Risk Of Ischemic Cardiovascular Events Research Articles

Biochemical profiles and risk of cardiovascular events in patients withType 2 Diabetes: implications for choice of novel antihyperglycemic therapy

Abstract Background Guidelines on type 2 diabetes (T2D) recommend targeting patients at greater risk of heart failure with sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and patients at greater risk of cardiovascular ischemic events with glucagon-like peptide-1 receptor agonists (GLP1-RA) or SGLT2-i. It is currently unclear whether distinct biochemical profiles are more or less associated with the occurrence of heart failure or a cardiovascular ischemic event. Purpose To investigate the risk of the first occurring event of either heart failure or a cardiovascular ischemic event associated with different biochemical profiles in newly diagnosed T2D patients without cardiovascular disease. Methods From Danish nationwide registers, we identified all patients newly diagnosed with T2D who were free of cardiovascular disease (heart failure, ischemic heart disease, peripheral artery disease, and previous stroke), from 2013-2021. Patients <40 years, and patients without a registered blood test within three months prior to the T2D diagnosis, were excluded. The absolute 5-year risk of the first occurring event of either heart failure or a cardiovascular ischemic event, was calculated for patients with different levels of three biochemical markers that are known to be associated with cardiovascular disease: 1) HbA1c 2) low-density lipoprotein (LDL); and 3) estimated glomerular filtration rate (eGFR) calculated from serum creatinine. Results Of the 81,095 patients included in the study, 53% were male and the median age was 60 years [interquartile range 52-69]. For all pre-defined biochemical profiles—HbA1c below or above 8%, LDL below or above 4 mmol/L, and eGFR below or above 60ml/min/1.73m2—the absolute 5-year risk of a cardiovascular ischemic event was greater than the risk of heart failure (risk ratio ranging from 2.3–4.2), as the first occurring event following the diagnosis of T2D. The highest risk of heart failure was observed in those with moderately to severely reduced eGFR (<60 ml/min/1.73m2). Conclusions Among patients newly diagnosed with T2D and free of cardiovascular disease, different biochemical profiles of HbA1c, LDL, and eGFR, were all associated with a higher risk of an ischemic cardiovascular event as the first occurring event following T2D diagnosis, as opposed to heart failure.Flowchart of patient selectionCumulative incidence of CIE Vs. HF

Antithrombotic and Statin Prescription After Intracerebral Hemorrhage in the Get With The Guidelines-Stroke Registry.

Survivors of intracerebral hemorrhage (ICH) face an increased risk of ischemic cardiovascular events. Current ICH guidelines do not provide definitive recommendations regarding the use of antithrombotic and statin therapies. We, therefore, sought to study practice patterns and factors associated with the use of such medications after ICH. This was a cross-sectional study of patients with ICH in the Get With The Guidelines-Stroke registry, between 2011 and 2021. Patients transferred to another hospital, those who died during hospitalization, and those with missing information on discharge medications were excluded. The study exposure was the proportion of patients who were prescribed antithrombotic or statin medications. We first ascertained the proportion of patients prescribed antithrombotic and lipid-lowering medications at discharge overall and across strata defined by pre-ICH use and history of previous ischemic vascular disease or atrial fibrillation. We then studied factors associated with the discharge prescription of these medications after ICH, using multiple logistic regressions. In the final cohort, 50 416 (10.4%) of 486 586 patients with ICH were prescribed antiplatelet medications, 173 322 (35.1%) of 493 491 patients with ICH were prescribed statins, and 27 085 (5.4%) of 486 585 patients with ICH were prescribed anticoagulation therapy at discharge. The proportion of patients with antiplatelet therapy was 16.6% with pre-ICH use and 15.6% in those with previous ischemic vascular disease. Statins were prescribed to 41.1% and 43.7% of patients on previous lipid-lowering therapy and ischemic vascular disease, respectively. Anticoagulation therapy was restarted in 11.1% of patients. In logistic regression analysis, factors associated with higher use of antithrombotic or statin therapies after ICH were younger age, male sex, pre-ICH medication use, previous ischemic vascular disease, atrial fibrillation, lower admission National Institutes of Health Stroke Scale, longer length of stay, and favorable discharge outcome. Few patients with ICH are prescribed antithrombotic or statin therapies at hospital discharge. Given the emerging association between ICH and future major cardiovascular events, trials examining the net benefit of antiplatelet and lipid-lowering therapy after ICH are warranted.

FRI107 Ketogenic Diet Prevents Development Of Atherosclerotic Plaques In Apolipoprotein E Knockout Mice

Abstract Disclosure: V. Marzolla: None. A. Armani: None. C. Mammi: None. S. Gorini: None. E. Camajani: None. M. Caprio: None. Higher aldosterone (aldo) levels are associated with increased risk of cardiovascular ischemic events and mortality. It has been demonstrated that aldo accelerates the development of atherosclerosis in apolipoprotein E knockout mice (ApoE KO). Ketogenic diet (KD) positively impacts several cardiovascular risk factors, yet its effect on atherosclerosis is elusive. We hypothesize that KD protects from development of atherosclerotic plaques in ApoE KO mice, a murine model of atherosclerosis. Eight-week-old male ApoE KO mice were fed a KD (90,5% Kcal from fat, 0.4% Kcal from carbohydrate, 9.1% Kcal from protein) or a moderate high fat die (HFD) (42% Kcal from fat, 42.7% Kcal from carbohydrate, 15.2% Kcal from protein) and treated with aldosterone (aldo, 6 μg/mouse per day) or vehicle through osmotic mini-pumps. Cholesterol content was comparable in KD and HFD. After 4 weeks of treatment, in all experimental groups, intraperitoneal glucose tolerance test was performed, and peripheral blood samples were collected. We analysed cryosections of embedded aortic root to quantify the atherosclerotic plaque size, lipid and collagen content. We assessed vascular inflammation in speciments of thoracic aorta by analysing pro-inflammatory (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) and anti-inflammatory (Arg-1, RETNLA, CCL5) genes. In ApoE KO mice treated with aldo, KD determined a significant improvement in glucose tolerance, compared to mice fed a HFD, without any significant effect on body weight. Beta-hydroxybutyrate levels were always significantly higher in KD-mice than in AD-mice, confirming nutritional ketosis in KD-mice. Analysis of aortic root showed that aldo treatment determined a significant increase in atherosclerotic plaque size and lipid content in HFD-mice. Such effects were significantly reduced in KD-mice, suggesting a favorable impact of ketosis in preventing atherosclerosis development. Plaque fibrosis did not differ among treatment groups. Finally, we observed a significant reduction in vascular inflammatory markers in KD-mice, when compared to HFD-mice. In particular, KD determined a significant reduction in gene expression of pro-inflammatory markers (ICAM-1, VCAM-1, IL-6, TNF-α, MCP-1) with the concomitant up-regulation of anti-inflammatory markers (Arg-1, RETNLA, CCL5), compared to HFD. The study suggests KD as a potential non-pharmacological approach to prevent the development of atherosclerotic disease in subjects with high cardiovascular risk. Presentation: Friday, June 16, 2023

Clinical characteristics and outcomes of patients with chronic systemic inflammatory disease in acute myocardial infarction.

Chronic systemic inflammatory diseases (CSIDs) such as rheumatoid arthritis (RA) are reportedly associated with an increased risk of ischemic cardiovascular events including acute myocardial infarction (MI). However, data are limited on clinical characteristics and ischemic and bleeding outcomes after acute MI in patients with CSIDs. This bi-center registry included a total of 1001 patients with acute MI undergoing percutaneous coronary intervention. CSIDs included inflammatory rheumatological conditions (RA, systemic lupus erythematosus, vasculitis, etc.) and organ-specific diseases (chronic hepatitis, psoriasis, inflammatory bowel disease, etc.). The primary endpoint was net adverse clinical events (NACE), a composite of ischemic (all-cause death, MI, and ischemic stroke) and major bleeding (Bleeding Academic Research Consortium type 3 or 5) events, during hospitalization and after discharge. Of the 1001 patients, 58 (5.8%) had CSIDs. The proportion of women was higher in patients with CSIDs than those without (37.9% vs. 22.1%, p = 0.009). During the hospitalization, no significant differences in the primary endpoint of NACE were observed between patients with and without CSIDs (10.3% vs. 12.7%, p = 0.84). During the median follow-up of 42.6 months after discharge, patients with CSIDs had a higher risk of NACE (22.5% vs. 10.1%, p = 0.01) than those without, mainly driven by an increased risk of ischemic events (18.4% vs. 8.4%, p = 0.03). A small but significant proportion of patients with acute MI (5.8%) had CSIDs. While the incidence of in-hospital events was similar, patients with CSIDs had worse outcomes after discharge, suggesting that further clinical investigations and therapeutic approaches are needed in this patient subset.

