ACEI/ARB (mean 10.1 days, SD 5.2) and hypertensive patients using other antihypertensive drugs (mean 11.7, SD 6.0). We calculated the mean difference between the groups which was 1.60 (95% CI-2.31-5.51).

Two studies found no statistically significant difference.

5. Ventilation
Ventilation was defined differently in each of the studies. Jung assesses mechanical ventilation, Felice assesses oxygen therapy and non-invasive ventilation, Gao assesses invasive mechanical ventilation, Mancia assisted ventilation and Selçuk endotracheal intubation.

5.1 Overall

5.1.1 ACE/ARBS

5.1.2 ARBs

Reynolds (2020) (included in the review of Mackay) studied the relation between ARBS and the composite outcome ‘severe COVID-19’, defined as ICU admission, use of noninvasive or mechanical ventilation, or death. The mean difference between users and non-users of this medication was −1.9 (95%CI −6.6 to 2.8) meaning that there was no statistically significant difference between both groups.

Jung (2020) studied the relation between ACEI/ARBS use and ventilation (mechanical ventilation). Since most of the included patients only used ARBS the results of this paper were used for the ARBS only category. Jung calculated an adjusted OR of 1.03 (95% CI 0.50-2.13; P=0.93).

Three studies found no statistically significant difference.

5.1.3 ACEI

Two studies found no statistically significant difference.

5.1.4 Thiazolidinediones

5.2 Hypertensive patients

5.2.1 ACEI/ARBS

Gao (2020) compared users of RAAS inhibitors (5;2.7%) with non-RAAS inhibitor users (25;4.7%) and found no statistically significant difference (P=0.292). Felice (2020) found an adjusted OR 0.58; 95%CI 0.21-1.60; P=0.296. Selçuk (2020) reported a statistically significant difference between ACEI/ARBS users (44.6% required ventilation) vs non-users (10.3% require ventilation) (P<0.001), however there was no correction for confounders performed.

5.2.2 ARBS

5.2.3 ACEI

5.2.4 Thiazolidinediones

6. Thromboembolic complications

6.1 Overall

6.1.1 ACEI/ARBS

López-Otero (2020) reported on heart failure (defined according to the European Society of Cardiology guidelines). In a multivariate analysis, there was no statistically significant difference between ACEI/ARBS users and non-users (OR 1.37; 95% CI 0.39-4.77; P=0.622). The absence of an impact on heart failure remained both in the multivariate analysis and in the propensity score model, including in the evaluation of treatment taken for more than 1 year.

6.1.2 ARBS

Jung (2020) reported on acute cardiac event defined as cardiac arrest, myocardial infarction or acute heart failure. Since most of the included patients only used ARBS the results of this paper are used for the ARBS only category. No statistically significant differences were observed between RAAS inhibitor users and nonusers in terms of acute cardiac injury (OR 0.88; 95% CI 0.59 1.31; P=0.53).

6.1.3 ACEI

Level of Evidence

The level of evidence was assessed according to the GRADE methodology (GRADE: Grading Recommendations Assessment, Development and Evaluation, http://www.gradeworkinggroup.org/).

1. Mortality

1.1 Overall

ACEI/ARBS

ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (not all patients may have reached the outcome mortality yet and were still hospitalized at the moment of analysis) and one level for indirectness (two studies used a composite outcome measure) to ‘low’.

ACEI

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (one study not peer reviewed, not all patients may have reached the outcome mortality yet and were still hospitalized at the moment of analysis), one level because of indirectness (two studies used a composite outcome measure and one study assessed 7-day mortality) to ‘low’.

NSAID

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (unable to assess if the groups are comparable and information is unavailable on how many patients were still hospitalized at the moment of analysis) and two levels for imprecision (only one study available, small number of patients included) to ‘very low’.

Thiazolidinediones

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level for indirectness (a composite outcome measure was used) to ‘low’.

1.2 Hypertensive patients

ACE/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (number of events sometimes not reported but only ORs), and one level for imprecision (difference in effect size) to ‘low’.

ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis), and one level because of indirectness (one study used a composite outcome measure) to ‘low’.

ACEI

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis), one level for imprecision (some studies show a statistically significant difference and some do not) and one level because of indirectness (a composite outcome measure was used) to ‘very low’.

Thiazolidinediones

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure mortality was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

2. IC admission

2.1 Overall

ACE/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias (one study not peer reviewed, follow up duration unclear), one level because of imprecision (some studies show no effect, one study shows a significant effect) and one level because of indirectness (in one study a composite outcome measure was used) to ‘very low’.

ARBS

Starting with a high of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by 1 level because of risk of bias (some patients were still hospitalized at the moment of analysis and still could be admitted to the IC at a later moment), one level for indirectness (one study used a composite outcome measure) and one level for imprecision (small number of events) to ‘very low’.

ACE

Starting with a high of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by 1 level because of risk of bias (some patients were still hospitalized at the moment of analysis and still could be admitted to the IC at a later moment), one level for indirectness (one study used a composite outcome measure) and one level because of imprecision (low number of events) to ‘very low’.

Thiazolidinedione

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

2.2 Hypertensive patients

ACEI/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias and one level for imprecision (wide range of effects) and one level because of indirectness (a composite outcome measure was used in one study and in one study the outcome was semi intensive care or intensive care) to ‘very low’.

ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

ACEI

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

Thiazolidinedione

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure IC admission was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

3. Hospital admission

3.1 Overall

ACE/ARBS

ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure hospital admission was downgraded by one level because of risk of bias (follow up duration unclear), one level for imprecision (small number of events) to ‘low’.

ACEI

3.2 Hypertensive patients

ACE/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure hospital admission was downgraded by one level because of risk of bias (the study only included hypertensive subjects who presented to the emergency department with acute respiratory symptoms/fever), and two levels because of imprecision (small sample size, wide CI) to ‘very low’.

4. Length of stay

4.2 Hypertensive patients

ACEI/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure length of stay was downgraded by two level because of risk of bias (no correction for confounders, in one study follow up duration unclear) and one level because of imprecision (small number of included patients) to ‘very low’.

5. Ventilation

5.1 Overall

ACE/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure ventilation was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

ARBS
Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure ventilation was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis), one level for imprecision (wide confidence interval) and one level because of indirectness (a composite outcome measure was used in two studies) to ‘very low’.

ACEI

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure ventilation was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis), one level for imprecision (wide confidence interval) and one level because of indirectness (a composite outcome measure was used in two studies) to ‘very low’.

Thiazolidinediones
Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure ventilation was downgraded by one level because of risk of bias (some patients may not have reached the outcome yet by the date of analysis) and one level because of indirectness (a composite outcome measure was used) to ‘low’.

5.2 Hypertensive patients

ACEI/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure ventilation was downgraded by one level because of risk of bias (some studies did not correct for confounding), one level for imprecision (some studies describe a significant difference, some studies found no significant difference) and one level because of indirectness (composite outcome measure, different definitions of ventilation) to ‘very low’.

