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Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis.
Ren, L, Yu, S, Xu, W, Overton, JL, Chiamvimonvat, N, Thai, PN
Journal of cardiology. 2021;(5):482-491
Abstract
BACKGROUND The association of antihypertensive drugs with the risk and severity of COVID-19 remains unknown. METHODS AND RESULTS We systematically searched PubMed, MEDLINE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and medRxiv for publications before July 13, 2020. Cohort studies and case-control studies that contain information on the association of antihypertensive agents including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium-channel blockers (CCBs), β-blockers, and diuretics with the risk and severity of COVID-19 were selected. The random or fixed-effects models were used to pool the odds ratio (OR) with 95% confidence interval (CI) for the outcomes. The literature search yielded 53 studies that satisfied our inclusion criteria, which comprised 39 cohort studies and 14 case-control studies. These studies included a total of 2,100,587 participants. We observed no association between prior usage of antihypertensive medications including ACEIs/ARBs, CCBs, β-blockers, or diuretics and the risk and severity of COVID-19. Additionally, when only hypertensive patients were included, the severity and mortality were lower with prior usage of ACEIs/ARBs (overall OR of 0.81, 95% CI 0.66-0.99, p < 0.05 and overall OR of 0.77, 95% CI 0.66-0.91, p < 0.01). CONCLUSIONS Taken together, usage of antihypertensive drugs is not associated with the risk and severity of COVID-19. Based on the current available literature, it is not recommended to abstain from the usage of these drugs in COVID-19 patients. REGISTRATION The meta-analysis was registered on OSF (https://osf.io/ynd5g).
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Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.
Chung, EY, Ruospo, M, Natale, P, Bolignano, D, Navaneethan, SD, Palmer, SC, Strippoli, GF
The Cochrane database of systematic reviews. 2020;(10):CD007004
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Abstract
BACKGROUND Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.
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Meta-Analysis Evaluating the Effects of Renin-Angiotensin-Aldosterone System Blockade on Outcomes of Heart Failure With Preserved Ejection Fraction.
Kuno, T, Ueyama, H, Fujisaki, T, Briasouli, A, Takagi, H, Briasoulis, A
The American journal of cardiology. 2020;(8):1187-1193
Abstract
Clinical trials of renin-angiotensin-aldosterone system (RAAS) antagonists in heart failure with preserved ejection fraction (HFpEF) have suggested neutral results and treatment is focused on associated symptoms and comorbidities. MEDLINE and EMBASE were searched through October 2019 for randomized controlled studies investigating the effects of different RAAS antagonists in patients with HFpEF. The main outcomes were all-cause mortality, trial defined cardiovascular mortality, and heart failure (HF) hospitalizations. To compare different RAAS antagonists, a random-effects restricted-maximum-likelihood network meta-analysis based on a frequentist framework for indirect and mixed comparisons was used. We used p scores to rank best treatments per outcome. Our search identified 5 eligible clinical trials (PEP-CHF, perindopril; CHARM-preserved, candesartan; I-PRESERVE, irbesartan; TOPCAT, spironolactone; PARAGON-HF, sacubitril-valsartan and valsartan) enrolling a total 10,523 on RAAS antagonists and 6,259 controls. We did not identify any statistical difference in all-cause and cardiovascular mortality among RAAS antagonists and placebo. The combination of sacubitril-valsartan was associated with significantly decreased HF hospitalization risk compared with controls (odds ratio 0.73, 95% confidence interval 0.61 to 0.87) and angiotensin II receptor blockers (odds ratio 0.80, 95% confidence interval 0.71 to 0.91), without heterogeneity among studies (I2 = 0). Angiotensin receptor neprilysin inhibitor (ARNI) ranked better than other RAAS antagonists for HF hospitalizations (p value 0.9). In conclusion, RAAS antagonists do not affect mortality but the combination of sacubitril-valsartan is associated with lower HF hospitalizations in HFpEF patients.
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Clinical Efficacy and Safety of Jinshuibao Combined With ACEI/ARB in the Treatment of Diabetic Kidney Disease: A Meta-Analysis of Randomized Controlled Trials.
Li, Y, Xu, G
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2020;(2):92-100
Abstract
OBJECTIVE The present study aims to compare the relative efficacy and safety of jinshuibao (JSB) combined with angiotensinconverting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) in the treatment of diabetic kidney disease. METHODS We searched EMBASE, MEDLINE, PubMed, China National Knowledge Internet, the Chinese Biomedical Database, and Wanfang database for articles from the building of the database to September 2018. RESULTS Fifty-one randomized controlled trials with 3,955 participants were included. The meta-analysis indicated that compared with the controls, JSB combined with ACEI/ARB group could remarkably improve the overall response rate (odds ratio 4.91; 95% confidence interval [CI] 3.32-7.25) and reduce 24 h proteinuria (mean difference [MD] -0.16; 95% CI -0.19 to -0.13), urine albumin excretion ratio (MD -28.20; 95% CI -36.30 to -20.11), serum creatinine (MD -13.84; 95% CI -18.01 to -9.68), blood urea nitrogen (MD -1.00; 95% CI -1.36 to -0.63), systolic blood pressure (MD -4.57; 95% CI -6.78 to -2.37), diastolic blood pressure (MD -3.96; 95% CI -5.73 to -2.19), fasting blood glucose (MD -0.85; 95% CI -1.45 to -0.24), hemoglobin A1c (MD -0.52; 95% CI -0.83 to -0.21), serum total cholesterol (MD -0.53; 95% CI -0.86 to -0.20), and triglyceride (MD -0.53; 95% CI -0.55 to -0.51). CONCLUSIONS JSB combined with ACEI/ARB in the treatment of diabetic kidney disease is superior to the single application of ACEI/ARB.
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Comparisons of Three Main Treatments on Renoprotective Effects in Diabetes Mellitus.
Huang, Q, Li, K, Li, M, Xu, G
Iranian journal of kidney diseases. 2019;(1):36-47
Abstract
INTRODUCTION Antihypertension, intensive glucose control (IGC), and lipid lowering were the main therapeutic strategies in diabetes mellitus. However, the comparative effects of them on renoprotection remain unclear. MATERIALS AND METHODS We searched the PubMed, EMBase, and Cochrane Library up to May 18, 2017, for studies with comparative interventions on regression, end-stage renal disease and all-cause death in diabetes mellitus. Statistical analysis was done using the Bayesian network meta-analysis (NMA). The surface under the cumulative ranking area and median rank were calculated to rank the interventions. RESULTS A total of 73 randomized controlled trials with 13 3703 participants were included for the comparisons of 14 interventions. Angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker (ACEI-ARB) ranked first in regression (odds ratio, 62; 95% confidence interval, 5.2 to > 999); ACEI-ARB also ranked first in end-stage renal disease decline (odds ratio, 0.58, 95% confidence interval, 0.39 - 0.85), followed by IGC hemoglobin A1c less than 6.5% (odds ratio, 0.58, 95% confidence interval, 0.36 - 0.90). The ACEI plus calcium channel blocker reduced all-cause death leaving other interventions insignificant (odds ratio, < 0.001; 95% confidence interval, < 0.001 to 0.30). ). The surface under the cumulative ranking area analyses also matched the result ranks. CONCLUSIONS Compared with antihypertension interventions, IGC including IGC hemoglobin A1c less than 6.5% and lipid lowering, ACEI-ARB showed the best renoprotective effects.
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The benefits of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers combined with calcium channel blockers on metabolic, renal, and cardiovascular outcomes in hypertensive patients: a meta-analysis.
