Remnant cholesterol as a new lipid-lowering target to reduce cardiovascular events.

PURPOSE OF REVIEW: Remnant cholesterol has become increasingly recognized as a direct contributor to the development of atherosclerosis and as an additional marker of cardiovascular risk. This review aims to summarize the pathophysiological mechanisms, and the current evidence base from epidemiological investigations and genetic studies that support a causal link between remnant cholesterol and atherosclerotic cardiovascular disease. Current and novel therapeutic approaches to target remnant cholesterol are discussed. RECENT FINDINGS: A recent Mendelian randomization study of over 12 000 000 single-nucleotide polymorphisms associated with high levels of remnant cholesterol, demonstrated a genetic association between remnant cholesterol and adverse cardiovascular events among 958 434 participants. SUMMARY: In this light, the emerging role of remnant cholesterol as an independent lipid risk marker warrants a reevaluation of lipid management guidelines and underscores the potential for novel therapeutic targets in cardiovascular disease prevention.

Cangrelor - Expanding therapeutic options in patients with acute coronary syndrome.

Cangrelor is the only intravenous P2Y12 receptor antagonist. It is an adenosine triphosphate analog that selectively, directly, and reversibly binds to the platelet P2Y12 receptors exerting its antiaggregatory effect. Cangrelor is characterized by linear, dose-dependent pharmacokinetics and rapid onset of action providing potent platelet inhibition exceeding 90%. Cangrelor is rapidly metabolized by endothelial endonucleotidase; thus, its half-life is 2.9 to 5.5 min, and its antiplatelet effect subsides within 60 to 90 min. Data originating from three pivotal cangrelor trials (CHAMPION PLATFORM, CHAMPION PCI, and CHAMPION PHOENIX) indicate that cangrelor reduces the risk of periprocedural thrombotic complications during percutaneous coronary intervention at the expense of mild bleedings. Its unique pharmacological properties allow it to overcome the limitations of oral P2Y12 receptor inhibitors, mainly related to the delayed and decreased bioavailability and antiplatelet effect of these agents, which are often observed in the setting of acute coronary syndrome. Subgroups of patients who could theoretically benefit the most from cangrelor include those in whom pharmacokinetics and pharmacodynamics of oral P2Y12 receptor antagonists are most disturbed, namely patients with ST-segment elevation myocardial infarction, those treated with opioids, with mild therapeutic hypothermia, or in cardiogenic shock. Cangrelor could also be useful if bridging is required in patients undergoing surgery. According to the current guidelines cangrelor may be considered in P2Y12 receptor inhibitor-naïve patients undergoing percutaneous coronary intervention in both acute and stable settings.

Low-Dose Aspirin for Primary Prevention of Cardiovascular Events Comparing East Asians With Westerners: A Meta-Analysis.

Background: East Asians have shown different risk profiles for both thrombophilia and bleeding than Western counterparts. Objectives: The authors sought to evaluate the effect of low-dose aspirin for primary prevention between these populations. Methods: We searched randomized clinical trials (RCTs) for intervention with low-dose aspirin (≤100 mg once daily) in participants without symptomatic cardiovascular disease until December 31, 2021. The number of events between the arms was extracted for analysis. Pooled risk ratios (RRs) and risk differences (RDs) were analyzed in each population. Outcomes included a major adverse cardiovascular event (MACE), cardiovascular death, myocardial infarction, stroke, and major bleeding (intracranial hemorrhage and major gastrointestinal bleeding). Results: Two RCTs included 17,003 East Asians, and 9 RCTs had 117,467 Western participants. Aspirin treatment showed a similar effect in reducing the MACE rate (RR of East Asians: 0.87; 95% CI: 0.71-1.05; RR of Westerners: 0.90; 95% CI: 0.85-0.95) (Pinteraction = 0.721). In contrast, the risk of major bleeding during aspirin vs control was greater in the East Asian population (RR: 2.48; 95% CI: 1.86-3.30) compared with the Western population (RR: 1.45; 95% CI: 1.26-1.66) (Pinteraction = 0.001), which was driven by more frequent gastrointestinal bleeding (RR of East Asians: 3.29; 95% CI: 2.26-4.80 vs RR of Westerners: 1.56; 95% CI: 1.29-1.88) (Pinteraction < 0.001). The net RDs (RD of MACE plus RD of major bleeding) were 8.04 and 0.72 per 1,000 persons in East Asian and Western participants, indicating 124 and 1,389 of the net number needed to harm, respectively. Conclusions: Low-dose aspirin for primary prevention in East Asians must be cautiously prescribed because of the increased risk of major bleeding relative to Western counterparts.