ARBS

ACEI

6. Tromboembolic complications

6.1 Overall

ACEI/ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure thromboembolic complications was downgraded by 1 level because of risk of bias (some patients were still hospitalized at the moment of analysis and still could develop thromboembolic complications), one level because of indirectness (thromboembolic complications was defined as hear failure) and one level because of imprecision (small number of events) to ‘very low’.

ARBS

Starting with a high level of evidence for observational studies (prognostic question), the level of evidence regarding the outcome measure thromboembolic complications was downgraded by 1 level because of risk of bias (some patients were still hospitalized at the moment of analysis and still could develop thromboembolic complications), one level because of indirectness (thromboembolic complications was defined as hear failure in one study and in one study a small number of patients in the I group were using ACEI) and one level because of imprecision (small number of events) to ‘very low’.

ACEI

Zoeken en selecteren

A review of the literature was performed to answer the following question:

What is the effect of using medication that influence ACE-2 expression (ACEi, ARBs, NSAIDs and thiazolidinediones) on the outcomes in patients with COVID-19?

P: All proven COVID-19 patients

I: Using medication before and during COVID-19 that influence ACE-2 expression: ACEi, ARBs, NSAIDs and thiazolidinediones

C: No use of medication that influence ACE-2 expression before and during COVID-19

O: Mortality, IC-admission, hospital admission, length of stay, thromboembolic complications (pulmonary embolism, stroke, transient ischemic attack), ventilation.

Relevant outcome measures

Mortality was considered as critical outcome measure for decision making and the other outcomes as important outcomes for decision making.

A priori, the working group did not define minimal clinically relevant differences for the outcome measures.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until June 24^th, 2020. The systematic literature search resulted in 567 hits. See search strategy for detail.

64 studies were initially selected based on title and abstract screening. After reading the full text, 56 studies were excluded (see the table with reasons for exclusion under the tab Methods), and nine studies were included.

Results

Nine studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias table.

Referenties

Felice C., Nardin C., Di Tanna GL., Grossi U., Bernardi E., Scaldaferri L., …& Rattazzi M. (2020). Use of
RAAS Inhibitors and Risk of Clinical Deterioration in COVID-19: Results From an Italian Cohort of 133 Hypertensives. Am J Hypertens. 2020 Oct 21;33(10):944-948.
Gao C., Cai Y., Zhang K., Zhou L., Zhang Y., Zhang X., …&Li F. (2020). Association of hypertension and
antihypertensive treatment with COVID-19 mortality: a retrospective observational study. Eur Heart J. 2020 Jun 7;41(22):2058-2066.
Imam Z., Odish F., Gill I., O'Connor D., Armstrong J., Vanood A., …& Halalau A. (2020). Older age and
comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States. J Intern Med. 2020 Oct;288(4):469-476.
Jung SY., Choi JC., You SH., Kim WY.(2020). Association of Renin-angiotensin-aldosterone System
Inhibitors With Coronavirus Disease 2019 (COVID-19)- Related Outcomes in Korea: A Nationwide Population-based Cohort Study. Clin Infect Dis. 2020 Nov 19;71(16):2121-2128.
López-Otero D., López-Pais J., Cacho-Antonio CE., Antúnez-Muiños PJ., González-Ferrero T., Pérez-
Poza M., …& González-Juanatey JR. (2020). Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a western population. CARDIOVID registry. Rev Esp Cardiol (Engl Ed). 2021 Feb;74(2):175-182.
Mackey K., King VJ., Gurley S., Kiefer M., Liederbauer E., Vela K., …& Kansagara D. (2020). Risks and
Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review. Ann Intern Med. 2020 Aug 4;173(3):195-203.
Selçuk M., Çınar T., Keskin M., Çiçek V., Kılıç Ş., Kenan B., …& Orhan AL. (2020). Is the use of ACE
inb/ARBs associated with higher in-hospital mortality in Covid-19 pneumonia patients? Clin Exp Hypertens. 2020 Nov 16;42(8):738-742.
Zhang X., Yu J., Pan LY., Jiang HY. (2020). ACEI/ARB use and risk of infection or severity or mortality
of COVID-19: A systematic review and meta-analysis. Pharmacol Res. 2020 Aug;158:104927.
Zhou X., Zhu J., Xu T. (2020). Clinical characteristics of coronavirus disease 2019 (COVID-19) patients
with hypertension on renin-angiotensin system inhibitors. Clin Exp Hypertens. 2020 Oct 2;42(7):656-660.

Evidence tabellen

Evidence table for systematic review of RCTs and observational studies (intervention studies)

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Zhang, 2020

SR and meta-analysis of cohort and case-control studies

Literature search between Jan 1, 2020 and May 9, 2020

A: Feng, 2020

B: Li Juyi, 2020

C: Mancia, 2020

D: Meng, 2020

E: Reynolds, 2020

F: Tedeschi, 2020

G: Yang, 2020

H: Zhang, 2020

I: Mehra, 2020

J: Yu, 2020

K: Mehta, 2020

L: Li xiaochen et al, 2020

Setting and country

A: China

B: China

C: Italy

D: China

E: USA

F: Italy

G: China

H: China

I: Asia, Europe, and

North America

J: China

K: USA

L: China

Source of funding and conflicts of interest:

This review was supported by Zhejiang Provincial Natural Science

Foundation of China

Conflicts of interest: none declared

Inclusion criteria SR: (1) study design: case-control, case-crossover, self-controlled

case series (SCCS) or cohort study; (2) antihypertensive treatment: ACEI/ARB use versus non-ACEI/ARB use; (3) outcomes: the incidence of

COVID-19, critical cases, or death; (4)

Exclusion criteria SR: editorials, correspondences, conference abstracts and commentary articles

12 studies included of which 8 report on mortality

Important patient characteristics at baseline:

N (ACE/ARB; Non ACE/ARB), mean age

A: N= 33; N=80, 53y

B: N= 115; N=247, 66y

C: N (ACEI) = 1502 (ARB)= 1394; N/A, 68y

D: N= 17; N=25, 64y

E: N= 091; N= 986, 64y

F: N= 165; N=136, 76y

G: N= 43; N=48, 66y

H: N= 188; N= 940, 64y

I: N (ACEI) = 770 N (ARB)= 556; N (non-ACEI)=8140 N (nonARB)= 8354, 49y

J: N= 103; N=173, 60y

K: N (ACEI)= 116 N(ARB)=98; N(non-ACEI)=

1619

N(nonARB)= 1637, 49y

L: N= 42; N= 503, 60y

Sex (% males):

A: 57%

B: 52%

C: NA

D: 57%

E: 50%

F: 72%

G: 49%

H: 53%

I: 60%

J: 53%

K: 40%

L: 51%

Groups comparable at baseline?