Pongpanich, P, Pitakpaiboonkul, P, Takkavatakarn, K, Praditpornsilpa, K, Eiam-Ong, S, Susantitaphong, P
International urology and nephrology. 2018;(12):2261-2278
Abstract
BACKGROUND The prevalence of hypertension and its associated complications are markedly growing. Most patients need more than one drug to achieve blood pressure (BP) target. However, most guidelines only focus on the first-line treatment. We conducted a meta-analysis to explore the benefits of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) combined with calcium channel blockers (CCBs) on metabolic, renal, and cardiovascular outcomes in hypertensive patients. METHODS A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov (until April 7, 2016) to identify randomized controlled trials (RCTs) comparing the benefits of ACEIs/ARBs combined with CCBs versus other dual or triple combinations on clinical outcomes in hypertensive patients. Random effects models were used to compute the weighted mean difference (WMD) for continuous variables. RESULTS Sixty RCTs (48,913 patients) were identified. When compared with other combinations, the combination of ACEIs/ARBs and CCBs had comparable WMD of systolic as well as diastolic BP (73 study arms) but provided better benefits on metabolic parameters, such as HDL, FBS, HbA1C, and serum uric acid; renal functions, including serum creatinine and estimated glomerular filtration rate; and cardiovascular diseases, including reduction of all cardiovascular events, myocardial infarction, and syncope/hypotension. A significant increase of serum potassium was observed. CONCLUSION The combination of ACEIs/ARBs with CCBs has superior benefits on metabolic, renal, and cardiovascular outcomes in hypertensive patients. Therefore, this combination should be considered whenever monotherapy does not achieve the guideline target.
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Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials.
Brownstein, DJ, Salagre, E, Köhler, C, Stubbs, B, Vian, J, Pereira, C, Chavarria, V, Karmakar, C, Turner, A, Quevedo, J, et al
The Australian and New Zealand journal of psychiatry. 2018;(1):24-38
Abstract
OBJECTIVE It is unclear whether blockade of the angiotensin system has effects on mental health. Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life. STUDY DESIGN Meta-analysis of published literature. DATA SOURCES PubMed and clinicaltrials.gov databases. The last search was conducted in January 2017. STUDY SELECTION Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected. Study participants were adults without any major physical symptoms. We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration. DATA SYNTHESIS Eleven studies were included in the analysis. When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15). CONCLUSIONS Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life. Mental health quality of life was a secondary outcome in the included studies. Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target.
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First-line renin-angiotensin system inhibitors vs. other first-line antihypertensive drug classes in hypertensive patients with type 2 diabetes mellitus.
Wang, G, Chen, Y, Li, L, Tang, W, Wright, JM
Journal of human hypertension. 2018;(7):494-506
Abstract
First-line renin-angiotensin system (RAS) inhibitors are recommended for diabetic patients because of their potential nephron-protective properties. For hypertensive patients with type 2 diabetes mellitus, little is known about first-line RAS inhibitors vs. other first-line antihypertensive agents in terms of cardiovascular outcomes. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the comparative efficacy of first-line RAS inhibitors vs. other first-line antihypertensive drug classes in hypertensive patients with type 2 diabetes mellitus. We identified RCTs by searching the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to December 15, 2015. Eighteen RCTs involving 18,862 participants were included. First-line RAS inhibitors were not different from first-line diuretics for all the primary outcomes. First-line RAS inhibitors reduced major cardiovascular events (2 RCTs, relative risk [RR] 0.78, 95% confidence interval [CI] 0.66, 0.91) and heart failure (4 RCTs, RR 0.72, 95% CI 0.61, 0.83) compared to first-line calcium channel blockers. Compared to β-blockers, RAS inhibitors reduced the risk of all-cause mortality (1 RCT, RR 0.63, 95% CI 0.47, 0.84), major cardiovascular events (1 RCT, RR 0.76, 95% CI 0.62, 0.93) and heart failure (1 RCT, RR 0.60, 95% CI 0.40, 0.92). Our meta-analysis indicates that, in patients with type 2 diabetes mellitus and hypertension, first-line RAS inhibitors reduced adverse cardiovascular events to the same degree as first-line diuretics but to a greater degree than first-line calcium channel blockers and first-line beta blockers.
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Pooled Analysis of Multiple Crossover Trials To Optimize Individual Therapy Response to Renin-Angiotensin-Aldosterone System Intervention.