De-escalation or abbreviation of dual antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention: a Consensus Statement from an international expert panel on coronary thrombosis.

Conventional dual antiplatelet therapy (DAPT) for patients with acute coronary syndromes undergoing percutaneous coronary intervention comprises aspirin with a potent P2Y purinoceptor 12 (P2Y12) inhibitor (prasugrel or ticagrelor) for 12 months. Although this approach reduces ischaemic risk, patients are exposed to a substantial risk of bleeding. Strategies to reduce bleeding include de-escalation of DAPT intensity (downgrading from potent P2Y12 inhibitor at conventional doses to either clopidogrel or reduced-dose prasugrel) or abbreviation of DAPT duration. Either strategy requires assessment of the ischaemic and bleeding risks of each individual. De-escalation of DAPT intensity can reduce bleeding without increasing ischaemic events and can be guided by platelet function testing or genotyping. Abbreviation of DAPT duration after 1-6 months, followed by monotherapy with aspirin or a P2Y12 inhibitor, reduces bleeding without an increase in ischaemic events in patients at high bleeding risk, particularly those without high ischaemic risk. However, these two strategies have not yet been compared in a head-to-head clinical trial. In this Consensus Statement, we summarize the evidence base for these treatment approaches, provide guidance on the assessment of ischaemic and bleeding risks, and provide consensus statements from an international panel of experts to help clinicians to optimize these DAPT approaches for individual patients to improve outcomes.

Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian Randomization Study.

BACKGROUND: Observational studies suggested that residual risk of cardiovascular events after LDL (low-density lipoprotein) cholesterol lowering may be linked to remnant cholesterol (RC). We conducted a large-scale Mendelian randomization study to investigate the causal role of RC to predict coronary artery disease (CAD), myocardial infarction (MI), and stroke risk. METHODS: We extracted single-nucleotide polymorphisms for RC and LDL from large-scale genome-wide association databases. We estimated the genetic association with outcomes from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics), the Metastroke consortium, as well as the GLGC (Global Lipids Genetics Consortium). Genetic variants were used as instruments, thereby minimizing residual confounding and reverse causation biases of observational studies. RESULTS: By leveraging data from a combined sample of 958 434 participants, we found evidence for a significant causal effect of RC on the risk of CAD (odds ratio [OR], 1.51 per SD unit increase in RC [95% CI, 1.42-1.60]; P=5.3×10-5), MI (OR, 1.57 [95% CI, 1.21-2.05]; P=9.5×10-4), and stroke (OR, 1.23 [95% CI, 1.12-1.35]; P=3.72×10-6). There was no evidence of pleiotropy. The effect of RC on CAD and MI remained consistent after accounting for the effects of RC-associated genetic variants on LDL cholesterol: OR, 1.49 (95% CI, 1.37-1.61) for CAD and OR, 1.80 (95% CI, 1.70-19.1) for MI without a meaningful indirect effect exerted on these outcomes via the LDL cholesterol mediator. CONCLUSIONS: This large-scale Mendelian randomization study showed a robust genetic causal association between RC and cardiovascular outcomes. The effect on CAD and MI is independent of LDL cholesterol. Early screening for RC along with long-term inhibition of RC should be the focus of future therapeutic interventions.

Effects of Elective Coronary Revascularization vs Medical Therapy Alone on Noncardiac Mortality: A Meta-Analysis.

BACKGROUND: Uncertainty exists whether coronary revascularization plus medical therapy (MT) is associated with an increase in noncardiac mortality in chronic coronary syndrome (CCS) when compared with MT alone, particularly following recent data from the ISCHEMIA-EXTEND (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. OBJECTIVES: This study conducted a large-scale meta-analysis of trials comparing elective coronary revascularization plus MT vs MT alone in patients with CCS to determine whether revascularization has a differential impact on noncardiac mortality at the longest follow-up. METHODS: We searched for randomized trials comparing revascularization plus MT vs MT alone in patients with CCS. Treatment effects were measured by rate ratios (RRs) with 95% CIs, using random-effects models. Noncardiac mortality was the prespecified endpoint. The study is registered with PROSPERO (CRD42022380664). RESULTS: Eighteen trials were included involving 16,908 patients randomized to either revascularization plus MT (n = 8,665) or to MT alone (n = 8,243). No significant differences were detected in noncardiac mortality between the assigned treatment groups (RR: 1.09; 95% CI: 0.94-1.26; P = 0.26), with absent heterogeneity (I2 = 0%). Results were consistent without the ISCHEMIA trial (RR: 1.00; 95% CI: 0.84-1.18; P = 0.97). By meta-regression, follow-up duration did not affect noncardiac death rates with revascularization plus MT vs MT alone (P = 0.52). Trial sequential analysis confirmed the reliability of meta-analysis, with the cumulative Z-curve of trial evidence within the nonsignificance area and reaching futility boundaries. Bayesian meta-analysis findings were consistent with the standard approach (RR: 1.08; 95% credible interval: 0.90-1.31). CONCLUSIONS: In patients with CCS, noncardiac mortality in late follow-up was similar for revascularization plus MT compared with MT alone.

Sex differences in treatment and outcomes amongst myocardial infarction patients presenting with and without obstructive coronary arteries: a prospective multicentre study.

Aims: Women have an increased prevalence of myocardial infarction (MI) with non-obstructive coronary arteries (MINOCA). Whether sex differences exist in the outcomes of patients with MI and obstructive coronary arteries (MIOCA) vs. MINOCA remains unclear. We describe sex-based differences in diagnosis, treatment, and clinical outcomes of patients with MINOCA vs. MIOCA. Methods and results: A large-scale cohort study of patients with ST/non-ST elevation MI undergoing coronary angiography (01/2015-12/2019). Patient demographics, diagnosis, prescribed discharge medications, in-hospital complications, and follow-up data were prospectively collected. A total of 13 202 participants were included (males 68.2% and females 31.8%). 10.9% were diagnosed with MINOCA. Median follow-up was 4.62 years. Females (44.8%) were as commonly diagnosed with MINOCA as males (55.2%), unlike the male preponderance in MIOCA (male, 69.8%; female, 30.2%). Less secondary prevention medications were prescribed at discharge for MINOCA than MIOCA. There was no difference in mortality risk between MINOCA and MIOCA [in-hospital: adjusted odds ratio (OR) 1.32, 95% confidence interval (CI) 0.74-2.35, P = 0.350; long term: adjusted hazard ratio (HR) 1.03, 95% CI 0.81-1.31, P = 0.813]. MINOCA patients had reduced mortality at long-term follow-up if prescribed secondary prevention medications (aHR 0.64, 95% CI 0.47-0.87, P = 0.004). Females diagnosed with MIOCA had greater odds of in-hospital and 1-year mortality than males (aOR 1.50, 95% CI 1.09-2.07, P = 0.014; aHR 1.18, 95% CI 1.01-1.38, P = 0.048). Conclusion: MINOCA patients have similar mortality rates as MIOCA patients. MINOCA patients were less likely than those with MIOCA to be discharged with guideline-recommended secondary prevention therapy; however, those with MINOCA who received secondary prevention survived longer. Females with MIOCA experienced higher mortality rates vs. males.