This information is not available

Confounder adjustment

A: No

B: No

C: No

D: No

E: No

F: Age, gender, presence of CV comorbidities

and COPD

G: No

H: Age, gender, comorbidities and in-hospital

medications

I: Age, race, coexisting conditions and

medications

J: Sex, age, smoking, symptom, diabetes,

cardiovascular diseases, chronic liver disease, and other comorbidity

K: Propensity score matched

L: No

The dose, name and moment in time (before and during COVID-19) the medication is used is not described. The systematic review only describes the number of patients per study on ACEi/ARBs and number of patients not on an ACEi/ARBs

N of patients on patients on ACEi/ARBs

A: 33

B: 115

C: ACEI 1502, ARB 1394

D: 17

E: 1091

F: 165

G: 43

H: 188

I: ACEI 770, ARB 556

J: 103

K: ACEI 116, ARB 98

L: 42

Measurement of

ACEI/ARB use

A: Medical record

review

B: Medical record

review

C: Databases of health

care use

D: Medical record

review

E: Pharmacy fill records

F: Medical record

review

G: Medical record

review

H: Medical record

review

I: Medical record

review

J: Medical record

review

K: Electronic medical

records

L: Medical record

review

For all studies the control group is defined as COVID-19 patients not on an ACEi/ARBs.

No. of patients not

on an ACEI/ARB

A: 80

B: 247

C: NA

D: 25

E: 986

F: 136

G: 83

H: 940

I: non-ACEI 8140,
non-ARB 8354

J: 173

K: non-ACEI 1619,
non-ARB 1637

L: 503

End-point of follow-up:

A-L: Not available

Study period

A: Jan 1 to Feb 15 2020

B: Jan 15 to Mar 15 2020

C: Feb 21 to Mar 11 2020

D: Jan 11 to Feb 23 2020

E: Mar 1 to Apr 15 2020

F: Feb 1 to Apr 4 2020

G: Jan 5 to Feb 22 2020

H: Dec 31 2019 to Feb 20 2020

I: Dec 20 2019 to Mar 12

2020

J: Jan 17 to Feb 19 2020

K: Mar 8 to Apr 12 2020

L: Jan 26 to Feb 5 2020

For how many participants were no complete outcome data available?

(intervention/control)

A-L: NA

1. Mortality

No definition for mortality provided.

A-L: NA

Meta-analysis (B, D, F, G, H, I, J, K )

Pooled OR = 0.73 [95 % CI 0.5–1.07] P = 0.11

Random effect analysis

The risk of mortality

in ACEI/ARB-exposed was similar to non-ACEI/ARB exposed COVID-19 patients
Heterogenitiy (I²): 70.7%
P = 0.001

Sub analysis ACEI/ARB exposure and risk of mortality in COVID-19 patients with antihypertensive indication

Pooled ES 0.62 [95%CI 0.38-1.02] P=0.059

Heterogenitiy (I²): 74.8%

2. IC-admission

Not reported

3. Hospital admission

Not reported

4. Length of stay

Not reported

5. Ventilation

Not reported

6. Thromboembolic complications

Not reported

The authors conclude that that ACEI/ARB use did not increase mortality risk among patients with COVID-19. However, patient exposure to ACEI/ARBs for the treatment of hypertension was associated with a lower risk of mortality.

Personal remarks:

Sensitivity analyses

Adjusted vs unadjusted estimates

no significant increase in the mortality risk of patients with ACEI/ARB exposure regardless of unadjusted OR = 0.66 [95 % CI, 0.38–1.12] P = 0.121 or adjusted estimates OR = 0.91 [95 % CI, 0.51–1.61] P = 0.87

Studies grouped by study location

There was a significantly lower mortality risk in studies from China OR=0.65 [95 % CI 0.46−0.91] P = 0.013. There were no significant increase in mortality risk in studies form other countries (OR = 0.88, 95 % CI, 0.48–1.62, P = 0.689).

Analysis limited to studies that only included patients on ACEi/ARBs for antihypertensive indications
A lower risk of mortality was observed among those who used ACEI/ARB

OR = 0.62 [95 % CI 0.38–1.02] P = 0.059
Heterogenity (I²): 74.85% P=0.001

After excluding studies that enrolled patients with hypertension not on antihypertensive

treatment, a meta-analysis of four studies found that ACEI/ARB exposure was associated with a lower risk of mortality compared to those on non-ACEI/ARB antihypertensive drugs
(OR = 0.48, 95 % CI, 0.29−0.81, P = 0.006; I² = 0%).

Heterogeneity:

The I²of 70.9% may represent substantial heterogeneity. The subgroup analysis described above does not explain the heterogeneity (unexplained). The heterogeneity may be explained by differences in the study populations (indication for ACEi/ARBs use, characteristics and comorbidities of the non-users, country), follow-up duration and completion of follow-up.

Mackay, 2020

SR of observational studies

Literature search MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, the World Health Organization database of COVID-19 publications and medRxiv.org through 17

April 2020; and ClinicalTrials.gov to 24 April 2020

A: Bean, 2020 (not peer reviewed)

B: Feng, 2020

C: Li, 2020

D: Liu, 2020

E: Mancia, 2020

F: Mehra, 2020

G: Meng, 2020

H: Rentsch, 2020 (not peer reviewed)

I: Reynolds, 2020

J: Rossi, 2020

K: Yang, 2020

L: Peng, 2020

M: Zeng, 2020

N: Zhang, 2020

Setting and country

A: adults with COVID-19 admitted to 2

hospitals; United

Kingdom

B: adults with COVID-19 admitted to 3

hospitals; China

C: adults

with COVID-19 and HTN

admitted to 1 hospital;

China

D: adults with COVID-19

aged >65 y with

preexisting HTN

admitted to 3 hospitals;

China

E: Patients with COVID-19

aged >40 y; Lombardy,

Italy

F: patients

with COVID-19 admitted

to 169 hospitals in Asia,

Europe, and North

America with discharge

status available in

registry

G: adults

with COVID-19 and pre-existing HTN

receiving medication

and admitted to 1

hospital; China

H: adults

born 1945–1965 with positive COVID-19 test

result; U.S. Veterans

Health Administration

I: patients

with HTN and positive

COVID-19 test result in 1

health system; United

States

J: patients

with COVID-19; Reggio

Emilia, Italy

K: adults with

preexisting HTN at 1 hospital; Hubei, China

L: adults

with COVID-19 and preexisting CVD at 1 hospital; China

M: adults with

COVID-19 admitted to 1

hospital; China

N: adults

aged 18–74 y with

COVID-19 admitted to 9

hospitals; China

Source of funding and conflicts of interest:

Authors did not receive funding for this study outside of salary support. No conflicts of interest were declared.

Inclusion criteria SR: observational studies of adults in any setting examining associations

between use of ACEIs or ARBs and risks for acquiring

SARS-CoV-2 and COVID-19, SARS, or MERS; observational

studies of adults with COVID-19, SARS, or MERS,

in any setting, examining associations between ACEI or

ARB use and risks for a broad range of clinical outcomes,

including death, severity of illness (mechanical

ventilation, intensive care unit [ICU] admission, length

of stay, need for non-invasive ventilation, hospitalization,

organ dysfunction), cardiovascular events, and radiologic findings; and trials in adults with COVID-19, in

any setting, comparing laboratory or clinical outcomes between patients treated with either ACEIs or ARBs and those receiving “usual care,” placebo, or other treatments.

