Upregulation of Nrf2 in myocardial infarction and ischemia-reperfusion injury of the heart.

Myocardial infarction (MI) is a leading cause of morbidity and mortality in the world and is characterized by ischemic necrosis of an area of the myocardium permanently devoid of blood supply. During reperfusion, reactive oxygen species are released and this causes further insult to the myocardium, resulting in ischemia-reperfusion (IR) injury. Since Nrf2 is a key regulator of redox balance, it is essential to determine its contribution to these two disease processes. Conventionally Nrf2 levels have been shown to rise immediately after ischemia and reperfusion but its contribution to disease process a week after the injury remains uncertain. Mice were divided into MI, IR injury, and sham surgery groups and were sacrificed 1 week after surgery. Infarct was visualized using H&E and trichrome staining and expression of Nrf2 was assessed using immunohistochemistry, Western blot, and ELISA. MI displayed a higher infarct size than the IR group (MI: 31.02 ± 1.45%, IR: 13.03 ± 2.57%; p < 0.01). We observed a significantly higher expression of Nrf2 in the MI group compared to the IR model using immunohistochemistry, spot densitometry of Western blot (MI: 2.22 ± 0.16, IR: 1.81 ± 0.10, Sham: 1.52 ± 0.13; p = 0.001) and ELISA (MI: 80.78 ± 27.08, IR: 31.97 ± 4.35; p < 0.01). There is a significantly higher expression of Nrf2 in MI compared to the IR injury group. Modulation of Nrf2 could be a potential target for therapeutics in the future, and its role in cardioprotection can be further investigated.

Upregulation of CIRP by its agonist prevents the development of heart failure in myocardial infarction rats.

BACKGROUND: Downregulated expression of cold-inducible RNA binding protein (CIRP), a stress-response protein, has been demonstrated in the hearts of patients with heart failure (HF). However, whether CIRP plays a critical role in the pathogenesis of HF remains unknown. Zr17-2 is a recently identified CIRP agonist, which can enhance the expression of CIRP in hearts. Herein, we evaluated the effects of zr17-2 on the development of HF in a rat model of myocardial infarction (MI). METHODS: Male SD rats were pretreated with CIRP agonist zr17-2 or vehicle saline for 6 consecutive days, followed by MI induction. 1-week post-MI, cardiac function, and structural and molecular changes were determined by echocardiography and molecular biology methods. RESULTS: Excitingly, we found that pretreatment with zr17-2 significantly attenuated MI-induced cardiac dysfunction and dilation, coupled with reduced infarction size and cardiac remodeling. In addition, increased inflammatory response in the peri-infarcted heart including macrophage infiltration and the expression of inflammatory genes were all significantly decreased by zr17-2 pretreatment, suggesting an anti-inflammatory effect of zr17-2. Moreover, zr17-2 pretreatment also upregulated the antioxidant genes (e.g. NQO-1, Nrf2, and HO-1) level in the hearts. In isolated cultured cardiomyocytes, pretreatment with zr17-2 markedly attenuated cell injury and apoptosis induced by oxidative injury, along with elevation of Nrf2-related antioxidant genes and CIRP. However, silencing CIRP abolished zr17-2's antioxidant effects against oxidative injury, confirming that zr17-2's role is dependent on CIRP. CONCLUSION: Collectively, our study suggests CIRP plays a crucial role in the development of HF and a beneficial effect of CIRP agonist in preventing MI-induced HF, possibly via anti-inflammatory and anti-oxidant pathways.

Even short periods of diabetes remission are linked to lower risk of heart attack and stroke.

The studyDambha-Miller H, Hounkpatin HO, Stuart B, Farmer A, Griffin S. Type 2 diabetes remission trajectories and variation in risk of diabetes complications: a population-based cohort study. PLoS ONE 2023;18. doi:10.1371/journal.pone.0290791To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/even-short-periods-of-diabetes-remission-are-linked-to-lower-risk-of-heart-attack-and-stroke/.

Sacubitril/valsartan improves the prognosis of acute myocardial infarction: a meta-analysis.

OBJECTIVE: To systematically evaluate the effect of sacubitril/valsartan (SV) on the prognosis of patients with acute myocardial infarction (AMI), and to provide evidence for expanding the clinical application of SV. METHODS: PubMed, EMbase, Web of Science, and Cochrane Library were searched from inception to October 2023 for randomized controlled trials (RCTs) of SV in patients with AMI. The article was screened and evaluated by the Cochrane 5.1.0 bias risk assessment tool. RevMan5.3 was used for meta-analysis of the outcome indicators. RESULTS: Ten RCTs involving 7230 patients were included. The results showed that SV increased left ventricular eject fraction ( MD  = 2.86, 95% CI [1.81-3.90], P  < 0.00001) and reduced readmission rate ( RR  = 0.46, 95% CI [0.32-0.68], P  < 0.0001), decreased N-terminal pro-brain natriuretic peptide ( MD = -477.46, 95% CI [-914.96 to -39.96], P  = 0.03), and reduced major adverse cardiovascular and cerebrovascular event (MACCE) ( RR  = 0.48, 95% CI [0.27-0.85], P  = 0.01). There was no significant difference in the rate of adverse reaction (AR) between the trial group and the control group ( RR  = 0.88, 95% CI [0.60-1.30], P  = 0.52). CONCLUSION: SV can effectively improve the prognosis of AMI, prevent complications, and there is no significant difference in safety compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

Lipoprotein(a), C-Reactive Protein, and Cardiovascular Risk in Primary and Secondary Prevention Populations.

Importance: Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective: To investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations. Design, Setting, and Participants: This cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp(a) and hs-CRP. The data analysis took place from November 2022 to November 2023. Exposure: Baseline plasma Lp(a), considered either as a continuous variable or dichotomized at 125 nmol/L. Main Outcomes and Measures: Risk of major adverse cardiovascular events (MACE) (composite of cardiovascular death, myocardial infarction [MI], or ischemic stroke), the individual MACE components, and peripheral artery disease (PAD). Results: Among 357 220 individuals in the UK Biobank without prevalent ASCVD, 232 699 (65%) had low hs-CRP (<2 mg/L), and 124 521 (35%) had high hs-CRP (≥2 mg/L) values. In a Cox proportional hazard model adjusted for ASCVD risk factors, higher Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP value for MACE (hs-CRP ≥2 mg/L: hazard ratio [HR] per 50-nmol/L higher Lp[a], 1.05; 95% CI, 1.04-1.07; P < .001; for hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.04-1.07; P < .001; P = .80 for interaction), as well as MI, ischemic stroke, and PAD individually. Among 34 020 individuals in the FOURIER and SAVOR trials with baseline cardiometabolic disease, there were 17 643 (52%) with low and 16 377 (48%) with high baseline hs-CRP values. In Cox proportional hazard models using aggregated data from FOURIER and SAVOR, higher baseline Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP for MACE (hs-CRP ≥2 mg/L: HR per 50-nmol/L higher Lp[a], 1.02; 95% CI, 1.00-1.05; P = .04; hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.02-1.08; P < .001; P = .16 for interaction), MI, and PAD. Conclusions and Relevance: In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.

Effect of statin use for the primary prevention of cardiovascular disease among older adults: a cautionary tale concerning target trials emulation.

OBJECTIVES: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older adults >65 years on April 1, 2013, with no CVD history and no statin use in the previous year. STUDY DESIGN AND SETTING: We included individuals who initiated statins and classified them as exposed if they were using statin at least 3 months after initiation and nonexposed otherwise. We followed them until March 31, 2018. The primary outcome was the composite endpoint of coronary events (myocardial infarction, coronary bypass, and percutaneous coronary intervention), stroke, and all-cause mortality. The intention-to-treat (ITT) effect was estimated with adjusted Cox models and per-protocol effect with inverse probability of censoring weighting. RESULTS: A total of 65,096 individuals were included (mean age = 71.0 ± 5.5, female = 55.0%) and 93.7% were exposed. Whereas we observed a reduction in the composite outcome (ITT-hazard ratio (HR) = 0.75; 95% CI: 0.68-0.83) and mortality (ITT-HR = 0.69; 95% CI: 0.61-0.77) among exposed, coronary events increased (ITT-HR = 1.46; 95% CI: 1.09-1.94). All multibias E-values were low indicating that the results were not robust to unmeasured confounding, selection, and misclassification biases simultaneously. CONCLUSION: We cannot conclude on the effectiveness of statins in primary prevention of CVD among older adults. We caution that an in-depth reflection on sources of biases and careful interpretation of results are always required in observational studies.

Impact of comprehensive air pollution control policies on six criteria air pollutants and acute myocardial infarction morbidity, Weifang, China: A quasi-experimental study.

Comprehensive air pollution control policies may reduce pollutant emissions. However, the impact on disease morbidity of the change for the concentration of air pollutants following the policies has been insufficiently studied. We aim to assess the impact of comprehensive air pollution control policies on the levels of six criteria air pollutants and acute myocardial infarction (AMI) morbidity in Weifang, China. This study performed an interrupted time series analysis. The linear model with spline terms and generalized additive quasi-Poisson model were used to estimate the immediate change from 2016 to 2019 in the daily concentration of six air pollutants (PM2.5, PM10, SO2, NO2, O3, and, CO) and AMI incident cases (Age ≥35) associated with the implementation of air pollution control policies in Weifang, respectively. After the implementation of air pollution control policies, air quality in Weifang had been improved. Specifically, the daily concentrations of PM2.5, PM10, SO2, and, CO immediately decreased by 27.9 % (95 % CI: 6.6 % to 44.3 %), 32.9 % (95 % CI: 17.5 % to 45.5 %), 14.6 % (95 % CI: 0.4 % to 26.8 %), and 33.9 % (95 % CI: 22.0 % to 44.0 %), respectively. In addition, the policies implementation was also associate with the immediate decline in the AMI morbidity (-6.5 %, 95 % CI: -10.4 % to -2.3 %). And subgroup analyses indicate that the health effects of the policy intervention were only observed in female (-9.4 %, 95 % CI: -14.4 % to -4.2 %) and those aged ≥65 years (-10.5 %, 95 % CI: -14.6 % to -6.2 %). During the final 20 months of the study period, the policy intervention was estimated to prevent 1603 (95 % CI: 574 to 2587) cases of incident AMI in Weifang. Our results provide strong rationale that the policy intervention significantly reduced ambient pollutant concentrations and AMI morbidity, which highlighted the importance for a comprehensive and rigorous air pollution control policy in regions with severe air pollution.

Monotherapy with P2Y12-inhibitors after dual antiplatelet therapy: Filling gaps in evidence.

BACKGROUND: Whether P2Y12 inhibitor monotherapy (P2Y12-I) is superior to aspirin following DAPT discontinuation post-PCI remains to be established. METHODS: We updated our prior network meta-analysis where P2Y12-I and aspirin had been compared with DAPT or directly with each other. The focus is specifically on the available direct evidence, now consisting of the three head-to-head comparisons of P2Y12-I and aspirin in event-free PCI patients after DAPT. We include a Trial Sequential Analysis of the direct evidence based on meta-analytical literature. RESULTS: The main finding reveals a 39% significantly lower risk of myocardial infarction with P2Y12-I (RR 0.61, 95% CI 0.47-0.78, p = 0.0001, I2 = 0%) with no difference in bleeding. Trial Sequential Analysis demonstrates clinically meaningful evidence for a reduction in the incidence of myocardial infarction with P2Y12-I that is also supported by statistical significance. CONCLUSIONS: Accruing data highlight that P2Y12-I following DAPT discontinuation after PCI is associated with lower risk for MI and a similar risk for bleeding as compared with ASA. In light of potential limitations to the widespread adoption of life-long P2Y12-I treatment, clinicians should consider identifying selected patients who are expected to derive the highest benefit.

Systematic review of clinical trials on antithrombotic therapy with factor XI inhibitors.

INTRODUCTION AND OBJECTIVE: Data from phase 2 clinical trials suggest that factor XI inhibitors may exhibit a more favorable efficacy/safety profile compared to current antithrombotic therapies. The aim of this systematic review is to analyze the available evidence derived from these studies. METHODS: A literature search in the PubMed, Cochrane Library, Scopus, EMBASE databases, and clinical trial registration platforms Clinical Trials and Cochrane Central Register of Controlled was conducted. In accordance with the PRISMA statement, results were reported. RESULTS: A total of 18 completed or ongoing clinical trials addressing multiple scenarios, including atrial fibrillation, stroke, myocardial infarction, and venous thromboembolism, were identified. Evidence from 8 studies with available results was analyzed. Phase 2 studies with factor XI inhibitors, overall, demonstrated an acceptable efficacy and safety profile. The benefit-risk balance, in terms of reducing venous thromboembolism in patients undergoing total knee arthroplasty, was more favorable. For this scenario, factor XI inhibitors showed a 50% reduction in the overall rate of thrombotic complications and a 60% reduction in the rate of bleeding compared to enoxaparin. Modest results in studies involving patients with atrial fibrillation, stroke, and myocardial infarction were observed. CONCLUSIONS: Factor XI inhibitors offer new prospects in antithrombotic treatment and prophylaxis. Ongoing phase 3 studies will help define the most suitable drugs and indications.

miRNA-146a-5p Inhibits Hypoxia-Induced Myocardial Fibrosis Through EndMT.

Cardiac Vascular disease particularly myocardial infarction (MI) is a threat to health worldwide. microRNAs (miRNAs) have been shown to regulate myocardial fibrosis. Therefore, it is potential to investigate the mechanism of miRNA and fibrosis following myocardial infarction. Hypoxia human cardiac microvascular endothelial cells (HCMECs) were selected for the vitro experimental model. The miR-146a-5p expression was tested via RT-qPCR. The level of endothelial-to-mesenchymal transition (EndMT) and fibrosis markers were detected by Western blotting and immunofluorescence. Then, the inflammation, cell viability and apoptosis were investigated. The target was predicted by an online database and verified by a dual-luciferase activity assay. An MI mouse model was created to validate that miR-146a-5p regulates cardiac fibrosis in vivo. MI mouse was transfected with miR-146a-5p lentivirus. Subsequently, its effect on cardiac fibrosis of infarcted hearts was assessed by In situ hybridization (ISH), Immunohistochemistry (IHC), Triphenylterazolium chloride (TTC) staining and Masson staining. Herein, we confirmed that miR-146a-5p was down-regulated in hypoxia HCMECs. Overexpression of miR-146a-5p inhibited hypoxia-induced cardiac fibrosis following myocardial infarction by inhibiting EndMT in HCMECs. Thioredoxin-interacting protein (TXNIP) was a target that was negatively regulated by miR-146a-5p. Up-regulation of miR-146a-5p inhibited cardiac fibrosis via regulating EndMT by targeting TXNIP, and it also regulated EndMT to inhibit cardiac fibrosis in vivo.

Hydrocortisone cardioprotection in ischaemia/reperfusion injury involves antioxidant mechanisms.

BACKGROUND: Glucocorticoid (GR) and mineralocorticoid (MR) receptors are highly expressed in cardiac tissue, and both can be activated by corticosteroids. MR activation, in acute myocardial infarction (AMI), worsens cardiac function, and increase NHE activity contributing to the deleterious process. In contrast, effects of GR activation are not fully understood, probably because of the controversial scenario generated by using different doses or potencies of corticosteroids. AIMS: We tested the hypothesis that an acute dose of hydrocortisone (HC), a low-potency glucocorticoid, in a murine model of AMI could be cardioprotective by regulating NHE1 activity, leading to a decrease in oxidative stress. MATERIALS AND METHODS: Isolated hearts from Wistar rats were subjected to regional ischemic protocol. HC (10 nmol/L) was added to the perfusate during early reperfusion. Infarct size and oxidative stress were determined. Isolated papillary muscles from non-infarcted hearts were used to evaluate HC effect on sodium-proton exchanger 1 (NHE1) by analysing intracellular pH recovery from acute transient acidosis. RESULTS: HC treatment decreased infarct size, improved cardiac mechanics, reduced oxidative stress after AMI, while restoring the decreased level of the pro-fusion mitochondrial protein MFN-2. Co-treatment with the GR-blocker Mifepristone avoided these effects. HC reduced NHE1 activity by increasing the NHE1 pro-inhibiting Ser648 phosphorylation site and its upstream kinase AKT. HC restored the decreased AKT phosphorylation and anti-apoptotic BCL-2 protein expression detected after AMI. CONCLUSIONS: Our results provide the first evidence that acute HC treatment during early reperfusion induces cardioprotection against AMI, associated with a non-genomic HC-triggered NHE1 inhibition by AKT and antioxidant action that might involves mitochondrial dynamics improvement.

Low-Dose Colchicine in Patients With Type 2 Diabetes and Recent Myocardial Infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

OBJECTIVE: The cardiovascular benefits of low-dose colchicine have been demonstrated in patients with coronary disease. Its effects were evaluated in this prespecified analysis in patients with type 2 diabetes (T2D) from the Colchicine Cardiovascular Outcomes Trial (COLCOT). RESEARCH DESIGN AND METHODS: COLCOT was a randomized, double-blinded trial of colchicine, 0.5 mg daily, versus placebo initiated within 30 days after a myocardial infarction. RESULTS: There were 959 patients with T2D enrolled and monitored for a median of 22.6 months. A primary end point event occurred in 8.7% of patients in the colchicine group and in 13.1% in the placebo group (hazard ratio 0.65; 95% CI 0.44-0.96; P = 0.03). Nausea was reported in 2.7% and 0.8% in the study groups (P = 0.03), and pneumonia occurred in 2.4% and 0.4% (P = 0.008). CONCLUSIONS: Among patients with T2D and a recent myocardial infarction, colchicine, 0.5 mg daily, leads to a large reduction of cardiovascular events. These results support the conduct of the COLCOT-T2D trial in primary prevention.

The effect of fibrates on lowering low-density lipoprotein cholesterol and cardiovascular risk reduction: a systemic review and meta-analysis.

AIMS: The effect of fibrate treatment on cardiovascular risk is inconsistent. This meta-analysis aimed to assess the effect of fibrates on major adverse cardiovascular outcome (MACE) reduction. METHODS AND RESULTS: PubMed, Embase, and Cochrane library databases were searched up to February 2023 for randomized controlled trials comparing fibrate therapy against placebo and reporting cardiovascular outcomes and lipid profile changes. The primary outcome was the clinical outcomes of each trial that most closely corresponding to MACE, a composite of cardiovascular death, acute myocardial infarction, stroke, and coronary revascularization. A pre-specified meta-regression analysis to examine the relationship between the changes in lipid levels after fibrate treatment and the risk of MACE was also performed. Twelve trials were selected for final analysis, with 25 781 patients and 2741 MACEs in the fibrate group and 27 450 patients and 3754 MACEs in the control group. Overall, fibrate therapy was associated with decreased risk of MACE [RR 0.87, 95% confidence interval (CI) 0.81-0.94] with moderate heterogeneity (I2 = 47%). In meta-regression analysis, each 1 mmol/L reduction in low-density lipoprotein cholesterol (LDL-C) after fibrate treatment reduced MACE (RR 0.71, 95% CI 0.49-0.94, P = 0.01), while triglyceride level changes did not show a significant association (RR per 1mmol/L reduction 0.96, 95% CI 0.53-1.40, P = 0.86). A sensitivity analysis with the composite outcome of cardiovascular death or acute myocardial infarction produced similar results. CONCLUSION: Treatment with fibrates was associated with decreased risk of MACE. The reduction in MACE risk with fibrate therapy appears to be attributable to LDL-C reduction rather than a decrease in triglyceride levels.