Comparison of De-escalation of DAPT Intensity or Duration in East Asian and Western Patients with ACS Undergoing PCI: A Systematic Review and Meta-analysis.

BACKGROUND: Guideline-recommended dual antiplatelet therapy (DAPT; aspirin plus prasugrel/ticagrelor) for 12 months in acute coronary syndrome (ACS) patients increases bleeding, with East Asians (EAs) exhibiting higher bleeding and lower ischemic risk, compared with non-East Asians (nEAs). We sought to compare DAPT "de-escalation" strategies in EA and nEA populations. METHODS: A systematic review and meta-analysis of randomized controlled trials assessing reduction of DAPT intensity or duration in ACS patients undergoing percutaneous coronary intervention, in EA and nEA, was performed using a random-effects model. RESULTS: Twenty-three trials assessed reduction of DAPT intensity (n = 12) or duration (n = 11). Overall, reduced DAPT intensity attenuated major bleeding (odds ratio [OR]: 0.78, 95% confidence interval [CI]: 0.65-0.94, p = 0.009), without impacting net adverse cardiovascular events (NACE) or major adverse cardiovascular events (MACE). In nEA, this increased MACE (OR: 1.20, 95% CI: 1.09-1.31, p < 0.0001) without impacting NACE or bleeding; while in EA, it reduced major bleeding (OR: 0.71, 95% CI: 0.53-0.95, p = 0.02) without affecting NACE or MACE. Overall, abbreviation of DAPT duration reduced NACE (OR: 0.90, 95% CI: 0.82-0.99, p = 0.03) due to major bleeding (OR: 0.69, 95% CI: 0.53-0.99, p = 0.006), without impacting MACE. In nEA, this strategy did not impact NACE, MACE, or major bleeding; while in EA, it reduced major bleeding (OR: 0.60, 95% CI: 0.4-0.91, p = 0.02) without impacting NACE or MACE. CONCLUSION: In EA, reduction of DAPT intensity or duration can minimize bleeding, without safety concerns. In nEA, reduction of DAPT intensity may incur an ischemic penalty, while DAPT abbreviation has no overall benefit.

PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection.

BACKGROUND: The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. OBJECTIVES: The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. METHODS: In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. RESULTS: Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: -30%; 95% CI: -53.40% to -6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: -56% vs -21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: -37.50%; 95% CI: -68.20% to -6.70%). CONCLUSIONS: PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105).

Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial.

BACKGROUND: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes. METHODS: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned. RESULTS: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52-1.14) with amiodarone and 0.97 (0.81-1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27-2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37-3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying. CONCLUSIONS: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.

P2Y12 inhibitor versus aspirin monotherapy for secondary prevention of cardiovascular events: meta-analysis of randomized trials.

Aim: To compare the efficacy and safety of P2Y12 inhibitor or aspirin monotherapy for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD). Methods and results: Medline, Embase, and Cochrane Central databases were searched to identify randomized trials comparing monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention in patients with ASCVD (cardiovascular, cerebrovascular, or peripheral artery disease). The primary outcome was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, and major bleeding. A random-effects model was used to calculate risk ratios (RR) and the corresponding 95% confidence interval (CI) and heterogeneity among studies was assessed using the Higgins I2 value. A total of 9 eligible trials (5 with clopidogrel and 4 with ticagrelor) with 61 623 patients were included in our analyses. Monotherapy with P2Y12 inhibitors significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84-0.95, I2 = 0%) and MI by 19% (0.81, 95% CI 0.71-0.92, I2 = 0%) compared with aspirin monotherapy. There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), or all-cause mortality (1.01, 95% CI 0.92-1.11). There was also no significant difference in the risk of major bleeding with P2Y12 inhibitor monotherapy compared with aspirin (0.94, 95% CI 0.72-1.22, I2 = 42.6%). Results were consistent irrespective of the P2Y12 inhibitor used. Conclusion: P2Y12 inhibitor monotherapy for secondary prevention is associated with a significant reduction in atherothrombotic events compared with aspirin alone without an increased risk of major bleeding.