Cost-Effectiveness of Icosapent Ethyl (IPE) for the Reduction of the Risk of Ischemic Cardiovascular Events in Canada.

Despite the use of statins, many patients with cardiovascular disease (CVD) have persistent residual risk. In a large Phase III trial (REDUCE-IT), icosapent ethyl (IPE) was shown to reduce the first occurrence of the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or hospitalization for unstable angina. We conducted a cost-utility analysis comparing IPE to placebo in statin-treated patients with elevated triglycerides, from a publicly funded, Canadian healthcare payer perspective, using a time-dependent Markov transition model over a 20-year time horizon. We obtained efficacy and safety data from REDUCE-IT, and costs and utilities from provincial formularies and databases, manufacturer sources, and Canadian literature sources. In the probabilistic base-case analysis, IPE was associated with an incremental cost of $12,523 and an estimated 0.29 more quality-adjusted life years (QALYs), corresponding to an incremental cost-effectiveness ratio (ICER) of $42,797/QALY gained. At a willingness-to-pay of $50,000 and $100,000/QALY gained, there is a probability of 70.4% and 98.8%, respectively, that IPE is a cost-effective strategy over placebo. The deterministic model yielded similar results. In the deterministic sensitivity analyses, the ICER varied between $31,823-$70,427/QALY gained. Scenario analyses revealed that extending the timeframe of the model to a lifetime horizon resulted in an ICER of $32,925/QALY gained. IPE represents an important new treatment for the reduction of ischemic CV events in statin-treated patients with elevated triglycerides. Based on the clinical trial evidence, we found that IPE could be a cost-effective strategy for treating these patients in Canada.

Hypertensive disorders in pregnancy increase subsequent risk of ischaemic cardiovascular events: genetic evidence from a Mendelian randomisation study

Abstract Background Hypertensive disorders in pregnancy are major causes of maternal and foetal morbidity and have also been associated with long-term maternal risk of cardiovascular diseases. Whilst many retrospective and prospective cohort studies have explored this relationship, it is difficult to make causal inferences from observational studies due to potential residual confounding and bias. Leveraging genetic data predisposing to exposures and outcomes in instrumental variable analysis, Mendelian randomisation (MR) can provide valuable information for causal inference. The aim of this study is to use MR to investigate the relationship between hypertensive disorders in pregnancy and cardiovascular diseases. Methods Uncorrelated single nucleotide polymorphisms (SNPs) were selected as instrumental variables from the FinnGen consortium summary statistics for the exposures of any hypertensive disorder in pregnancy, and its two subgroups of gestational hypertension, and pre-eclampsia or eclampsia. Genetic association estimates for outcomes were extracted from GWAS studies of 122,733 for coronary artery disease, 34,217 cases for ischaemic stroke, 47,309 cases for heart failure and 60,620 cases for atrial fibrillation. All studies included patients predominantly of European ancestry. Primary analysis was conducted using inverse-variance weighted MR. Results Hypertensive disorders in pregnancy were associated with increased risk of coronary artery disease (odds ratio (OR) 1.24; 95% confidence interval (CI) 1.08–1.43; p=0.002); and this association was evident for both gestational hypertension (OR= 1.08; 95% CI: 1.00–1.17; p=0.040) and pre- or eclampsia (OR=1.06; 95% CI: 1.01–1.12; p=0.030). Hypertensive disorders in pregnancy were also associated with increased risk of ischaemic stroke (OR=1.27; 95% CI: 1.12–1.44; p=2.87x10–4). Neither gestational hypertension nor pre-eclampsia were independently associated with increased risk of ischaemic stroke, though effect estimates were consistent in direction. No associations were noted between the three hypertensive disorders in pregnancy and the outcomes of heart failure or atrial fibrillation. Conclusions Our findings provide genetic evidence that supports a likely causal association between hypertension in pregnancy and increased risk of coronary artery disease and stroke. This is consistent with observational evidence and supports the classification of hypertensive disorders in pregnancy as risk factors for cardiovascular disease. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council GEPSI 946647 for EAWSBritish Heart Foundation RG/16/3/32175 for FSN

Long-term Effects of P2Y12 Inhibitor Monotherapy After Percutaneous Coronary Intervention

Although P2Y12 inhibitor monotherapy after a minimum period of dual antiplatelet therapy (DAPT) is a well-known way to reduce the risk of bleeding after percutaneous coronary intervention (PCI), data comparing long-term clinical outcomes between P2Y12 inhibitor monotherapy and extended DAPT in patients undergoing PCI have been unavailable. To identify the long-term safety and efficacy of P2Y12 inhibitor monotherapy following 3 months of DAPT after PCI. The Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy and Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-CHOICE) trial was an open-label, noninferiority, randomized clinical trial, enrolling patients who underwent PCI with drug-eluting stent at 33 hospitals in Korea from March 2014 through July 2017. Clinical follow-up was extended to 3 years and completed in August 2020. Patients were randomly assigned to either P2Y12 inhibitor monotherapy after 3 months of DAPT or DAPT for 12 months or longer. The primary end point was major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) at 3 years. The secondary end points included the components of the primary end point, bleeding (defined as Bleeding Academic Research Consortium [BARC] types 2-5), and major bleeding (BARC types 3-5). In total, 2993 patients were randomly assigned to receive P2Y12 inhibitor monotherapy after 3 months of DAPT (1495 patients [50%]; mean [SD] age, 64.6 [10.7] years; 1087 [72.7%] male) or prolonged DAPT (1498 patients [50%]; mean [SD] age, 64.6 [10.7] years; 1111 [74.2%] male) after PCI. At 3 years, the primary end point occurred in 87 individuals (6.3%) in the P2Y12 inhibitor monotherapy group and 83 (6.1%) in the prolonged DAPT group (hazard ratio [HR], 1.06 [95% CI, 0.79-1.44]; P = .69). P2Y12 inhibitor monotherapy significantly reduced the risk of bleeding (BARC types 2-5: 112 [3.2%] vs 44 [8.2%]; HR, 0.39 [95% CI, 0.28-0.55]; P < .001) and major bleeding (BARC types 3-5; 17 [1.2%] vs 31 [2.4%]; HR, 0.56 [95% CI, 0.31-0.99]; P = .048), compared with prolonged DAPT. The landmark analyses between 3 months and 3 years and per-protocol analyses showed consistent results. Among patients who underwent PCI and completed 3-month DAPT, P2Y12 inhibitor monotherapy was associated with a lower risk of clinically relevant major bleeding than prolonged DAPT. Although the 3-year risk of ischemic cardiovascular events was comparable between the 2 groups, this result should be interpreted with caution owing to the limited number of events and sample size. ClinicalTrials.gov Identifier: NCT02079194.

FC059: Cardiovascular Outcomes in Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis in Denmark 1996–2018

Abstract BACKGROUND AND AIMS Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of autoimmune systemic inflammatory diseases, with cardiovascular disease being the leading cause of death. However, large-scale real-world data on the risk of long-term cardiovascular outcomes associated with AAV are limited. Therefore, to understand, screen and optimize prevention of cardiovascular disease in AAV patients, we investigated the risk of long-term ischemic cardiovascular events, including ischemic heart disease, coronary angiogram (CAG), percutaneous coronary intervention (PCI) and ventricular arrhythmia/use of implantable cardioverter-defibrillator (ICD) devices. Secondary outcomes included heart failure (HF), atrial fibrillation (AF), stroke, venous thrombotic events and cardiac arrest. METHOD We included all incident patients with AAV diagnosed during 1996–2018. Patients were identified from the Danish nationwide healthcare registries by use of a recently validated method (positive predictive value of 97%) [1] comprising at least two consecutive hospital encounters registered as either polyangiitis with granulomatosis or microscopic polyangiitis (International Classification of Diseases, 10th Edition [ICD-10]: DM31.3 and DM31.7). Patients with AAV were matched 1:3 with controls from the general population on age and gender. We computed adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for each cardiovascular outcome, with all-cause mortality accounted for as a competing risk. G-computation of HRs was performed to estimate 5-year absolute risks standardized to the distribution of risk factors in the population. RESULTS A total of 2306 AAV patients [median age: 62.9 years (25th–75th percentile: 50.9–72.0 years), 52.6% male gender] were matched with 6918 controls. Median study follow-up was 9.5 years (25th–75th percentile: 5.3–15.8 years). Compared with controls, AAV patients had a higher rate of ischemic heart disease [HR 1.67 (95% CI 1.45–1.95)], myocardial infarction [HR 1.43 (95% CI 1.11–1.83)], CAG [HR 1.51 (95% CI 1.27–1.80)], PCI [HR 1.42 (95% CI 1.11–1.88)] and ventricular arrhythmia/ICD implantation [HR 2.03 (95% CI 1.17–3.55)]. Secondarily, AAV patients also had an increased rate of additional adverse cardiovascular events: HF [HR 1.77 (95% CI 1.48–2.11)], deep vein thrombosis [HR 2.89 (95% CI 2.24–3.72)], pulmonary embolism [HR 3.59 (95% CI 2.74–4.72)], AF [HR 1.73 (95% CI 1.51–1.98)], ischemic stroke [HR 1.34 (95% CI 1.12–1.61)] and in-hospital cardiac arrest [HR 1.97 (95% CI 1.29–2.99)]. AAV patients had a significantly increased standardized 5-year absolute risk of all outcomes except for MI, PCI and ventricular arrhythmia/ICD implantations compared with controls. CONCLUSION In this large nationwide registry-based follow-up study, AAV patients had a higher risk of ischemic cardiovascular events and were more likely to require revascularization therapy compared with matched control subjects. Moreover, AAV patients had a higher risk of HF, atrial- and ventricular arrhythmias as well as venous thrombotic events and ischemic stroke when compared with matched control subjects.

The cardiovascular effects and safety of colchicine

Colchicine is an alkaloid obtained from the bulb and seed of the Crocus (Colchicum autumnale L. (Liliaceae), Autumn Crocus) plant with a history of 2000 years and is currently prescribed for the treatment of rheumatic diseases. In 2015, the European Society of Cardiology supported and recommended colchicine as a first-choice treatment agent that can be added to traditional anti-inflammatory treatments to improve response to treatment, increase remission rates and reduce relapses in acute and recurrent pericarditis in the diagnosis and treatment guidelines of pericardial diseases. In addition, the use of colchicine in the Secondary Prevention of Atherosclerosis is recommended with evidence level A in the European Society of Cardiology Guidelines published in 2021. It was concluded that colchicine is a safe and effective treatment modality to prevent AF recurrence after catheter ablation. It has been noted that colchicine, used secondary to the currently used preventive drugs against CHD, has lower rates of cardiovascular death, MI, stroke, or emergency hospitalization due to angina requiring coronary revascularization, and the risk of acute cardiovascular events compared to placebo. In addition, it has been reported that the use of colchicine in patients with MI reduces the risk of ischemic cardiovascular events. Colchicine is an effective and safe option as a first-choice treatment agent that can be added to conventional anti-inflammatory treatments in patients with recurrent cardiovascular events despite optimal medical therapy and in the secondary prevention of atherosclerotic cardiovascular diseases where other risk factors cannot be adequately controlled.

Fractional Flow Reserve to Guide Treatment of Patients With Multivessel Coronary Artery Disease

BackgroundThere is limited evidence that fractional flow reserve (FFR) is effective in guiding therapeutic strategy in multivessel coronary artery disease (CAD) beyond prespecified percutaneous coronary intervention or coronary graft surgery candidates. ObjectivesThe FUTURE (FUnctional Testing Underlying coronary REvascularization) trial aimed to evaluate whether a treatment strategy based on FFR was superior to a traditional strategy without FFR in the treatment of multivessel CAD. MethodsThe FUTURE trial is a prospective, randomized, open-label superiority trial. Multivessel CAD candidates were randomly assigned (1:1) to treatment strategy based on FFR in all stenotic (≥50%) coronary arteries or to a traditional strategy without FFR. In the FFR group, revascularization (percutaneous coronary intervention or surgery) was indicated for FFR ≤0.80 lesions. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events at 1 year. ResultsThe trial was stopped prematurely by the data safety and monitoring board after a safety analysis and 927 patients were enrolled. At 1-year follow-up, by intention to treat, there were no significant differences in major adverse cardiac or cerebrovascular events rates between groups (14.6% in the FFR group vs 14.4% in the control group; hazard ratio: 0.97; 95% confidence interval: 0.69-1.36; P = 0.85). The difference in all-cause mortality was nonsignificant, 3.7% in the FFR group versus 1.5% in the control group (hazard ratio: 2.34; 95% confidence interval: 0.97-5.18; P = 0.06), and this was confirmed with a 24 months’ extended follow-up. FFR significantly reduced the proportion of revascularized patients, with more patients referred to exclusively medical treatment (P = 0.02). ConclusionsIn patients with multivessel CAD, we did not find evidence that an FFR-guided treatment strategy reduced the risk of ischemic cardiovascular events or death at 1-year follow-up. (Functional Testing Underlying Coronary Revascularisation; NCT01881555)

PCV55 Cost-Effectiveness of Icosapent Ethyl (IPE) for the Reduction of the Risk of Ischemic Cardiovascular Events in Canada.

PCV55 Cost-Effectiveness of Icosapent Ethyl (IPE) for the Reduction of the Risk of Ischemic Cardiovascular Events in Canada.

Questions and Answers on Practical Thrombotic Issues in SARS-CoV-2 Infection: A Guidance Document from the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology.

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk–benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

Low-dose colchicine in patients treated with percutaneous coronary interventions for myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT)

Abstract Background/Introduction Experimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent anti-inflammatory medication that was shown to significantly lower the risk of ischemic cardiovascular events compared to placebo among subjects with a recent myocardial infarction (MI) in the main COLCOT trial. Patients treated with percutaneous coronary intervention (PCI) after MI represent an important subpopulation that may derive particularly important benefits from colchicine. Purpose To assess the impact of low-dose colchicine on cardiovascular events in subjects treated with PCI for an index MI. Methods We performed an international, randomized, double-blind trial involving patients recruited within 30 days after a MI (main COLCOT trial; n=4745). In this trial, patients were eligible if they had a confirmed myocardial infarction within 30 days before enrollment, had completed any planned percutaneous revascularization procedures and were treated medically according to national guidelines that included the intensive use of statins. Subjects were randomly assigned to receive oral colchicine 0.5 mg once daily or matching placebo. Among the entire COLCOT study population, 4408 subjects were treated with PCI for the index MI and form the COLCOT-PCI study population. We analyzed the time to the first positively adjudicated event of the composite of CV death, resuscitated cardiac arrest, acute MI, stroke or urgent hospitalization for angina requiring coronary revascularization (primary endpoint). Results In the main COLCOT trial, low-dose colchicine led to a significantly lower risk of the primary endpoint (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; p=0.02). In the COLCOT-PCI subpopulation, low-dose colchicine was associated with a large reduction in the risk of a primary endpoint event (hazard ratio, 0.72; 95% confidence interval [CI], 0.57 to 0.92; p=0.008). The hazard ratios for individual components of the composite primary endpoint were 0.71 (95% CI, 0.37 to 1.33) for death from cardiovascular causes, 0.84 (95% CI, 0.26 to 2.75) for resuscitated cardiac arrest, 0.90 (95% CI, 0.66 to 1.21) for myocardial infarction, 0.25 (95% CI, 0.08 to 0.76) for stroke, and 0.42 (95% CI, 0.25 to 0.71) for urgent hospitalization for angina requiring coronary revascularization. Conclusion Low-dose colchicine markedly reduces the risk of ischemic cardiovascular events in patients treated with PCI for their index MI. Funding Acknowledgement Type of funding source: Other. Main funding source(s): Government of Quebec and Canadian Institutes of Health Research

International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial and the appropriateness of revascularization.

