Al‐Mallah, Mouaz H.

Background: Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are known to increase the expression of angiotensin converting enzyme 2 receptor, which has been shown to be the receptor for the acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Areas of Uncertainty: Based on these observations, speculations raised the concerns that ACEIs/ARBs users would be more susceptible to SARS-CoV-2 infection and would be at higher risk for severe COVID-19 disease and death. Therefore, we systematically reviewed the literature and performed a meta-analysis of the association between prior use of ACEIs and ARBs and mortality due to COVID-19 disease. Data Sources: A comprehensive search of several databases from November 2019 to June 18, 2020 was conducted. The databases included Ovid MEDLINE(R) and Epub Ahead of Print, In-Process and Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Medrxiv.org was also searched for unpublished data. Therapeutic Advances: Nine studies with a total of 18,833 patients infected with SARS-CoV-2 met our eligibility criteria. Prior use of ACEIs and/or ARBs was associated with reduced mortality among SARS-CoV-2-infected patients, with a pooled adjusted relative risk (aRR) from 6 studies of 0.63, 95% confidence interval (CI) (0.42–0.94) (I 2 = 65%). Three studies reported separately on ACEIs or ARBs and their association with survival among SARS-CoV-2-infected patients, with a pooled adjusted relative risk of 0.78, 95% CI (0.58–1.04) (I 2 = 0%) and 0.97, 95% CI (0.73–1.30) (I 2 = 0%) respectively. The results of sensitivity analyses were consistent with the main analysis. Conclusion: Our meta-analysis suggests that use of ACEIs/ARBs is associated with a decreased risk of death among SARS-CoV-2-infected patients. This finding provides a reassurance to the public not to stop prescribed ACEIs/ARBs because of fear of severe COVID-19.

Abstract Importance:SARS-CoV-2 virus gains access and infects target cells via angiotensin converting enzyme 2 (ACE2) receptor. Because angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) could increase the expression of ACE2, there are growing concerns that their use could increase the risk of SARS-CoV-2 infection. Cardiac societies have called for epidemiological research about this emerging controversy. Objective:We sought to systematically review the literature and perform a meta-analysis about prior use of ACEI/ARBs and risk of SARS-CoV-2 infection.Data source:We searched multiple data sources including PubMed , ClinicalTrial.org , and medrxiv.org from November 2019 through May 16, 2020. Study selection:Any study that reported on the adjusted association of prior use of ACEIs / ARBs and risk of acquiring SARS-CoV-2 infection was eligible. Two authors independently reviewed eligible studies and extracted data into a prespecified data collection form. Data synthesis:An inverse variance meta-analytic approach was used to pool adjusted odds ratios using a random effect model meta-analysis. I2 test was used to assess in-between studies heterogeneity. The Newcastle–Ottawa quality assessment scale (NOS) was used to assess the quality of included studies. Main outcome and Measures:The association between the prior use of ACEIs or ARBs and risk of SARS-CoV-2 infection was assessed using pooled OR and 95% confidence interval. Results:Six case control studies that enrolled a total of 5657 patients (2536 patients in ACEIs arm and 3121 patients in ARBs arm ) and 721,859 controls were included in our meta-analysis. Two of the included studies were from the USA, one from Italy, one from China, one from Spain, and one from South Korea. All included studies scored high based on NOS scale. Prior use of ACEIs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.93, CI (0.85,1.02), I2=20%. Similarly, prior use of ARBs was not significantly associated with an increased risk of SARS-CoV-2 infection, OR 0.86, CI (0.67,1.10), I2=93%. Sensitivity analysis was performed by removing a study that could have been affected by residual confounding; OR for ARB 1.04, CI (0.96,1.12), I2=32%.Conclusion:Findings from this systematic review and meta-analysis suggest that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19. Our results are in support of the recent recommendations of cardiac societies and provide a reassurance to the public not to discontinue prescribed ACEIs/ARBs due to fear of COVID-19.

AbstractAimsPioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta‐analysis to evaluate the magnitude of this association and the quality of the supporting evidence.MethodsElectronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer.ResultsSix studies involving 215 142 patients using pioglitazone were included, with a median period of follow‐up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09–1.39; I2 = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years.ConclusionsPatients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti‐hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer.