Net clinical benefit of extended dual pathway inhibition according to Baseline risk in patients with chronic coronary syndrome: a COMPASS substudy.

AIMS: Guidelines recommend extended dual pathway inhibition (DPI) with aspirin and rivaroxaban in patients with chronic coronary syndrome (CCS) at high ischemic risk. The CHADS-P2A2RC score improves risk prediction and enables antithrombotic treatment allocation in these patients. This study evaluated the net clinical benefit of DPI treatment according to baseline risk as classified by the CHADS-P2A2RC score in patients with CCS included in the COMPASS trial. METHODS: COMPASS patients with CCS (n = 14 670), randomized to aspirin alone or DPI, were stratified according to cardiovascular risk using the CHADS-P2A2RC score. Endpoints were major adverse cardiovascular events (MACE), all-cause death, fatal/critical organ bleeding, and composite adverse events (MACE and bleeding). Net clinical benefit was the 30-month risk difference of MACE and bleeding. RESULTS: 30-month incidences of MACE (7.9% vs 3.9%, HR 2.01, 95% CI 1.83-2.18) and fatal/critical organ bleeding (1.2% vs 0.8%, HR 1.49 [1.06-1.92]) were higher in high-risk (CHADS-P2A2RC ≥ 4) than low/moderate-risk (CHADS-P2A2RC < 4) patients. DPI reduced MACE (low/moderate-risk: HR 0.62 [0.47-0.82]; high-risk: HR 0.82 [0.68-0.99], p for interaction 0.09) and all-cause death (low/moderate-risk: HR 0.65 [0.46-0.91]; high-risk: HR 0.81 [0.65-1.00], p for interaction 0.29), without substantially increasing fatal/critical organ bleeding (low/moderate-risk: HR 1.35 [0.72-2.53]; high-risk: HR 1.18 [0.73-1.90], p for interaction 0.73). DPI provided net clinical benefit of similar magnitude in low/moderate-risk (-1.81% [-3.00 to -0.62]) and high-risk CCS patients (-1.96% [-3.60 to -0.33]). CONCLUSIONS: As classified by the CHADS-P2A2RC score, low/moderate- and high-risk patients with CCS derived similar net clinical benefit and reduction in all-cause death from DPI treatment.

Antithrombotic treatment for chronic coronary syndrome: Evidence and future perspectives.

Background The clinical presentation of coronary artery disease can range from asymptomatic, through stable disease in the form of chronic coronary syndrome, to acute coronary syndrome. Chronic coronary syndrome is a frequent condition, and secondary prevention of ischaemic events is essential. Summary Antithrombotic therapy is a key component of secondary prevention strategies, and it may vary in type and intensity depending on patient characteristics, comorbidities, and revascularisation modalities. Dual antiplatelet therapy is the default strategy in patients with chronic coronary syndrome and recent coronary stent implantation, while antiplatelet monotherapy is commonly prescribed for long-term prevention of cardiovascular events. Oral anticoagulation, in combination with antiplatelet therapy or alone, is used in patients with e.g., concomitant atrial fibrillation or venous thromboembolism. Key messages This review provides an overview of antithrombotic treatment strategies in patients with chronic coronary syndrome. Key messages from current guidelines are conveyed, and we provide future perspectives on long-term antithrombotic strategies.

Antithrombotic treatment beyond 1 year after percutaneous coronary intervention in patients with atrial fibrillation.

