The Impact of Cardiac Injury on COVID-19 Patients Mortality: A Systematic Review and Meta-Analysis

Background: Cardiovascular system was the second most common organ system affected by COVID-19. Cardiac injury has been reported in many COVID-19 cases. The purpose of this study was to investigate the correlation between cardiac injury with mortality in COVID-19 patients. Methods: We performed a systematic review and meta-analysis study. The relevant studies were identified through scientific electronic databases such as PubMed, Cochrane, and ScienceDirect up to August 2020. The study quality assessment was conducted using the GRADE approach. The pooled odds ratio (OR) and 95% confidence interval (CI) were estimated using the random-effects model. Results: A total of 10 studies involving 2619 patients were included in the meta-analysis. The incidence of cardiac injury in COVID-19 patients was 28.5%. The all-cause mortality was significantly higher in patients with cardiac injury (52.8% vs. 13.1%; OR = 13.78; 95% CI = 7.22-26.32; I 2 = 88%; Z= 7.95; P < 0.00001). Conclusion: Cardiac injury is associated with higher mortality in COVID-19 patients. The cardiac injury should be considered as an important variable in the risk stratification for mortality in COVID-19.

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Impact of cardiovascular disease and cardiac injury on in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis

Heart ◽

10.1136/heartjnl-2020-317062 ◽

2020 ◽

Vol 106 (15) ◽

pp. 1142-1147 ◽

Cited By ~ 25

Author(s):

Xintao Li ◽

Bo Guan ◽

Tong Su ◽

Wei Liu ◽

Mengyao Chen ◽

...

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

Hospital Mortality ◽

Mortality Risk ◽

Meta Analysis ◽

Cardiac Injury ◽

Sensitivity Analyses ◽

Future Research ◽

Cardiovascular Comorbidities ◽

The Impact

BackgroundCoronavirus disease 2019 (COVID-19) has produced a significant health burden worldwide, especially in patients with cardiovascular comorbidities. The aim of this systematic review and meta-analysis was to assess the impact of underlying cardiovascular comorbidities and acute cardiac injury on in-hospital mortality risk.MethodsPubMed, Embase and Web of Science were searched for publications that reported the relationship of underlying cardiovascular disease (CVD), hypertension and myocardial injury with in-hospital fatal outcomes in patients with COVID-19. The ORs were extracted and pooled. Subgroup and sensitivity analyses were performed to explore the potential sources of heterogeneity.ResultsA total of 10 studies were enrolled in this meta-analysis, including eight studies for CVD, seven for hypertension and eight for acute cardiac injury. The presence of CVD and hypertension was associated with higher odds of in-hospital mortality (unadjusted OR 4.85, 95% CI 3.07 to 7.70; I2=29%; unadjusted OR 3.67, 95% CI 2.31 to 5.83; I2=57%, respectively). Acute cardiac injury was also associated with a higher unadjusted odds of 21.15 (95% CI 10.19 to 43.94; I2=71%).ConclusionCOVID-19 patients with underlying cardiovascular comorbidities, including CVD and hypertension, may face a greater risk of fatal outcomes. Acute cardiac injury may act as a marker of mortality risk. Given the unadjusted results of our meta-analysis, future research are warranted.

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Statins and Major Adverse Limb Events in Patients with Peripheral Artery Disease: A Systematic Review and Meta-Analysis

Thrombosis and Haemostasis ◽

10.1055/s-0040-1709711 ◽

2020 ◽

Vol 120 (05) ◽

pp. 866-875 ◽

Cited By ~ 5

Author(s):

Daniele Pastori ◽

Alessio Farcomeni ◽

Alberto Milanese ◽

Francesco Del Sole ◽

Danilo Menichelli ◽

...

Keyword(s):

Systematic Review ◽

Peripheral Artery Disease ◽

Meta Analysis ◽

Graft Occlusion ◽

Peripheral Artery ◽

All Cause Mortality ◽

Statin Prescription ◽

Secondary Endpoints ◽

Artery Disease ◽

The Impact

Abstract Background Statins are guidelines recommended in patients with peripheral artery disease (PAD) for the prevention of cardiovascular (CV) events. Comprehensive meta-data on the impact of statins on major adverse limb events (MALE) in PAD patients are lacking. We examined the association of statin use with MALE in patients with PAD. Methods We performed a systematic review (registered at PROSPERO: number CRD42019137111) and metanalysis of studies retrieved from PubMed (via MEDLINE) and Cochrane (CENTRAL) databases addressing the impact of statin on MALE including amputation and graft occlusion/revascularization. Secondary endpoints were all-cause death, composite CV endpoints, CV death, and stroke. Results We included 51 studies with 138,060 PAD patients, of whom 48,459 (35.1%) were treated with statins. The analysis included 2 randomized controlled trials, 20 prospective, and 29 retrospective studies. Overall, 11,396 MALE events, 21,624 deaths, 4,852 composite CV endpoints, 4,609 CV deaths, and 860 strokes were used for the analysis. Statins reduced MALE incidence by 30% (pooled hazard ratio [HR]: 0.702; 95% confidence interval [CI]: 0.605–0.815) and amputations by 35% (HR: 0.654; 95% CI: 0.522–0.819), all-cause mortality by 39% (pooled HR: 0.608, 95% CI: 0.543–0.680), CV death by 41% (HR: 0.594; 95% CI: 0.455–0.777), composite CV endpoints by 34% (pooled HR: 0.662; 95% CI: 0.591–0.741) and ischemic stroke by 28% (pooled HR: 0.718; 95% CI: 0.620–0.831). Conclusion Statins reduce the incidence of MALE, all-cause, and CV mortality in patients with PAD. In PAD, a high proportion of MALE events and deaths could be prevented by implementing a statin prescription in this patient population.

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Gender-Related Differences in Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis

Pulse ◽

10.1159/000517618 ◽

2021 ◽

Vol 9 (1-2) ◽

pp. 38-46

Author(s):

Angkawipa Trongtorsak ◽

Natchaya Polpichai ◽

Sittinun Thangjui ◽

Jakrin Kewcharoen ◽

Ratdanai Yodsuwan ◽

...

Keyword(s):

Systematic Review ◽

Hypertrophic Cardiomyopathy ◽

Cohort Studies ◽

Meta Analysis ◽

Phenotypic Expression ◽

Female Gender ◽

Increased Risk ◽

All Cause Mortality ◽

The Impact ◽

Related Mortality

Background: Gender-related differences in phenotypic expression and outcomes have been established in many cardiac conditions; however, the impact of gender in hypertrophic cardiomyopathy (HCM) remains unclear. We conducted a systematic review and meta-analysis to assess the differences in clinical outcomes between female and male HCM patients. Methods: We searched MEDLINE and EMBASE from inception to October 2020. Included were cohort studies that compared outcomes of interest including all-cause mortality, HCM-related mortality, and worsening heart failure (HF) or HF hospitalization between male and female. Data from each study were combined using the random effects model to calculate pooled odds ratio (OR) with 95% confidence interval (CI). Results: Eleven retrospective cohort studies with a total of 9,427 patients (3,719 females) were included. Female gender was significantly associated with an increased risk of all-cause mortality (pooled OR = 1.63, 95% CI: 1.26–2.10, p ≤ 0.001), HCM-related mortality (pooled OR = 1.47, 95% CI: 1.08–2.01, p = 0.015), and worsening HF or HF hospitalization (pooled OR = 2.05, 95% CI: 1.76–2.39, p ≤ 0.001). Conclusions: Female gender was associated with a worse prognosis in HCM. These findings suggest the need for improved care in women including early identification of disease and more possible aggressive management. Moreover, gender-based strategy may benefit in HCM patients.

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High burden of acute kidney injury in COVID-19 pandemic: systematic review and meta-analysis

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-207023 ◽

2020 ◽

pp. jclinpath-2020-207023

Author(s):

Camila Barbosa Oliveira ◽

Camilla Albertina Dantas Lima ◽

Gisele Vajgel ◽

Antonio Victor Campos Coelho ◽

Paula Sandrin-Garcia

Keyword(s):

Systematic Review ◽

Acute Kidney Injury ◽

Critically Ill ◽

Random Effects ◽

Meta Analysis ◽

Kidney Injury ◽

Random Effects Model ◽

Risk Of Death ◽

Meta Analyses ◽

The Impact

AimsHospitalised patients with COVID-19 have a variable incidence of acute kidney injury (AKI) according to studies from different nationalities. The present systematic review and meta-analysis describes the incidence of AKI, need for renal replacement therapy (RRT) and mortality among patients with COVID-19-associated AKI.MethodsWe systematically searched electronic database PubMed, SCOPUS and Web of Science to identify English articles published until 25 May 2020. In case of significant heterogeneity, the meta-analyses were conducted assuming a random-effects model.ResultsFrom 746 screened publications, we selected 21 observational studies with 15 536 patients with COVID-19 for random-effects model meta-analyses. The overall incidence of AKI was 12.3% (95% CI 7.3% to 20.0%) and 77% of patients with AKI were critically ill (95% CI 58.9% to 89.0%). The mortality among patients with AKI was 67% (95% CI 39.8% to 86.2%) and the risk of death was 13 times higher compared with patients without AKI (OR=13.3; 95% CI 6.1 to 29.2). Patients with COVID-19-associated AKI needed for RRT in 23.4% of cases (95% CI 12.6% to 39.4%) and those cases had high mortality (89%–100%).ConclusionThe present study evidenced an incidence of COVID-19-associated AKI higher than previous meta-analysis. The majority of patients affected by AKI were critically ill and mortality rate among AKI cases was high. Thus, it is extremely important for health systems to be aware about the impact of AKI on patients’ outcomes in order to establish proper screening, prevention of additional damage to the kidneys and adequate renal support when needed.

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Abstract 20116: The Impact of Atrial Fibrillation Type on the Risk of Thromboembolism, Mortality and Bleeding: A Systematic Review and Meta-analysis

Circulation ◽

10.1161/circ.132.suppl_3.20116 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Anand Ganesan ◽

Derek Chew ◽

Trent Hartshorne ◽

Joseph B Selvanayagam ◽

Philip Aylward ◽

...

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Risk Ratio ◽

Meta Analysis ◽

Case Series ◽

Outcome Data ◽

Risk Models ◽

Thromboembolic Risk ◽

All Cause Mortality ◽

The Impact

Introduction: Thromboembolic risk stratification schemes and clinical guidelines for atrial fibrillation regard risk as independent of classification into paroxysmal (PAF) and nonparoxysmal atrial fibrillation (NPAF). The aim of the current study was to conduct a systematic review and meta-analysis evaluating the impact of AF type on thromboembolism, bleeding and mortality. Hypothesis: AF type would predict rates of thromebolism, mortality and bleeding. Methods: Pubmed was searched for randomized controlled trials, cohort studies, and case series reporting prospectively collected clinical outcomes stratified by AF type. The incidence of thromboembolism, mortality and bleeding was extracted. Results: AF clinical outcome data was extracted from 12 studies containing 99,996 patients. The pooled unadjusted risk ratio (RR) for thromboembolism in NPAF vs. PAF was RR 1.339 (95% CI: 1.140-1.644, P<0.001). In studies providing estimates of thromboembolism risk adjusted for baseline clinical risk factors, the pooled adjusted hazard ratio (HR) in NPAF vs. PAF was HR 1.384 (95% CI, 1.191-1.608, P<0.001). The pooled unadjusted risk ratio for all-cause mortality in NPAF vs. PAF was RR 1.462 (95% CI: 1.255-1.703 P<0.001). The pooled adjusted HR for all-cause mortality in NPAF vs. PAF was HR 1.217 (95% CI: 1.085-1.365, P<0.001. Rates of bleeding in NPAF and PAF were similar, unadjusted RR 1.00 (95% CI 0.919-1.087, P=0.994), pooled adjusted HR 1.025 (95% CI: 0.898-1.170, P=0.715). Conclusions: These data suggest a need for re-evaluation of the paradigm of thromboembolic risk equivalence between PAF and NPAF, and emphasize AF type as a powerful predictor of AF-related morbidity and mortality. Future studies exploring integration of AF type into thromboembolic risk models are needed.

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The Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers on Clinical Outcomes of Acute Kidney Disease Patients: A Systematic Review and Meta-Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.665250 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jui-Yi Chen ◽

I-Jung Tsai ◽

Heng-Chih Pan ◽

Hung-Wei Liao ◽

Javier A. Neyra ◽

...

Keyword(s):

Systematic Review ◽

Angiotensin Ii ◽

Kidney Disease ◽

Meta Analysis ◽

Converting Enzyme ◽

Angiotensin Ii Receptor ◽

Acute Kidney Disease ◽

All Cause Mortality ◽

Continued Use ◽

The Impact

Background: Acute kidney injury (AKI) may increase the risk of chronic kidney disease (CKD), development of end-stage renal disease (ESRD), and mortality. However, the impact of exposure to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (ACEi/ARB) in patients experiencing AKI/acute kidney disease (AKD) is still unclear.Methods: In this systematic review, we searched all relevant studies from PubMed, Embase, Cochrane, Medline, Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, and ClinicalTrials.gov until July 21, 2020. We evaluated whether the exposure to ACEi/ARB after AKI onset alters recovery paths of AKD and impacts risks of all-cause mortality, recurrent AKI, or incident CKD. We rated the certainty of evidence according to Cochrane methods and the GRADE approach.Results: A total of seven articles, involving 70,801 patients, were included in this meta-analysis. The overall patient mortality rate in this meta-analysis was 28.4%. Among AKI patients, all-cause mortality was lower in ACEi/ARB users than in ACEi/ARB nonusers (log odds ratio (OR) −0.37, 95% confidence interval (CI): −0.42–−0.32, p < 0.01). The risk of recurrent adverse kidney events after AKI was lower in ACEi/ARB users than in nonusers (logOR −0.25, 95% CI: −0.33–−0.18, p < 0.01). The risk of hyperkalemia was higher in ACEi/ARB users than in nonusers (logOR 0.43, 95% CI: 0.27–0.59, p < 0.01). Patients with continued use of ACEi/ARB after AKI also had lower mortality risk than those prior ACEi/ARB users but who did not resume ACEi/ARB during AKD (logOR −0.36, 95% CI: −0.4–−0.31, p < 0.01).Conclusions: Exposure to ACEi/ARB after AKI is associated with lower risks of all-cause mortality, recurrent AKI, and progression to incident CKD. Patients with AKI may have a survival benefit by continued use of ACEi/ARB; however, a higher incidence of hyperkalemia associated with ACEi/ARB usage among these patients deserves close clinical monitoring.

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Abstract P541: High Allostatic Load is Associated With Increased Risk of All-cause Mortality - A Systematic Review and Meta-analysis

Circulation ◽

10.1161/circ.141.suppl_1.p541 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Haley W Parker ◽

Alyssa M Abreu ◽

Mary Sullivan ◽

Maya K Vadiveloo

Keyword(s):

Systematic Review ◽

Allostatic Load ◽

Meta Analysis ◽

Study Quality ◽

Increased Risk ◽

All Cause Mortality ◽

Meta Analyses ◽

Sample Age ◽

The Relationship ◽

Cvd Mortality

Introduction: Allostatic load (AL) is a measure of physiological damage from chronic stress, quantified using a variety of neuroendocrine, metabolic, cardiovascular, and immune biomarkers. While AL has been associated with several mortality risk factors (e.g., metabolic disorders, inflammation, cardiovascular disease (CVD), frailty), to date, no meta-analyses have examined the relationship between AL and mortality. This systematic review and meta-analysis examines the relationship between AL and mortality (CVD and all-cause). Hypothesis: Higher AL (i.e., increased dysregulation) will be associated with an increased risk of all-cause and CVD mortality. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guided this review. Two databases (PubMed and EMBASE) were searched in Feb 2019 with the terms: ((mortality) OR survival) AND ((allostatic load) OR allostasis); references of included studies were also screened. Included studies met the a priori inclusion criteria (i.e. compared mortality (all-cause and/or CVD) in high vs. low AL (defined by study) in adults). Study quality was assessed with the Newcastle Ottawa Criteria. Findings were qualitatively synthesized then the meta-analysis was completed in Review Manager 5.3. Subgroups were examined by design and sample age. Results: Database searches and references identified 400 studies; after removing duplicates, 266 abstracts were screened and 32 full texts were reviewed. The systematic review included 12 observational studies (2001-18) examining all-cause mortality; half were also included in meta-analyses. Of the 12 included studies, most examined CVD mortality (n=7), were longitudinal (n=7), from the US (n=7), and had a balanced sex distribution. In the qualitative review, high AL was consistently associated with increased risk of all-cause mortality (n=11 of 12 studies, hazard ratio (HR) range=1.13-2.98), however, the association was less consistent for CVD mortality (n=4 of 7 studies, HR=1.12-3.06). In meta-analyses, high AL was associated with increased risk of all-cause (HR= 1.46 [1.24, 1.72], n=6) and CVD mortality (HR= 1.18 [1.02, 1.38], n=4). High AL was associated with all-cause mortality in subgroup analyses stratified by design (cross-sectional HR=1.44 [1.14, 1.81], n=3; longitudinal HR=1.61 [1.11, 2.33], n=3) and sample age (older adults HR=1.17 [1.10, 1.24], n=3; all adults HR=1.94 [1.45, 2.60], n=3). Heterogeneity was high (I 2 =85-96%) in analyses except for the older adults subgroup (I 2 =18%). Study quality was good in 7 studies (including all studies in the meta-analysis), fair in 3 studies, and poor in 2 studies. Conclusions: In this review of relatively high-quality studies, high AL was associated with a 46% increased risk of all-cause mortality and may also be associated with CVD mortality. Thus, AL shows promise as a prognostic indicator for mortality.

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Pneumococcal vaccination in adults at very high risk or with established cardiovascular disease: systematic review and meta-analysis

European Heart Journal - Quality of Care and Clinical Outcomes ◽

10.1093/ehjqcco/qcaa030 ◽

2020 ◽

Cited By ~ 2

Author(s):

Miguel Marques Antunes ◽

Gonçalo S Duarte ◽

Dulce Brito ◽

Margarida Borges ◽

João Costa ◽

...

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

High Risk ◽

Observational Studies ◽

Meta Analysis ◽

Pneumococcal Vaccination ◽

Significant Heterogeneity ◽

All Cause Mortality ◽

The Impact ◽

Very High

Abstract Aims There are several guidelines that recommend pneumococcal vaccination (PPSV23 and/or PCV13) in adults with a history of cardiovascular disease (established heart failure, coronary disease, and cerebrovascular disease) or at a very high risk of cardiovascular disease. However, there is no randomized controlled trial (RCT) systematic review that evaluates the impact of vaccination on all-cause mortality compared to no vaccination in this particular population. Our objective is to conduct a systematic review and meta-analysis of the impact of pneumococcal vaccination in the referred population. Methods and results We searched CENTRAL and MEDLINE for relevant RCTs and observational studies. Data were screened, extracted, and appraised by two independent reviewers. We pooled results using a random effects model, and used hazard ratios (HRs) with 95% confidence intervals (CIs) to assess measure of effect. The primary outcome was all-cause mortality and we assessed the confidence in the evidence using the GRADE framework. No RCTs were found. Seven observational studies were included for analyses. Pooled results from five studies enrolling a total of 163 756 participants showed a significant decrease in all-cause mortality (HR 0.78, 95% CI 0.73–0.83, very low confidence), without statistically significant heterogeneity (χ2 test P = 0.21; I2 = 32%). Conclusions Pneumococcal vaccination was associated with a 22% decrease of all-cause mortality in patients with cardiovascular disease or at a very high cardiovascular risk. However, limitations due to study design and the serious risk of bias in three of the included studies leads to a decreased level of result confidence.

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Efficacy of betablockers in patients with acute coronary syndrome: a systematic review and meta analysis of randomized trials

European Heart Journal ◽

10.1093/ehjci/ehaa946.1741 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Zamiri ◽

H Alradaddi ◽

T Adli ◽

S Jolly ◽

C Ainsworth ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Systematic Review ◽

Cardiogenic Shock ◽

Meta Analysis ◽

Nonfatal Myocardial Infarction ◽

Controlled Trials ◽

Coronary Syndrome ◽

All Cause Mortality ◽

The Impact

Abstract Background Since the inception of clinical guidelines on the management of patients with acute coronary syndrome (ACS), betablocker therapy has been included as a class I recommendation. However, most studies evaluating betablockers in ACS were conducted in the pre-reperfusion era. Currently, the great majority of patients undergo reperfusion and secondary prevention therapy has evolved; the impact of treatment with a betablocker in these patients may be different. Purpose We conducted a systematic review and meta-analysis to evaluate the impact of betablockers on mortality in patients after an ACS in the reperfusion era. Methods We searched MEDLINE, EMBASE, and Cochrane Central Registry of Controlled Trials for RCTs from inception to September 2019. We included randomized controlled trials comparing betablockers to no betablockers in adult patients presenting with an ACS. Independently and in duplicate, we screened titles and abstracts, reviewed the full-text report of potentially eligible studies and extracted data. Two reviewers also evaluated the risk of bias in duplicate. Disagreements were addressed by consensus. We considered trials to be conducted in the reperfusion era if reperfusion was attempted in more than 50% of patients, either with thrombolytics or primary angioplasty. Our primary outcome of interest was all-cause mortality. Secondary outcomes included hospitalization for heart failure, nonfatal myocardial infarction, stroke and cardiogenic shock. We pooled trial outcomes using a fixed effects model. The study protocol is registered with PROSPERO (CRD42019143158). Results After the initial screening of 10,969 references and full-text review of 176 articles, nine RCTs comprising a total of 49,639 patients with ACS were eligible for the final analysis. Predominantly, these patients presented with ST elevation myocardial infarction. Treatment with a betablocker did not improve all-cause mortality at 30 days (risk ratio (RR) 0.98 [95% CI 0.92–1.04], I2=44%), or at longest follow up (up to three years) with RR 0.97 ([95% CI 0.91–1.03], I2=0%). Betablocker therapy was associated with an increased risk of HF hospitalization (RR 1.10 [95% CI 1.05–1.15], I2=52%) and cardiogenic shock during index hospitalization (RR 1.29, [95% CI 1.18–1.40], I2=0%). However, betablocker therapy reduced the risk of nonfatal myocardial infarction (RR 0.72 [95% CI 0.63–0.83], I2=0%); it did not impact the risk of stroke (RR 1.13 [95% CI 0.95–1.35], I2=0%). Conclusion In the reperfusion era, betablocker therapy after an ACS does not appear to improve short or long-term survival. Although betablocker therapy was associated with a reduction in nonfatal myocardial infarction, it increased the risk of heart failure hospitalization and cardiogenic shock. In light of these findings, clinical guidelines should reconsider the strength of their recommendation for betablocker use in the ACS population until further contemporary evidence is available. Funding Acknowledgement Type of funding source: None

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Glucose-Lowering and the Risk of Cardiovascular Events with Novel Antidiabetic Therapies: A Systematic Review and Additive-effects Network Meta-Analysis

10.21203/rs.3.rs-983766/v1 ◽

2021 ◽

Author(s):

Luiz Sergio Fernandes de Carvalho ◽

Ana Claudia Cavalcante Nogueira ◽

Riobaldo Marcelo Ribeiro Cintra ◽

Isabella Bonilha ◽

Beatriz Luchiari ◽

...

Keyword(s):

Systematic Review ◽

Cardiovascular Events ◽

Meta Analysis ◽

Cardiovascular Effects ◽

Major Adverse Cardiovascular Events ◽

Control Group ◽

Additive Effects ◽

Glucose Lowering ◽

All Cause Mortality ◽

The Impact

Abstract Background: Among individuals with type 2 diabetes mellitus (T2DM), RCTs designed to investigate the cardiovascular effects of achieving HbA1c ≤7.0% by using insulin and sulfonylureas were unable to prevent the incidence of major adverse cardiovascular events (MACE) defined as CV death, non-fatal myocardial infarction, and non-fatal stroke. Intense glucose-lowering with newer antidiabetic therapies (ADTs) including SGLT2i, GLP1-RA, pioglitazone and DPP4i show lower risk of hypoglycemia and could lead to additive effect in preventing MACE. In this context, this study was designed to assess the impact of the HbA1c levels achieved with newer ADTs on the risk of MACE. Methods. We searched MEDLINE/PubMed, Cochrane and ClinicalTrials.gov. RCTs published up to January/2021 reporting the occurrence of MACE and all-cause mortality in individuals with T2DM, including a sample size ≥100 individuals in each study arm and follow-up ≥24 weeks, were selected. Data was extracted by four independent observers following PRISMA guidelines. We performed a systematic review and additive-effects network meta-analysis with random effects and a multivariate meta-regression to assess the impact of achieved HbA1c on incident MACE. Results. A total of 122 RCTs were included with 139 treatment arms, 256,990 individuals, and 689,346 individuals-years who were randomized to an active treatment vs. control group. Therapy with SGLT2i, GLP1-RA, or pioglitazone similarly reduced the risk of MACE compared to placebo (HR 0.88 [95%CI 0.83, 0.94, p<0.001], 0.89 [95% CI 0.85, 0.94, p<0.0001], and 0.86 [95% CI 0.76, 0.98, p=0.025], respectively). The achievement of HbA1c≤7.0% in RCTs with SGLT2i, DPP4i, TZD, or GLP1-RA in the active arm was associated with an adjusted HR of 0.91 (95% CI 0.80, 0.97; p=0.039) compared with HbA1c>7.0%. All-cause mortality was not influenced by HbA1c thresholds.Conclusions: Achieving lower glucose levels with newer ADTs is linearly associated with a reduced risk of MACEs, without affecting all-cause mortality. Targeting HbA1c between 6.5 and 7% with SGLT2i, GLP1A, pioglitazone or DPP4i brings cardiovascular benefits considering the available RCT evidence.Study registration: PROSPERO CRD42020200649

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