Exclusion criteria SR:

case reports and case series with fewer than 10 patients

19 studies included of which 6 report on mortality, 2 on hospitalization and 1 on IC-admission

Important patient characteristics at baseline:

A: n = 205

Mean age: 63 y

Male: 52%

HTN: 51%

Diabetes: 30%

Heart disease: 15%

B: n = 476

Median age: 53 y

Male: 57%

HTN: 24%

Diabetes: 10%

Heart disease: 8%

C: n = 362

Mean age: 66 y

Male: 52%

HTN: 100%

Diabetes: 35%

Heart disease: 17%

D: n = 46

Age, sex, and comorbid

conditions NR

E: n = 6272

Mean age: 68 y

Male: 63%

HTN (receiving

medication): 58%

CVD: 30%

F: n = 8910

Mean age: 49 y

HTN: 26%

Coronary artery

disease: 11%

Diabetes: 14%

G: n = 42 Median age: 65 y

Male: 57% HTN:

100%

H: n = 585

Median age: 66 y

Male: 95%

HTN: 72%

Diabetes: 44%

Vascular disease: 28%

I: n = 2573

(Demographics

reported for patients

with HTN tested for

COVID-19)

Median age: 64 y

Male: 51%

HTN: 100%

Diabetes: 40%

History of MI: 11%

CKD: 25%

J: n = 2653

Mean age: 63 y

Male: 50%

HTN: 18%

Diabetes: 12%

Heart failure: 6%

K: n = 126

Median age: 66 y

Male: 49%

HTN: 100%

Diabetes: 30%

Heart disease: 18%

L: n = 112

Patients with preexisting

CVD

Mean age: 62 y

Male: 47%

HTN: 82%

Diabetes: 21%

M: n = 75

Patients with COVID

pneumonia and HTN

Mean age: 67 y

Male: 55%

HTN: 100%

Diabetes: 31%

N: n = 1128

Mean age: 64 y

Male: 53%

HTN: 100%

Groups comparable at baseline?

This information is not available

The dose, name and moment in time (before and during COVID-19) the medication is used is not described

N of patients on patients on ACEi/ARBs

NA (the SR describes the N of patients receiving

ACEI or ARB with

severe Illness (%), and

non-severe illness (%)

A: ACEI only: 9/53 (17);

37/152 (24)

B: 2/124 (2); 29/352 (9)

C: 57/173 (32.9);

58/189 (30.7)

D: 4/28 (14.3); 8/18

(44.4)

E: NA

F: ACEI: 16/515 (3.1);

754/8395 (9.0)

ARB: 38/515 (7.4);

518/8395 (6.2)

G: 4/17 (23.5);

12/25 (48)

H: Hospitalization:

147/297 (49.5)

ICU admission:

69/122 (56.6)

Not hospitalized:

108/288 (37.5)

I: NA

J: 501/1075 (46.6);

317/1578 (20.1

K: 15/50 (30.0); 28/76

(36.8)

L: 3/16 (18.6); 19/96

(19.8)

M: 15/30 (50);

13/45 (29)

N: NA

For all studies the control group is defined as COVID-19 patients not on an ACEi/ARBs. No further details are available.

No. of patients not

on an ACEI/ARB

A-N: NA

Study period:

A: 3/1/20–3/22/20

B: 1/1/20–2/15/20

C: /15/20–3/15/20

D: Time varied by site (range, 12/27/19–2/29/20);

E: NA

F: 12/20/19–3/15/20;

G: 1/11/20–2/23/20

H: 2/8/20–3/30/20

I: 3/1/20–4/15/20

J: 2/27/20–4/2/20

K: 1/5/20–2/22/20

L: 1/20/20–2/15/20

M: 1/5/20–3/8/20

N: 12/31/19–2/20/20

For how many participants were no complete outcome data available?

(intervention/control)

A-N: NA

1. Mortality

No definition for mortality provided.

Unadjusted

A: (Mortality and transfer

to critical care

within 7 d of

symptom onset)

ACEi OR 0.64 (0.28–1.43)

ACEi aOR 0.29 (0.10–0.75)

C: OR 0.76 [95%CI 0.43–1.33]

E: Assisted ventilation or

Death
ACEI:aOR 0.91 (0.69–1.21)

ARB: aOR 0.83

(0.63–1.10)

F: ACEI OR 0.33 [95% CI 0.19–0.54]

ARB OR 1.21 [95%CI 0.86–1.71]

I: severe covid: ICU admission, use of

noninvasive or

mechanical

ventilation, or

death

Overall

ACEi (mean diff for severe covid) −1.9 (−6.6 to 2.8)

ARB (mean diff) −1.4 (−6.1 to 3.3)

ACEi or ARB mean diff −0.1 (−3.7 to 3.5)

Thiazide diuretic (mean diff) −3.4 (−8.3 to 1.6)

hypertensive patients

ACE inhibitor (mean diff for severe covid) −3.3 (−8.2 to 1.7)

ARB mean diff 0.1 (−4.8 to 4.9)

ACE inhibitor or ARB mean diff −0.5 (−4.3 to 3.2)

Thiazide diuretic (mean diff)

0.6 (−4.5 to 5.7)

J: HR for death with ACEI

0.8 [95%CI 0.50–1.3]

K: OR 0.32 [95%CI 0.07–1.51]

M: OR 0.65 [95%CI 0.12–3.58]

F: Adjusted for severe illness

ACEI OR 0.33 [95%CI 0.20–0.54]

ARB OR 1.23 [95% CI 0.87–1.74]

N: Adjusted HR (age, sex, comorbid conditions, and in-hospital medications) 0.42 [95%CI 0.19–0.92]

2. IC-admission

A: see mortality

H: unadjusted OR 1.94 [95%CI 1.30–2.90]
adjusted OR 1.69

[95%CI 1.01–2.84]

I: see mortality

3. Hospital admission

H: unadjusted OR 1.63 [95%CI 1.17–2.27]
Adjusted (age, race, comorbid conditions, and Veterans Aging Cohort Study index) aOR 1.24

[95%CI 0.79–1.95]

J: aHR with ACEI (age, sex, and Charlson comorbidity score): 1.13 [95%CI 1.1–1.5]
aHR (age, sex, and Charlson comorbidity score, and restricted to patients with CVD) with ACEI

aHR 1.12 [95%CI 0.82–1.54]

4. Length of stay

Not reported

5. Ventilation

E: see mortality

I: see mortality

6. Thromboembolic complications

Not reported

The authors conclude that no indication exists to prophylactically

stop ACEI or ARB treatment because of concerns

about COVID-19.

1= Reported for hypertensive patients; 2= Calculated for 610 COVID 19 patients out of total of 49 277; 3 = Patients tested for COVID-19; 4= Patients aged over 35 years suspected of or diagnosed with COVID-19; 5= Not on any antihypertensive drug; 6= Before matching; 7= After matching; 8= Other regimens; 9 = Reported for COVID-19-positive patients (187 out of 288 suspected of or diagnosed patients)

Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies [cohort studies, case-control studies, case series])¹

This table is also suitable for diagnostic studies (screening studies) that compare the effectiveness of two or more tests. This only applies if the test is included as part of a test-and-treat strategy – otherwise the evidence table for studies of diagnostic test accuracy should be used.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Felice, (2020)

Type of study: retrospective observational study

Setting and country: hypertensive patients who presented to the emergency department, Italy

Funding and conflicts of interest: Funding not reported. No conflicts of interest declared.

Inclusion criteria: all consecutive hypertensive subjects who presented to the emergency department (ED) with acute respiratory symptoms/fever, and were diagnosed with COVID-19 infection

Exclusion criteria: NA

N total at baseline: 133

ACEI N=40

ARB N=42

Not on RAAS inhibitors N=51

Important prognostic factors²:

Mean age (SD):

ACEI: 73.1 (11.5)

ARB: 69.0 (13.4)

Not on RAAS: 76.2 (11.9)

Sex male (%):

ACEI: 28 (70)

ARB: 31 (74)

Not on RAAS 27 (53)

Groups comparable at baseline?
No significant differences were observed for all demographics and clinical parameters, except for the history of chronic heart failure, which was more frequently observed in hypertensive patients not on RAAS inhibitors (31%; P=0.007).

Hypertensive patients on ACEI

Patients on ACEI were chronically using ACEIs. 70% were taking ramipril.

Hypertensive patients on ARB

Patients on ARB were chronically using ARBs. Olmesartan was used in more than 50% of patients.

Hypertensive patients using other blood pressure lowering medications then ACEI or ARBs.

Length of follow-up:

Mean 15.8 ± 8.6 days

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

OR of 0.41 (CI 95%, 0.18-0.92; P=0.030)

aOR (gender, BMI, days with symptoms prior to admission, previous cardiovascular events, diabetes and cancer)
OR 0.56, CI95% 0.17-1.83, P=0.341

2. IC-admission

(semi intensive care/ic)

OR 0.36 [95%CI 0.17-0.75] P=0.007

aOR (gender, BMI, days with symptoms prior to admission, previous cardiovascular events, diabetes and cancer)
OR 0.25 [CI95% 0.09-0.66] P=0.006

Admission to semi-intensive/intensive care units, less likely to occur in hypertensive patients using ARB or ACEI (significant).

3. Hospital admission

OR 0.45 [95%CI 0.09-2.24]

P=0.327

aOR 0.39 [95%CI 0.05-2.94] P=0.365

4. Length of stay

Not reported

5. Ventilation

Defined as Oxygen therapy

OR 0.46 [95%CI 0.18-1.18] P=0.107
aOR 0.51 [95%CI 0.15-1.78] P=0.292

Defined as non-invasive ventilation

OR 0.70 [95%CI 0.34-1.44] P=0.336

aOR 0.58[95%CI 0.21-1.60] P=0.2966.

6. Thromboembolic complications

Not reported

Gao (2020)

Type of study: retrospective observational

Setting and country: Covid patients admitted to the hospital, China (for our outcome measures only hypertensive patients)

Funding and conflicts of interest: Not reported and no conflicts of interest declared.

Inclusion criteria: All patients admitted

to Huo Shen Shan Hospital, Wuhan, China, from 5 February to 15 March 2020, with confirmed COVID-19

Exclusion criteria: NA

Patients were confirmed or suspected COVID-19 patients

N total at baseline:

N total: 2877

N hypertensive patients on antihypertensive medication=710 (183 on RAAS inhibiter, 527 on non-RAAS inhibitor)

Important prognostic factors²:

age ± SD:

Non-RAAS inhibitor: 64.84 ± 11.19

RAAS inhibitor: 62.64 ± 11)

Sex (%male):

Non-RAAS inhibitor: 266 (50.5%)

RAAS inhibitor: 104 (56.8%)

Groups comparable at baseline?

Yes, for all (symptoms at admission, blood pressure, medical history) except shivering

Hypertensive patients on ACEI and/or ARBs

Hypertensive patients not on RAAS (but on B blockers, antidiuretics etc)

Length of follow-up:
median 21 (12–

32) days

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

RAASI: 4/183 (2.2%)

Non-RAASI: 19/527 (3.6%)

Unadjusted 0.60 (95% CI 0.20–1.76) P= 0.354

Adjusted (age, sex, medical history of diabetes, insulin-treated diabetes, myocardial infarction, underwent PCI/CABG, renal failure, stroke, heart failure, and COPD)

ORa 0.85 [95% CI 0.28–2.58] P= 0.774

Propensity score adjusted 0.93 [95% CI 0.31–2.84] P=0.901

2. IC-admission

Not reported

3. Hospital admission

Not reported

4. Length of stay

Not reported

5. Ventilation

Defined as invasive mechanical ventilation

RAASI: 5 (2.7%)

Non-RAASI: 25 (4.7%)
P=0.292

There is no significant difference in mechanical ventilation between hypertensive patients on RAAS inhibitors and on non-Raas inhibitors.

6. Thromboembolic complications

Not reported

Imam (2020)

Type of study: Retrospective, multicenter cohort

Setting and country: patients hospitalized with COVID-19, US

Funding and conflicts of interest: none and none declared

Inclusion criteria: patients hospitalized with SARS-CoV-2 infection demonstrated by a positive RT-PCR on nasopharyngeal swab per world health organization (WHO) guidance between March 1-April 1,2020

Exclusion criteria: NA

N total at baseline:

Total N=1305

ACEI or ARBs N=565 (43.3%)

NSAIDS N= 466 (35.7%)

Important prognostic factors²:

Not available per group

age ± SD: 61.0 ±16.3

Male Sex 702 (53.8%)

Groups comparable at baseline? NA because the groups are not defined as in the PICO

NSAID use

ACEI/ARBs use

No further details available

patients hospitalized with SARS-CoV-2

Length of follow-up: NA

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

Univariate analysis

NSAIDS use

OR 0.55 [95% CI0.39-0.78] P=.001

ACE-I/ARB use OR 1.55 [95% CI 1.15-2.10] P=.004

Multivariate analysis (Age, Initial Serum Creatinine, CCI, NSAID, HTN, ACE-I/ARB use, CKD)

NSAID use

OR 0.57 [95%CI 0.40-0.82] P=0.002

ACE-I/ARB use
OR 1.20 [95%CI 0.86-1.68] P=0.278

2. IC-admission

Not reported

3. Hospital admission

Not reported

4. Length of stay

Not reported

5. Ventilation

Not reported

6. Thromboembolic complications

Not reported

Jung (2020)

Type of study: population based cohort using a database of de-identified COVID-19 patient data

Setting and country: patients admitted to the hospital and patients not admitted to the hospital, Korea

Funding and conflicts of interest: No funding and no conflicts of interest declared.

Inclusion criteria: patients with COVID-19 who were ≥18 years old

Exclusion criteria: NA

N total at baseline:

N total = 5179

N hospitalized (with clinical outcomes) = 1954

N (hospitalized RAASi users) = 377

N (hospitalized non RAASi users) = 1577

Important prognostic factors for total:

age ± SD:

RAASi:62.5 ± 14.7

Non-RAASI: 41.5 ± 16.6

Sex (% male):

RAASi: 400 (52)

Non-RAASi: 1895 (43)

Charlson comorbidity index (mean (SD))

RAASi: 3.3 (2.8)

Non-RAASi: 1.2 (1.9)

Groups comparable at baseline?