The spoils of war and the long-term spoiling of health conditions of entire nations.

The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population.

Oral NAloxone to overcome the moRphine effect in acute COronary syndrome patients treated with TICagrelor - NARCOTIC trial.

BACKGROUND: Numerous worldwide clinical trials have proven the indisputably negative influence of morphine on the pharmacokinetics and pharmacodynamics of P2Y12 receptor inhibitors in patients presenting with acute coronary syndromes. The aim of this trial was to evaluate whether oral coadministration of an anti-opioid agent, naloxone, can be considered a successful approach to overcome 'the morphine effect'. METHODS: Consecutive unstable angina patients receiving ticagrelor and morphine with or without orally administered naloxone underwent assessment of platelet reactivity using Multiplate analyzer as well as evaluation of the pharmacokinetic profile of ticagrelor and its active metabolite, AR-C124910XX, at 9 pre-defined time points within the first 6 hours following oral intake of the ticagrelor loading dose. RESULTS: The trial shows no significant differences regarding the pharmacokinetics of ticagrelor between both study arms throughout the study period. AR-C124910XX plasma concentration was significantly higher 120 min after the ticagrelor loading dose administration (p = 0.0417). However, the evaluation of pharmacodynamics did not show any statistically significant differences between the study arms. CONCLUSIONS: To conclude, this trial shows that naloxone co-administration in ticagrelor-treated acute coronary syndrome patients on concomitant treatment with morphine shows no definite superiority in terms of ticagrelor pharmacokinetic and pharmacodynamic profile.

Meta-analysis of controlled studies on minimally interrupted vs. continuous use of non-vitamin K antagonist oral anticoagulants in catheter ablation for atrial fibrillation.

AIMS: At present, there are no guideline recommendations for minimally interrupted use of non-vitamin K antagonist oral anticoagulants (mi-NOAC) during catheter ablation (CA) for atrial fibrillation (AF). Current evidence is predominantly based on observational studies, with continuous use of vitamin K antagonist in the control arm. This quantitative summary reflects the first high-level evidence on contemporary regimens, with continuous NOAC use (c-NOAC) as the current gold standard. METHODS AND RESULTS: Meta-analysis (Pubmed, Embase, and Web of Science) on prospective, controlled studies comparing contemporary mi-NOAC (without bridging) with c-NOAC. Net adverse clinical events (major bleeding, thrombo-embolic events) were the primary outcome. In addition, we analysed total bleeding, minor bleeding, and silent cerebral embolism. Eight studies (six randomized, two observational) with 2168 patients were summarized. The primary endpoint occurred in 1.0% (18/1835): 1.1% (11/1005) vs. 0.8% (7/830) for the mi-NOAC and c-NOAC groups, respectively; odds ratio (OR) 1.20 [95% confidence interval (CI) 0.49-2.92, P = 0.64]. The OR for total bleeding on mi-NOAC was 1.26 (95% CI 0.97-1.63, P = 0.07). ORs for minor bleeding and silent cerebral embolism were 1.17 (95% CI 0.80-1.70, P = 0.34) and 2.62 (95% CI 0.54-12.61, P = 0.12), respectively. CONCLUSION: This synopsis provides a quantitative synthesis of high-level evidence on a contemporary strategy of mi-NOAC in CA for AF, and overall clinical outcomes were not different from continuous NOAC use. Despite preprocedural interruption, there was no sign of lower bleeding rates. Additional higher volume datasets are warranted for more precise treatment effect estimations of this everyday alternative anticoagulation strategy in AF ablation.