AIMS: Beyond 1 year after percutaneous coronary intervention (PCI), guidelines recommend anticoagulant monotherapy in patients with atrial fibrillation (AF) rather than dual therapy with an anticoagulant and an antiplatelet drug. The risks and benefits of this strategy, however, remain uncertain. We examined hospitalization for bleeding and ischaemic risk beyond 1 year after PCI in patients with AF treated with monotherapy vs. dual therapy. Furthermore, among patients treated with monotherapy, we compared direct oral anticoagulant (DOAC) therapy and vitamin K antagonist (VKA) therapy. METHODS AND RESULTS: We included all patients with AF undergoing first-time PCI between 2003 and 2017 from the Western Denmark Heart Registry and followed them for up to 4 years. Follow-up started 15 months after PCI to enable assessment of medical treatment after 12 months. Using a Cox regression model, we computed weighted hazard ratios (HRw) of hospitalization for bleeding and major adverse cardiac events (MACEs). Analyses comparing monotherapy vs. dual therapy included 3331 patients, and analyses comparing DOAC vs. VKA monotherapy included 1275 patients. Risks of hospitalization for bleeding [HRw 0.90, 95% confidence interval (CI) 0.75-1.09] and MACE (HRw 1.04, 95% CI 0.90-1.19) were similar with monotherapy and dual therapy. Similarly, risks of hospitalization for bleeding (HRw 1.27, 95% CI 0.84-1.92) and MACE (HRw 1.15, 95% CI 0.87-1.50) were equal with DOAC and VKA monotherapy. CONCLUSION: Our results support long-term OAC monotherapy beyond 1 year after PCI in patients with atrial fibrillation and suggest that DOAC monotherapy is as safe and effective as VKA monotherapy.

Effectiveness and Safety of Ticagrelor Implementation in Patients with Acute Coronary Syndrome undergoing Percutaneous Coronary Intervention: A Cohort Study in Western Denmark.

BACKGROUND: Ticagrelor was introduced in Denmark in 2011 after randomised data showed its superiority over clopidogrel for patients with acute coronary syndrome (ACS). We assessed the effectiveness and safety of ticagrelor implementation in ACS patients undergoing percutaneous coronary intervention (PCI). METHODS: We identified PCI-treated ACS patients in Western Denmark who redeemed a P2Y12 inhibitor prescription within 14 days. Using Danish health registries, 1-year outcomes were compared before (2007-2010) and after (2012-2015) introduction of ticagrelor. Outcomes were MACE (death, myocardial infarction, and ischaemic stroke) and hospitalisation for bleeding. Inverse probability of treatment weights were used to estimate weighted incidence rate ratios (wIRRs). FINDINGS: We included 14,450 patients; 7,102 were treated in the earlier time period (99·9% clopidogrel) and 7,348 in the later time period (87·8% ticagrelor). Ticagrelor implementation was not associated with a clinically relevant difference in 1-year risk of MACE with 413 events in the ticagrelor period vs. 424 events in the clopidogrel period (cumulative incidence percentage [CIP] 5·6% vs. 6·0%; wIRR 1·06, 95% CI 0·92-1·22). The 1-year risk of bleeding was also similar between groups with 335 bleedings requiring hospitalisation in the ticagrelor period vs. 309 events in the clopidogrel period (CIP 4·6% vs. 4·4%; wIRR 1·05, 95% CI 0·89-1·23). Results were robust in patients above and below 70 years of age. INTERPRETATION: Implementation of ticagrelor was not associated with changes in risks of ischaemic or bleeding events in Danish PCI-treated ACS patients.

Thirteen-year trends in cardiovascular risk in men and women with chronic coronary syndrome.

AIMS: To examine combined and sex-specific temporal changes in risks of adverse cardiovascular events and coronary revascularization in patients with chronic coronary syndrome undergoing coronary angiography. METHODS AND RESULTS: We included all patients with stable angina pectoris and coronary artery disease examined by coronary angiography in Western Denmark from 2004 to 2016. Patients were stratified by examination year interval: 2004-2006, 2007-2009, 2010-2012, and 2013-2016. Outcomes were 2-year risk of myocardial infarction, ischaemic stroke, cardiac death, and all-cause death estimated by adjusted incidence rate ratios using patients examined in 2004-2006 as reference. A total of 29 471 patients were included, of whom 70% were men. The 2-year risk of myocardial infarction [2.8% vs. 1.9%, adjusted incidence rate ratio 0.65, 95% confidence interval (CI) 0.53-0.81], ischaemic stroke (1.8% vs. 1.1%, adjusted incidence rate ratio 0.48, 95% CI 0.37-0.64), cardiac death (2.1% vs. 0.9%, adjusted incidence rate ratio 0.38, 95% CI 0.29-0.51), and all-cause death (5.0% vs. 3.6%, adjusted incidence rate ratio 0.65, 95% CI 0.55-0.76) decreased from the first examination interval (2004-2006) to the last examination interval (2013-2016). Coronary revascularizations also decreased (percutaneous coronary intervention: 51.6% vs. 42.5%; coronary artery bypass grafting: 24.6% vs. 17.5%). Risk reductions were observed in both men and women, however, women had a lower absolute risk. CONCLUSION: The risk for adverse cardiovascular events decreased substantially in both men and women with chronic coronary syndrome from 2004 to 2016. These results most likely reflect the cumulative effect of improvements in the management of chronic coronary artery disease.

Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score.

AIMS: According to the 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndromes (CCS), adding a P2Y12 inhibitor or rivaroxaban to aspirin should be considered in high-risk patients. We estimated the proportion of patients eligible for treatment with the ESC criteria and examined if a recently validated risk score (CHADS-P2A2RC) could improve risk prediction. METHODS AND RESULTS: We included 61 338 CCS patients undergoing first-time coronary angiography in Western Denmark (2003-16) and classified them according to the ESC criteria and the CHADS-P2A2RC score. The ESC criteria identified 33.9% as high risk, 53.3% as moderate risk, and 12.8% as low risk. The CHADS-P2A2RC score identified 24.9% as high risk (≥4 points), 48.1% as moderate risk (2-3 points), and 27.0% as low risk (≤1 points). Major adverse cardiovascular events per 100 person-years were 4.8 [95% confidence interval (CI) 4.6-5.0] in patients considered high risk with both schemes, 2.1 (95% CI 2.0-2.2) in patients considered high risk with the ESC but low-to-moderate risk with the CHADS-P2A2RC criteria, 3.8 (95% CI 3.6-4.1) in patients considered low-to-moderate risk with the ESC but high risk with the CHADS-P2A2RC criteria, and 1.5 (95% CI 1.5-1.6) in patients considered low-to-moderate risk with both schemes. The CHADS-P2A2RC score enabled correct downward risk reclassification of 5161 patients (8%) without events, yielding an improved specificity of 9.7%, a loss of sensitivity of 4.4%, and an overall net reclassification index of 0.053. CONCLUSION: Based on the 2019 ESC guidelines, dual antithrombotic treatment should be considered in one-third of CCS patients. The CHADS-P2A2RC score improved risk classification and may particularly identify low-risk patients with limited benefit from treatment.

CHA2 DS2 -VASc impact on risk following percutaneous coronary intervention in atrial fibrillation.

AIMS: In 2010, the European Society of Cardiology Guidelines on atrial fibrillation (AF) introduced the CHA2 DS2 -VASc score to guide initiation of oral anticoagulation. In patients with AF undergoing percutaneous coronary intervention (PCI), triple therapy with oral anticoagulation and dual antiplatelet therapy was recommended to reduce ischaemic risk. We examined how the CHA2 DS2 -VASc score impacted oral anticoagulation use and risks of ischaemic and hospitalized bleeding events in patients with AF undergoing PCI. METHODS: We included 6,014 patients with AF undergoing first-time PCI in Western Denmark between 2003 and 2017. We divided patients into four groups based on year of PCI and estimated 1-year risks of major adverse cardiac events (MACE) and hospitalization for bleeding. RESULTS: The proportion of oral anticoagulation users was 48% in 2003-2006 and 49% in 2006-2010. Following the CHA2 DS2 -VASc score implementation, the proportion increased to 59% in 2011-2014 and 77% in 2015-2017. Using 2003-2006 as reference, risks of MACE were similar in 2007-2010 (adjusted relative risk [RRadj ] 0.99, 95% confidence interval [CI] 0.83-1.18) and 2011-2014 (RRadj 0.92, 95% CI 0.78-1.09), but declined by 23% in 2015-2017 (RRadj 0.77, 95% CI 0.65-0.92). Hospitalizations for bleeding did not increase despite wider use of triple therapy. CONCLUSION: Implementation of the CHA2 DS2 -VASc score in the 2010 European guidelines on AF was associated with an increased utilization of oral anticoagulation and triple therapy among AF patients undergoing PCI. These changes were associated with a gradual decline in the risk of MACE, while the risk of hospitalized bleeding remained unchanged.

Insulin-treated versus noninsulin-treated diabetes and risk of ischemic stroke in patients with atrial fibrillation.

BACKGROUND: Diabetes mellitus (DM) and atrial fibrillation (AF) are known risk factors for ischemic stroke. Recent data, however, suggest that only insulin-treated DM is a risk factor for ischemic stroke among AF patients. OBJECTIVES: To evaluate the risk of stroke in patients with insulin and noninsulin treated DM. METHODS: We included AF patients undergoing coronary angiography in Western Denmark between 2003 and 2016. Patients were categorized as 1) insulin treated DM, 2) noninsulin treated DM, or 3) nonDM patients. The main outcome was ischemic stroke >30 days after CAG. RESULTS: AF patients (n = 21,223) were included, of whom 17,181 (81%) did not have DM, 2890 (14%) had noninsulin-treated DM and 1152 (5%) had insulin-treated DM. Median follow-up was 5.3 years. Ischemic stroke rates were 0.83 per 100 person-years for nonDM, 1.19 for noninsulin-treated DM and 1.40 for insulin-treated DM. Insulin-treated DM (adjusted hazard ratio (HRadj) 1.48, 95% CI 1.15-1.91) and noninsulin-treated DM patients (HRadj 1.30, 95% CI 1.09-1.54) had higher risks of ischemic stroke than nonDM patients. There was no difference between insulin-treated DM and noninsulin-treated DM (HRadj 1.09, 95% CI 0.82-1.46). Stratification by coronary artery disease yielded comparable risk estimates. CONCLUSION: In patients with AF, DM increases the risk of ischemic stroke, regardless of treatment.

[Menorrhagia during oral anticoagulant therapy].

Menorrhagia is a common complication to oral anticoagulant therapy in premenopausal women. Clinical management of menorrhagia poses a clinical dilemma with the need of weighting bleeding risk against the risk of recurrent thrombosis. In this review, we describe the risk of menorrhagia during oral anticoagulant therapy, with emphasis on the differences between the specific anticoagulant drugs. We critically assess the treatment options for anticoagulant-associated menorrhagia, and we provide a treatment algorithm for the management of anticoagulant-associated menorrhagia.

Risk of Myocardial Infarction in Patients Without Angiographic Coronary Artery Disease Compared With the General Population.

We examined the 10-year risk of myocardial infarction (MI) and death in patients without obstructive coronary artery disease (CAD) compared with the general population. We conducted a cohort study of every patient without obstructive CAD by coronary angiography (CAG) between 2003 and 2016 in Western Denmark. Patients were matched by gender and age with individuals from the general population of Western Denmark with no history of CAD. End points were MI and death. Ten-year risk differences in cumulative incidence proportions were computed, accounting for the competing risk of death in the case of MI. Unadjusted and adjusted incidence rate ratios (aIRRs) were estimated using conditional Poisson regression. We included 46,467 patients and 234,654 individuals from the general population. Median follow-up was 7.7 years. The 10-year cumulative incidence of MI was 2.40% (95% confidence interval [CI] 2.24 to 2.57) in patients without obstructive CAD in the CAG and 2.70% (95% CI 2.62 to 2.78) in the general population, with a reduced absolute 10-year risk (risk difference -0.30%, 95% CI -0.49 to -0.12) and a reduced aIRR (aIRR 0.70, 95% CI 0.63 to 0.77). Ten-year mortality was higher in patients without obstructive CAD in the CAG (21.44%, 95% CI 20.99 to 21.89) compared with the general population (17.25%, 95% CI 17.06 to 17.44). However, mortality rates were similar after adjustment (aIRR 1.00, 95% CI 0.96 to 1.02). In conclusion, the absence of obstructive CAD according to CAG is associated with a lower risk of MI than in the general population, and similar 10-year mortality.

The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease.

BACKGROUND: The ABO locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the ABO risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants. METHODS: We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the ABO locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential. RESULTS: The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 - 1.09], p = 0.01) but not with clot lysis time (p = 0.97). The rs12936587 (p = 0.04), rs4773144 (p = 0.02), and rs501120 (p = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (p-values > 0.05). CONCLUSION: The ABO risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in ABO risk variant carriers.

Diabetes is not a risk factor for myocardial infarction in patients without coronary artery disease: A study from the Western Denmark Heart Registry.