No, there is a significant difference between the groups on all included factors (age, sex, comorbidities, Charlson comorbidity index, immunosuppression)

RAAS inhibitor users were defined as patients with RAAS inhibitor use at 1–30 days before the index date

Patients who had never received RAAS inhibitors or had received them at 31–365 days before the index date. A prescription duration of ≥7 days was required to define drug use.

Length of follow-up:

All patients were followed until the first instance of death or April 8, 2020

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

Defined as in-hospital mortality

Observed for 33/377 RAAS inhibitor users (9%) and for 51/1577 nonusers (3%) (p<0.001)

Univariate analysis (total group)

OR 3.88 [95%CI 2.48 6.05] P<0.001

Multivariate analysis (total group, adjusted for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type))

adjusted OR, 0.88 [95% CI 0.53–1.44] p=0.60

RAAS inhibitor use was not independently associated with a higher risk of mortality among COVID-19 patients

Multivariate analysis (adjusted for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type) hypertensive patients

adjusted OR 0.71 [95% CI 0.40–1.26] p=0.25

RAAS inhibitor use was not independently associated with a higher risk of mortality among hypertensive COVID-19 patients.

2. IC-admission

Not reported

3. Hospital admission

Not reported

4. Length of stay

Not reported

5. Ventilation

Defined as mechanical ventilation)

OR 3.74 [95% CI 1.91 7.34] P<0.001

Adjusted OR 1.03 [0.50 2.13] P=0.93

RAAS inhibitor use was not independently associated with a higher risk of mechanical ventilation

6. Thromboembolic complications

Defined as acute cardiac event

OR 1.69 [95% CI 1.19 2.39] P= 0.003

Adjusted OR 0.88 [95% CI 0.59 1.31] P=0.53

RAAS inhibitor use was not independently associated with a higher risk of an acute cardiac event

López-Otero (2020)

Type of study: Single-center, retrospective, observational cohort study

Setting and country: Hospitalized and non-hospitalized patients, Spain

Funding and conflicts of interest: Funding information NA, no conflict of interest declared.

Inclusion criteria: all cases of laboratory-confirmed SARS-CoV-2

infection in the area,

Exclusion criteria:

N total at baseline:

Total N=965

ACEI/ARB N= 213
No ACEI/ARB N = 755

Important prognostic factors²:

age ± SD:

ACEI/ARB : 72.1 ± 13.2

No ACEI/ARB: 56.0 ± 20.5

Sex (%female):

ACEI/ARB : 43.8 59.5

No ACEI/ARB: 59.5

Groups comparable at baseline?

The cohort of patients under ACEI/ARB was older (72.1 ± 13.2 vs 56.0 ± 20.5; P < .01) and had more cardiovascular risk factors (hypertension,

diabetes, smoking, and dyslipidemia) and cardiovascular comorbidities (coronary artery diseases and ventricular dysfunction) than the

cohort without ACEI/ARB. There were fewer women in the ACEI/ARB group (43.8% vs 59.5%; P < .01). Renal impairment and peripheral vasculopathy were also more prevalent in patients taking ACEI/ARB.

Use of ACEI, ARB or both

Of the COVID-19 patients, 210 (21.8%) were under ACEI or ARB treatment at the time of diagnosis; of these, 165 (78.57%) were taking them for more than 1 year.

No use of ACEI or ARB

Length of follow-up:

Study period from 10 March to 6 April

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

Univariate analysis

OR 1.49 [95%CI 0.73-3.06] p=0.276

Multivariate analysis (adjusted for fever,

oxygen saturation

< 95%, age, sex, obesity, health personnel, dependency status,

hypertension, diabetes mellitus, dyslipidemia, arterial disease, heart disease, atrial fibrillation, pneumonia, chronic renal disease, cerebrovascular disease, autoimmune disease, anticoagulation, beta-blockers)

OR 0.62 [95%CI 0.17-2.26] P=0.468

Propensity score matching
ACEI/ARBs OR 0.47 [95%CI 0.14-1.64] P=0.239

Previous treatment with ACEI/ARB (combined and individually)

showed no impact on mortality.

2. IC-admission

Univariate analysis

OR 1.36 [95%CI 0.64-2.90] P=0.427

Multivariate analysis (adjusted for arterial oxygen saturation

< 95%, diabetes

mellitus, hypoxemia, hypercapnia, lymphocytes, creatinine, elevated troponin,

ferritin, C-reactive protein, interleukin-6)

OR 0.87 [95%CI 0.30-2.50] P=0.798

Previous treatment with ACEI/ARB (combined and individually)

showed no impact on IC admission

3. Hospital admission

Univariate analysis

OR 2.27 [95% CI 1.63-3.16] P<.001

Multivariate analysis (adjusted for days with symptoms, fever, arterial oxygen saturation

< 95%, age, sex,

health personnel, institutionalized, dependency status, dementia, hypertension,

dyslipidemia, ventricular dysfunction, lung disease, previous cancer, hypothyroidism,

antiplatelet therapy)

OR 0.85 [95%CI 0.45-1.64] P=0.638

Previous treatment with ACEI/ARB (combined and individually)

showed no impact on hospital admission.

4. Length of stay

Not reported

5. Ventilation

Not reported

6. Thromboembolic complications

Defined as heart failure

Univariate analysis

OR 2.20 [95%CI 1.09-4.44] P=0.028

Multivariate analysis (adjusted for fever,

oxygen saturation

< 95%, age, sex, obesity, health personnel, dependency status,

OR 1.37 [95%CI 0.39-4.77] P=0.622

Subgroup of patients requiring hospitalization,

The absence of an impact on mortality and on heart failure remained both in the multivariate analysis and in the propensity score model, including in the evaluation of treatment taken for more than 1 year

Selçuk (2020)

Type of study: observational

Setting and country: hypertensive patients

admitted due to Covid-19 infection, Turkey

Funding and conflicts of interest: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. No conflicts of interest were declared.

Inclusion criteria: consecutive

hypertensive patients admitted to our centers due to Covid-

19 infection

Exclusion criteria:

Patients with the absence of in-hospital

clinical data, heart failure patients with hypertension were not included in the study

N total at baseline:

N total = 113

ACE inh/ARBs users N=74

Non-users N=39

Important prognostic factors²:

age ± SD:

ACE inh/ARBs users: 67 ± 11

Non-user: 58 ± 10

Sex (N, % male):

ACE inh/ARBs users: 36 (48.6)

Non-user: 23 (59.0)

Groups comparable at baseline?

The patients in the ACE inh/ARBs group were older. The frequency

of coronary artery disease was significantly higher in patients using an ACE inh/ARBs as anti-hypertensive treatment

(p = .009). The other baseline features and medical treatments

were indifferent between the groups. patients in the ACE inh/ARBs group had

significantly higher white blood cell (WBC) and neutrophils

count

Patients on ACEI and/or ARBs

All patients were on other than ACE inh/ARBs antihypertensive

therapy unless no contraindication was present.