The recently published ISCHEMIA trial which is a prospective randomized multi-centre trial has concluded that there was no evidence that an initial invasive strategy of revascularisation in patients with stable angina reduced the risk of ischaemic cardiovascular events or death from any cause. The trial has confirmed that patients with stable angina do not greatly benefit from revascularisation and optimal medical treatment (OMT) is an acceptable alternative. The trial has also confirmed that in patients with stable angina and end-stage renal impairment, OMT is once again an equally effective initial strategy. While the ISCHEMIA trial is one of the most rigorously and meticulously conducted trial, exclusion of symptomatic patients, recruitment of patients who are not known to derive significant benefit from revascularisation and those who were at low risk of clinical events, along with a short follow-up period, may all have contributed to the lack of difference seen between the groups. The fact that the ISCHEMIA trial does not represent the entire cohort of real-life patients requiring revascularisation should be borne in mind, and care should be taken in extrapolating these results to the wider group of patients requiring revascularisation for coronary artery disease.

Initial Invasive or Conservative Strategy for Stable Coronary Disease

BackgroundAmong patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.MethodsWe randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.ResultsOver a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, −1.8 percentage points; 95% CI, −4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).ConclusionsAmong patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.)

Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction

BackgroundExperimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis.MethodsWe performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed.ResultsA total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P=0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P=0.03).ConclusionsAmong patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.)

Anti-inflammatory therapy for secondary prevention after MI.

In patients with a recent myocardial infarction, anti-inflammatory therapy with low-dose colchicine reduces the risk of ischaemic cardiovascular events compared with placebo.

Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes. ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11). After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes. Sanofi and Regeneron Pharmaceuticals.

Can a PCSK9 Inhibitor Prevent Events After Acute Coronary Syndrome

Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce the risk for ischemic cardiovascular events in patients with stable

Incidence, timing, and type of first and recurrent ischemic events in patients with and without peripheral artery disease after an acute coronary syndrome

BackgroundPatients with peripheral artery disease (PAD) are known to have an increased risk of ischemic cardiovascular events. However, the influence of concomitant PAD on first and subsequent recurrent ischemic events after an acute coronary syndrome (ACS) remains poorly characterized. MethodsWe analyzed the combined data set from 4 randomized trials (PLATO, APPRAISE-2, TRA-CER, and TRILOGY ACS) in ACS for a follow-up length of 1 year. Using multivariable regression, we examined the association between PAD and major adverse cardiovascular events, a composite of cardiovascular death, myocardial infarction, and stroke. Among patients with a nonfatal first event, we evaluated the incidence and type of a second recurrent event. ResultsA total of 4,098 of 48,094 (8.5%) post-ACS patients had a history of PAD. The unadjusted frequency of major adverse cardiovascular events was 2-fold higher in patients with PAD (14.3% vs 7.5%) over a median (25th-75th) follow-up of 353 (223-365) days with an adjusted hazard ratio of 1.63 (95% CI: 1.48-1.78; P < .001). The frequency of recurrent ischemic events among those patients with a first, nonfatal event was higher among those with PAD (40.0% vs 27.7%). The relative frequency of each event type (cardiovascular death, noncardiovascular death, myocardial infarction, or stroke) within first and subsequent ischemic events was similar regardless of PAD status at baseline. ConclusionsPatients with PAD have a significantly higher risk of first and recurrent ischemic events in the post-ACS setting. These findings highlight the opportunity for improved treatments in patients with PAD who experience an ACS.