BACKGROUND: Diabetes is considered a risk factor for myocardial infarction. However, we have previously found that diabetes was not a short-term risk factor for myocardial infarction in the absence of obstructive coronary artery disease. METHODS: We conducted a cohort study of patients undergoing coronary angiography from 2003 to 2012 and followed them by cross-linking Danish health registries. Patients were stratified according to coronary artery disease and diabetes. Endpoints included myocardial infarction, cardiac death, all-cause death and coronary revascularization. RESULTS: 86,202 patients were included in total (diabetes: n = 12,652). Median follow-up was 8.8 years. Using patients with neither coronary artery disease nor diabetes as reference (cumulative myocardial infarction incidence 2.6%), the risk of myocardial infarction was low and not substantially increased for patients with diabetes alone (3.2%; hazard ratio 1.202, 95% confidence interval 0.996-1.451), was increased for patients with coronary artery disease alone (9.3%; hazard ratio 2.75, 95% confidence interval 2.52-3.01) and was highest for patients with both coronary artery disease and diabetes (12.3%; hazard ratio 3.79, 95% confidence interval 3.43-4.20). Similar associations were observed for cardiac death and coronary revascularization. CONCLUSION: Diabetes patients without coronary artery disease by coronary angiography have a low risk of myocardial infarction, not substantially increased compared to patients with neither coronary artery disease nor diabetes. In the presence of coronary artery disease, however, diabetes increases the risk of myocardial infarction.

A Novel Model for Prediction of Thromboembolic and Cardiovascular Events in Patients Without Atrial Fibrillation.

Patients without atrial fibrillation (AF) constitute approximately 75% of patients suffering thromboembolism and major adverse cardiovascular events (MACE), but evidence supporting risk stratification in these patients is sparse. We aimed to develop a risk prediction model for identification of patients without AF at high risk of first-time thromboembolic events. We included 72,381 coronary angiography patients without AF and without previous ischemic stroke or transient ischemic attack. The cohort was randomly divided into a derivation cohort (80%, n = 57,680) and a validation cohort (20%, n = 14,701). The primary thromboembolic end point was a composite of ischemic stroke, transient ischemic attack, and systemic embolism. MACE was defined as a composite of cardiac death, myocardial infarction, and ischemic stroke. The final model was compared with 2 validated clinical risk models (CHADS2 and CHA2DS2-VASc). The risk prediction model assigned 1 point to heart failure, hypertension, diabetes mellitus, renal disease, age 65 to 74 years, active smoking, and multivessel obstructive coronary artery disease, and 2 points to age ≥75 years and peripheral artery disease. A C-index of 0.66 (95% CI 0.64 to 0.69) for prediction of the composite thromboembolic end point was found in the validation cohort, which was higher than for CHADS2 (C-index 0.63 [95% CI 0.60 to 0.67]; p < 0.001) and CHA2DS2-VASc (C-index 0.64 [95% CI 0.62 to 0.67]; p = 0.034). The model also predicted MACE (C-index 0.71 [95% CI 0.69 to 0.73]). In conclusion it is possible to identify patients without AF at high risk of first-time thromboembolic events and MACE by use of a simple clinical prediction model.

Comorbidity and risk of venous thromboembolism after hospitalization for first-time myocardial infarction: A population-based cohort study.

BACKGROUND: Myocardial infarction (MI) is a risk factor for venous thromboembolism (VTE). Although comorbidities affect MI prognosis, it is unclear whether they affect VTE risk after MI. OBJECTIVES: We examined the impact of comorbidity on VTE risk after MI. METHODS: We used nationwide population-based registries to identify first-time hospitalizations for MI and subsequent occurrence of VTE in Denmark (1995-2013). We included a comparison cohort from the general population matched 5:1 with MI patients by sex, age, and comorbidities. We computed 30-day and 1- to 12-month cumulative risks, rates, and hazard ratios of VTE. We also assessed the interaction between MI and comorbidity, defined as excess VTE risk in patients with both MI and comorbidity, by computing interaction contrasts and attributable fractions relating to the interaction. RESULTS: Thirty-day and 1- to 12-month VTE risks were 0.6% and 0.5% in the MI cohort (n = 160 338) and 0.03% and 0.3% in the comparison cohort (n = 792 384). The 30-day hazard ratio for VTE in the MI cohort was 23 (95% confidence interval, 20-27), which decreased during 1-year follow-up. Thirty days after MI, interactions between MI and comorbidity accounted for 16% and 39% of VTE rates in MI patients with low-to-moderate and high comorbidity, respectively. The interactions were driven primarily by hemiplegia and cancer. CONCLUSIONS: Thirty-day VTE risk was substantially increased after MI compared with the general population. Although the absolute VTE risk was low, comorbidity substantially increased this risk, especially hemiplegia and cancer. VTE prophylaxis might be indicated in such high-risk patients but warrants further investigation.