A systematic review and meta-analysis including 12 trials and 53 231 patients were performed to investigate the effect of fibrates on lowering cardiovascular risk. Overall, fibrate therapy was associated with significantly decreased risk of cardiovascular events. In further analysis, the decrease in cardiovascular risk achieved with fibrate treatment was found to be largely attributable to low-density lipoprotein cholesterol reduction.

The role of aspirin, statins, colchicine, and IL-1 inhibitors in prevention of cardiovascular events: a systematic integrative review.

CONTEXT: Cardiovascular disease (CVD) is the leading cause of death in the United States. As such, an unmet need exists in the primary and secondary prevention of adverse cardiovascular events (CVEs). Specifically, identifying drugs that can reduce the progression of CVD and serious adverse events is much needed. Drugs that work by reducing platelet aggregation, blocking cholesterol formation (3-hydroxy-3-methyl-glutaryl-coenzyme A [HMG-CoA] reductase inhibitors), and/or blocking inflammation pathways (mainly interleukin-1b [IL-1b]) have been linked to preventing adverse CVEs, including acetylsalicylic acid (ASA, aspirin), statins, colchicine, and IL-1 inhibitors (interleukin-1 receptor antagonists). This systematic review aims to provide insight into utilizing these four agents for the primary and/or secondary prevention of CVD. OBJECTIVES: In this systematic review, we opted to review the efficacy of aspirin, statins, colchicine, and IL-1 inhibitors in the primary and secondary prevention of CVE to provide clinical practitioners with evidence-based practice approaches and determine any unmet needs in their utilization. METHODS: Between October 1 and 12, 2021, a search was conducted and completed on five databases: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Biomedical Reference Collection: Comprehensive. A total of 13 researchers (V.A., A.H., S.B., V.G., D.C., C.C., C.B., C.A., S.K., J.H., A.K., S.F., and S.E.) were involved in the search and screening of the articles. Search terms included "aspirin, statins, colchicine, IL-1 inhibitors, and primary, secondary, myocardial infarction (MI)." Inclusion criteria included clinical study design, English language articles, all genders older than 50 years old, and established patient history of CVD, including MI. In addition, articles were excluded if they were animal models, in vitro studies, pharmacokinetic studies, systematic reviews, literature reviews, and studies exploring therapies other than those listed in the inclusion criteria. First, five individuals independently sorted through abstracts or articles based on the inclusion and exclusion criteria. Then, a team of 13 individuals sorted through full-text articles of selected abstracts based on the same criteria. A separate researcher resolved conflicts between the team. RESULTS: A total of 725 articles were identified from all databases, from which 256 duplicated articles were removed. Thus, a total of 469 articles abstracts were screened, of which 425 articles either did not meet the inclusion criteria or met the exclusion criteria. A total of 42 articles were retrieved and assessed for full-text review, from which 15 articles were retrieved for analysis. CONCLUSIONS: Statins may prevent primary CVEs based on their role in preventing cholesterol formation. Aspirin, canakinumab, and colchicine may be helpful in the secondary prevention of CVEs due to their blocking of various steps in the inflammation pathway leading to CVD. Future research should primarily focus on the use of canakinumab and colchicine in preventing CVD due to the limited number of studies on these drugs.

Safety and Efficacy of Direct Oral Anticoagulant in Addition to Antiplatelet Therapy After Acute Coronary Syndrome: A Systemic Review and Meta-analysis of 53,869 Patients.