Length of follow-up:

Loss-to-follow-up:

INA

Incomplete outcome data:

1. Mortality

Univariate analysis

OR 6.30 (95%CI 2.03–19.58)

P0.001

Multivariate analysis (adjusted for age, coronary artery disease, ACE inh/ARBs

use, D-dimer, WBC count, creatinine, plasma glucose, and lactate dehydrogenase)
OR 3.66 (95%CI:

1.11–18.18) p= .032
ACEI/ARB use is an independent predictor of inhospital mortality.

Kaplan-Meir curve analysis displayed that patients on ACE inh/ ARBs therapy had higher incidence of in-hospital death than those who were not [log rank test p value <.001

2. IC-admission

ACE inh/ARBs users: 37 (50.0)

Non-user: 7 (17.9) ) P=.001

3. Hospital admission

Not reported

4. Length of stay (days)

ACE inh/ARBs users: 9 ± 6
Non-user: 8 ± 4
P=0.524

5. Ventilation

Defined as endotracheal intubation
ACE inh/ARBs users: 33 (44.6)

Non-user: 4 (10.3)
P<0.0016.

6. Thromboembolic complications

Not reported

Zhou (2020)

Type of study: Retrospective, single center cohort

Setting and country: discharged patients with COVID-19, China

Funding and conflicts of interest: not reported and none declared

Inclusion criteria: confirmed patients with COVID-19 at Wuhan Fourth Hospital discharged from January 25 to February 20, 2020.

Exclusion criteria: NA

N total at baseline:

Total N=110

History of hypertension N=36 (32.7%)

ACEI or ARBs N=15 (41.7%) (43.3%)

Other antihypertensive drugs (control) N=21 (58.3%)

Important prognostic factors²:

Age ± SD

ACEI/ARBs users:

58.5 ± 10.1 years

Other: 69.2 ± 7.5 years

Male Sex: N (%)

ACEI/ARBs users:

9 (60%)

Other: 10 (47.6%)

Groups comparable at baseline? Age was significant different (p=0.001) between groups. Other factors were comparable.

Patients taking ACEI/ARBs

No further details available

Patients taking other antihypertensive drugs.

No further details available

Length of follow-up: NA

Loss-to-follow-up:

Incomplete outcome data:

1. Mortality

ACEI/ARBs users: 2 (13.3%)

Non-user: 5 (23.8%)
P<0.676.

2. IC-admission

Not reported

3. Hospital admission

Not reported

4. Length of stay

Mean (SD)

I: 10.1(5.2)

C: 11.7(6.0)

P=0.405

5. Ventilation

Not reported

6. Thromboembolic complications

Not reported

Notes:

Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
Provide data per treatment group on the most important prognostic factors [(potential) confounders]
For case-control studies, provide sufficient detail on the procedure used to match cases and controls
For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders

Table of quality assessment for systematic reviews of RCTs and observational studies

Based on AMSTAR checklist (Shea et al.; 2007, BMC Methodol 7: 10; doi:10.1186/1471-2288-7-10) and PRISMA checklist (Moher et al 2009, PLoS Med 6: e1000097; doi:10.1371/journal.pmed1000097)

Study First author, year	Appropriate and clearly focused question?¹ Yes/no/unclear	Comprehensive and systematic literature search?² Yes/no/unclear	Description of included and excluded studies?³ Yes/no/unclear	Description of relevant characteristics of included studies?⁴ Yes/no/unclear	Appropriate adjustment for potential confounders in observational studies?⁵ Yes/no/unclear/notapplicable	Assessment of scientific quality of included studies?⁶ Yes/no/unclear	Enough similarities between studies to make combining them reasonable?⁷ Yes/no/unclear	Potential risk of publication bias taken into account?⁸ Yes/no/unclear	Potential conflicts of interest reported?⁹ Yes/no/unclear
Zhang, 2020	Yes	Yes	Yes	No (number of events not reported per study)	Unclear (some studies in the SR adjusted for counfounders but not all)	Yes	Yes (subgroup analysis were performed to make reasonable combining of studies)	Yes (publication bias could not be assessed because less than 10 studies were included in the meta-analysis)	No
Mackay, 2020	Yes	Yes	No (no exclusion reason were provided)	Yes	Unclear (some studies in the SR adjusted for counfounders but not all)	Yes	Yes (a meta-analysis might not be appropriate and was not performed)	No	No (not for included studies)

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Zhang, 2020

Yes

No (number of events not reported per study)

Unclear (some studies in the SR adjusted for counfounders but not all)

Yes

Yes (subgroup analysis were performed to make reasonable combining of studies)

Yes (publication bias could not be assessed because less than 10 studies were included in the meta-analysis)

Mackay, 2020

Yes

No (no exclusion reason were provided)

Yes

Unclear (some studies in the SR adjusted for counfounders but not all)

Yes

Yes (a meta-analysis might not be appropriate and was not performed)

No (not for included studies)

Research question (PICO) and inclusion criteria should be appropriate and predefined
Search period and strategy should be described; at least Medline searched; for pharmacological questions at least Medline + EMBASE searched
Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons
Characteristics of individual studies relevant to research question (PICO), including potential confounders, should be reported
Results should be adequately controlled for potential confounders by multivariate analysis (not applicable for RCTs)
Quality of individual studies should be assessed using a quality scoring tool or checklist (Jadad score, Newcastle-Ottawa scale, risk of bias table etc.)
Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, intervention and definition of outcome measure to allow pooling? For pooled data: assessment of statistical heterogeneity using appropriate statistical tests (e.g. Chi-square, I²)?
An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies.
Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.

Risk of bias table for intervention studies (observational: non-randomized clinical trials, cohort and case-control studies)