Petrykiv, SI, Laverman, GD, Persson, F, Vogt, L, Rossing, P, de Borst, MH, Gansevoort, RT, de Zeeuw, D, Heerspink, HJL
Clinical journal of the American Society of Nephrology : CJASN. 2017;(11):1804-1813
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Abstract
BACKGROUND AND OBJECTIVES In the treatment of CKD, individual patients show a wide variation in their response to many drugs, including renin-angiotensin-aldosterone system inhibitors (RAASi). To investigate whether therapy resistance to RAASi can be overcome by uptitrating the dose of drug, changing the mode of intervention (with drugs from similar or different classes), or lowering dietary sodium intake, we meta-analyzed individual responses to different modes of interventions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Randomized crossover trials were analyzed to assess correlation of individual responses to RAASi and nonsteroidal anti-inflammatory drugs (NSAIDs; n=395 patients). Included studies compared the antialbuminuric effect of uptitrating the dose of RAASi (n=10 studies) and NSAIDs (n=1), changing within the same class of RAASi (e.g., angiotensin-converting enzyme inhibition to angiotensin receptor blockers; n=5) or NSAIDs (n=1), changing from RAASi to NSAIDs (n=2), and changing from high to low sodium intake (n=5). A two-stage meta-analysis was conducted: Deming regression was conducted in each study to assess correlations in response, and individual study results were then meta-analyzed. RESULTS The albuminuria response to one dose of RAASi or NSAIDs positively correlated with the response to a higher dose of the same drug (r=0.72; 95% confidence interval [95% CI], 0.66 to 0.78), changes within the same class of RAASi or NSAIDs (r=0.54; 95% CI, 0.35 to 0.68), changes between RAASi and NSAIDs (r=0.44; 95% CI, 0.16 to 0.66), and changes from high to moderately low salt intake (r=0.36; 95% CI, 0.22 to 0.48). Results were similar when the individual systolic BP and potassium responses were analyzed, and were consistent in patients with and without diabetes. CONCLUSIONS Individuals who show a poor response to one dose or type of RAASi also show a poor response to higher doses, other types of RAASi or NSAIDs, or a reduction in dietary salt intake. Whether other drugs or drug combinations targeting pathways beyond the renin-angiotensin-aldosterone system and prostaglandins would improve the individual poor response requires further study.
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Short- and long-term outcomes with renin-angiotensin-aldosterone inhibitors in renal transplant recipients: A meta-analysis of randomized controlled trials.
Liao, RX, Lyu, XF, Tang, WJ, Gao, K
Clinical transplantation. 2017;(4)
Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor type 1 blockers (ARBs) are often prescribed for renal transplant recipients (RTRs), but the outcomes of these medications in RTRs remain controversial. METHODS The PubMed, Embase, and Cochrane Library databases were systematically searched. Randomized controlled trials investigating the outcomes of ACEI/ARBs in RTRs were included for meta-analysis. RESULTS Twenty-two trials with 2242 patients were identified. After treatment for at least 12 months, ACEI/ARBs were associated with a decline in glomerular filtration rate (GFR) (weighed mean differences [WMD] -5.76 mL/min; 95% confidence intervals [CI]: -9.31 to -2.20) and a decrease in hemoglobin (WMD -9.81 g/L; 95% CI: -14.98 to -4.64). There were no significant differences in mortality between ACEI/ARB and non-ACEI/ARB groups (risk ratio [RR] 0.98, 95% CI: 0.58 to 1.76), nor in graft failure (RR 0.68, 95% CI: 0.38 to 1.32). After short-term treatment (less than 1 year), significant differences were found in changes of 24-hour proteinuria (WMD-0.57 g/d; 95% CI: -0.72 to -0.42) and serum potassium (WMD 0.25 mEq/L; 95% CI: 0.14 to 0.37) in ACEI/ARB groups compared to control arm, while these differences were not confirmed in the long run. CONCLUSION This meta-analysis indicates ACEI/ARBs may be prescribed to RTRs with GFR and hemoglobin being carefully monitored.