INTRODUCTION: Significant progress has been made in the management of patients with acute coronary syndrome (ACS) during the past few decades. However, the role of direct oral anticoagulants (DOACs) in post-ACS prophylactic therapy remains unknown. This study aims to assess the efficacy and safety of DOACs plus antiplatelet treatment (APT) after ACS. METHODS: A systematic literature search was conducted to identify randomized clinical trials comparing DOACs plus APT with APT alone after ACS. The primary efficacy end points were cardiovascular mortality, myocardial infarction, all-cause mortality, and stroke and systemic embolization (SSE). The primary safety end point was major bleeding. The random-effects model was used to calculate relative risk (RR) and corresponding 95% CIs. RESULTS: Nine trials with a total of 53,869 patients were identified, with 33,011 (61.2%) in the DOACs plus APT group and 20,858 (38.8%) in the APT alone group. The use of DOACs did not decrease the risk of cardiovascular death (RR = 0.87; 95% CI, 0.75-1.01; P = 0.08; I2 = 0%) or myocardial infarction (RR = 0.90; 95% CI, 0.80-1.02; P = 0.10; I2 = 6%). However, the risk of SSE was significantly lower in patients who received DOACs plus APT compared with APT alone (RR = 0.67; 95% CI, 0.50-0.90; P = 0.008). Moreover, all-cause mortality was significantly lower in the DOACs plus APT group (RR = 0.83; 95% CI, 0.71-98; P = 0.03; I2 = 0%). However, the risk of major bleeding was significantly higher in patients treated with DOACs plus APT compared with APT alone (RR = 2.53; 95% CI, 1.96-3.26; P < 0.01; I2 = 0%), as was the risk of nonmajor bleeding (RR = 2.27; 95% CI, 1.51-3.41; P < 0.01). IMPLICATIONS: DOACs plus APT for the prevention of left ventricular thrombus in patients with ACS were associated with a lower risk of SSE and all-cause mortality but increased the risk of major and nonmajor bleeding. The benefits and risks of this approach should be weighed based on a patient's individual clinical characteristics.

Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13 970 Contemporary High-Risk Patients With Statin Intolerance.

BACKGROUND: Among patients treated with statin therapy to guideline-recommended cholesterol levels, residual inflammatory risk assessed by high-sensitivity C-reactive protein (hsCRP) is at least as strong a predictor of future cardiovascular events as is residual risk assessed by low-density lipoprotein cholesterol (LDLC). Whether these relationships are present among statin-intolerant patients with higher LDLC levels is uncertain but has implications for the choice of preventive therapies, including bempedoic acid, an agent that reduces both LDLC and hsCRP. METHODS: The multinational CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) randomly allocated 13 970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a 4-component composite of incident myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and for all-cause mortality. Quartiles of increasing baseline hsCRP and LDLC were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment. RESULTS: Compared with placebo, bempedoic acid reduced median hsCRP by 21.6% and mean LDLC levels by 21.1% at 6 months. Baseline hsCRP was significantly associated with the primary composite end point of major cardiovascular events (highest versus lowest hsCRP quartile; hazard ratio [HR], 1.43 [95% CI, 1.24-1.65]), cardiovascular mortality (HR, 2.00 [95% CI, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% CI, 1.79-2.73]). By contrast, the relationship of baseline LDLC quartile (highest versus lowest) to future events was smaller in magnitude for the primary composite cardiovascular end point (HR, 1.19 [95% CI, 1.04-1.37]) and neutral for cardiovascular mortality (HR, 0.90 [95% CI, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% CI, 0.78-1.16]). Risks were high for those with elevated hsCRP irrespective of LDLC level. Bempedoic acid demonstrated similar efficacy in reducing cardiovascular events across all levels of hsCRP and LDLC. CONCLUSIONS: Among contemporary statin-intolerant patients, inflammation assessed by hsCRP predicted risk for future cardiovascular events and death more strongly than hyperlipidemia assessed by LDLC. Compared with placebo, bempedoic acid had similar efficacy for reducing cardiovascular risk across hsCRP and LDLC strata. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02993406.