Study reference (first author, year of publication)	Bias due to a non-representative or ill-defined sample of patients?¹ (unlikely/likely/unclear)	Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?² (unlikely/likely/unclear)	Bias due to ill-defined or inadequately measured outcome ?³ (unlikely/likely/unclear)	Bias due to inadequate adjustment for all important prognostic factors?⁴ (unlikely/likely/unclear)
Felice, (2020)	Unlikely (hypertensive confirmed covid patients)	unlikely	Mortality: Unlikely IC-admission: unclear (admitted to semi/ intensive care) Hospital admission: unclear (criteria not defined) Oxygen therapy: unlikely Non-invasive ventilation: unlikely	Mortality: Unlikely (adjusted for for gender, BMI, days with symptoms prior to admission, previous cardiovascular events, diabetes and cancer) IC admission: unlikely (adjusted for gender, BMI, days with symptoms prior to admission, previous cardiovascular events, diabetes and cancer) Hospital admission: unlikely (adjusted) Oxygen therapy: unlikely (adjusted) Non-invasive ventilation: unlikely (adjusted)
Gao (2020)	Unlikely (hypertensive confirmed or susptected covid patients)	Unlikely	Mortality: unlikely Invasive mechanical ventilation: unlikely	Mortality: Unlikely (age, sex, medical history of diabetes, insulin-treated diabetes, myocardial infarction, underwent PCI/CABG, renal failure, stroke, heart failure, and COPD) Invasive mechanical ventilation: likely (no correction for confounders)
Imam (2020)	Unclear (the groups are different then in the PICO so samples not possible to assess)	Unclear (information is missing on how many patients were still hospitalized at the moment of analysis)	Mortality: unlikely	Unlikely (multivariate analysis performed)
Jung (2020)	unlikely	Unclear (information is missing on how many patients were still hospitalized at the moment of analysis)	Mortality: unlikely Mechanical ventilation: unlikely Acute cardiac event: unlikely	Mortality: Unlikely (age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type) Mechanical ventilation: unlikely (age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type) Acute cardiac event: unlikely (adjusted for age, sex, Charlson Comorbidity Index, immunosuppression, and hospital type)
López-Otero (2020)	Unlikely (confirmed COVID patients)	Unclear (unclear how long the follow up duration was and how many patients are still hospitalized)	Mortality: unlikely IC admission: unclear Heart failure: according to the European Society of Cardiology guidelines	Unlikely (adjusted for days with symptoms, fever, arterial oxygen saturation < 95%, age, sex, health personnel, institutionalized, dependency status, dementia, hypertension, dyslipidemia, ventricular dysfunction, lung disease, previous cancer, hypothyroidism, antiplatelet therapy) Hospital admission: unlikely IC-admission: unlikely Heart failure: unlikely
Selçuk (2020)	Unlikely (hypertensive confirmed covid patients)	Unclear (there is no information available on follow-up duration)	Mortality: unlikely IC admission: unclear (criteria not described, may depend on capacity) Length of stay: unclear (discharge criteria not described, may depend on capacity) Ventilation: unlikely	Mortality: unlikely (adjusted for adjusted for age, coronary artery disease, ACE inh/ARBs use, D-dimer, WBC count, creatinine, plasma glucose, and lactate dehydrogenase) IC-admission: likely (no correction for confounders) Length of stay: likely (no correction for confounders) Ventilation: likely (no correction for confounders)
Zhou (2020)	Unlikely	Unlikely (all included patients have been discharged)	Mortality: unlikely Length of stay: unclear (discharge criteria not described, may depend on capacity)	Mortality: likely (no correction for confounders) Length of stay: likely (no correction for confounders)

Failure to develop and apply appropriate eligibility criteria: a) case-control study: under- or over-matching in case-control studies; b) cohort study: selection of exposed and unexposed from different populations.
2 Bias is likely if: the percentage of patients lost to follow-up is large; or differs between treatment groups; or the reasons for loss to follow-up differ between treatment groups; or length of follow-up differs between treatment groups or is too short. The risk of bias is unclear if: the number of patients lost to follow-up; or the reasons why, are not reported.
Flawed measurement, or differences in measurement of outcome in treatment and control group; bias may also result from a lack of blinding of those assessing outcomes (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
Failure to adequately measure all known prognostic factors and/or failure to adequately adjust for these factors in multivariate statistical analysis.

Table of excluded studies

Author and year	Reason for exclusion
de Abajo (2020)	Wrong C: C are not COVID-19 patients
Grover (2020)	Search strategy unclear. The authors state a quality assessment was performed but the results are not available
Guo (2020)	This is a research letter not a research paper, does not describe methods or results very well. Info regarding the characteristics of included studies is missing
Iaccarino (2020)	The authors analyse in a multilevel model the associatoin with mortality, number of patients on ACE inhibitors not available.
Bean (2020)	Included in review Mackey
Cannata (2020)	Wrong comparison (continuation vs discontinuation), correspondence making it hard to assess methodology
Emilsson (2020)	Wrong O: outcome is serum level ace2
Guo (2020)	Wrong I: use of medication was not a factor, not described in paper. Wel opgenomen in een van de reviews
Huang (2020)	Wrong outcome
Khera (2020)	Wrong C: comparison of ACEi and ARBs users
Mancia (2020)	Included in review Mackay
Mehra (2020)	Included in review Zhang
Peng (2020)	Paper is in Chinese
Pirola (2020)	Wrong outcome: composite outcome (in-hospital death and/or severe illness)
Reynolds (2020)	Included in review Mackay
Tadic (2020)	Wrong study design: prevalence of hypertension and CVD. 2 studies included that match our PICO, but both these studies are already in the literature set.
Yang (2020)	Included in review Mackay
Zhang (2020)	Included in review Zhang
Johnson (2020)	Used publicly available country level data
Morales (2020)	Wrong comparison (no control group)
Spaak (2020)	Paper in Swedish
Zhang (2020)	Wrong intervention: statin with ACEI/ARB
Calò (2020)/Journal of hypertension	Is a correspondence, not a research paper including a method and result section.
Calò (2020)/Journal of medical virology	It is a letter to the editor not a research paper including a method and result section
Rauch (2020)	Wrong outcome and not a research paper including a method and result section, merely a discussion based on other (not necisarily covid) literature
Saber-Ayad (2020)	Description of literature on the topic but not systematic (no search strategy, no outcomes defined etc)
Sunden-Cullberg (2020)	This is a research letter not a research paper, does not describe methods or results very well
Tan (2020)	Wrong outcome (effects on the digestive system)
Bravi (2020)	Wrong outcome (severe COVID-19 and death is combined)
Timerbulatov (2020)	Paper not in English (Russian)
Li (2020)	Included in review Mackay
Talreja (2020)	This is a viewpoint that describes literature on the topic but is not a systematic literature overview (does not describe search strategy or or a systematic description of outcomes)
Amat-Santos (2020)	Wrong study design: non-pre-specified interim analysis, only 11 COVID19 patients included
Autor Anonymous (2020); Title EMA advice on renin-angiotensin system medicines during covid-19 pandemic	Wrong study design: no original study: summary of EMA advice
Chen (2020)	Wrong population: patients with diabetes and covid-19: focus on insulin, subgroup using ACE inhibitor (n=32)
Chodick (2020)	Wrong outcome: risk of COVID infection
de Abajo (2020)	same as rayyan-79961775
Feng (2020)	Wrong study design: description of characteristics
Feng (2020)	same as rayyan-79961796
Fosbol (2020)	Wrong outcome: risk of COVID infection
Gianfrancesco (2020)	Specifically focused on patients with reumatic disease
Kolin (2020)	Wrong outcome
Mehta (2020)	Wrong outcome: risk of Covid infection
Rico-Mesa (2020)	Not a systematic evaluation of literature. Outcomes not defined
Singh (2020)	Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in the included studiees yet. So intervention not present
Sriram (2020)	Wrong outcome: outcome in this study is ACE2 expression
Vaduganathan (2020)	No original data, no systematic review
Yang (2020)	Same as rayan 79962048
Yousefifard (2020)	Wrong P, not COVID-19 patients
Zhang (2020)	Same as Rayan 79962053
Zhou (2020)	Same as rayyan-79962061
Kim (2020)	wrong outcome and analysis based on big data
Arjomandi Rad (2020)	Wrong outcome: outcome is tromboembolic events
Bidulka (2020)	Wrong P: no patients with COVID, wrong O: staf. Aureus
Russo (2020)	Aim of this study is to describe the prevalence of pre-admission antithrombotic therapies
Stafford (2020)	Wrong P (not covid patients), wrong outcome (pulmonary adverse drug events)

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