Diabetes Mellitus Is Associated With Increased Risk of Ischemic Stroke in Patients With and Without Coronary Artery Disease.

Background and Purpose- Diabetes mellitus (DM) and non-DM patients without coronary artery disease (CAD) have a similar low risk of myocardial infarction after coronary angiography. The risk of ischemic stroke in DM patients dependent on CAD status is less explored. We examined whether DM patients without CAD have a risk of ischemic stroke similar to that in patients with neither DM nor CAD. Methods- We conducted a cohort study of patients who underwent coronary angiography between 2004 and 2012 in Western Denmark. Patients diagnosed with previous ischemic stroke or transient ischemic attack were excluded. Patients were stratified according to the presence of DM and CAD. Follow-up started 30 days after coronary angiography. We computed event rates and adjusted incidence rate ratios using patients without DM or CAD as reference. We examined the trend between CAD extent and ischemic stroke in patients with DM. Results- A total of 81 909 patients were included. Median follow-up was 3.8 years. Patients with both DM and CAD were at the highest risk of ischemic stroke (1.32 events per 100 person-years; adjusted incidence rate ratio, 2.00 [95% CI, 1.72-2.32]). Patients with CAD alone (0.77 events per 100 person-years; adjusted incidence rate ratio, 1.27 [95% CI, 1.12-1.44]) or DM alone (0.95 events per 100 person-years; adjusted incidence rate ratio, 1.74 [95% CI, 1.42-2.15]) were at intermediate risk, whereas patients with neither DM nor CAD (0.52 events per 100 person-years) were at the lowest risk. Among patients with DM, extent of CAD was further predictive of risk (Ptrend<0.001). Conclusions- Not only CAD but also DM are associated with the risk of ischemic stroke after coronary angiography. Their combination further increases the risk of ischemic stroke depending on the extent of CAD.

[Anticoagulant therapy of patients undergoing cardioversion for atrial fibrillation].

Cardioversion of atrial fibrillation entails a risk of thromboembolic events, especially ischaemic stroke. Oral anticoagulation therapy before and after cardioversion is therefore crucial. Assessing ischaemic stroke risk and time of arrhythmia onset is important when deciding on the optimal anticoagulation strategy. For decades, vitamin K antagonists (VKA) have been the primary anticoagulant drugs used in relation to cardioversion, but non-VKA oral anticoagulants may be preferred because of their rapid onset of action and predictable anticoagulant effect without the need for monitoring.

External applicability of the COMPASS trial: the Western Denmark Heart Registry.

AIMS: In the COMPASS trial, combined aspirin and rivaroxaban treatment reduced ischaemic events in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We estimated the proportion of COMPASS eligible patients among unselected patients undergoing coronary angiography (CAG) and compared outcome rates among COMPASS eligible and non-eligible patients. METHODS AND RESULTS: We applied the COMPASS study criteria on patients undergoing CAG in Western Denmark (2004-11). Both COMPASS eligible and non-eligible patients had CAD/PAD and met no exclusion criteria, but only COMPASS eligible patients met the inclusion criteria. We assessed the COMPASS primary endpoint of cardiovascular death, ischaemic stroke, haemorrhagic stroke, or myocardial infarction (MI). We computed event rates and adjusted incidence rate ratios (aIRRs). Of 80 071 patients undergoing CAG, 27 939 did not have CAD or PAD and were not considered. Of the 52 132 patients remaining, 11 930 were COMPASS eligible. Rates of the primary endpoint were 4.8 (95% confidence interval 4.6-5.0) events per 100 person-years among COMPASS eligible patients and 2.3 (2.2-2.4) among COMPASS non-eligible patients [aIRR 1.7 (1.6-1.9)]. COMPASS eligible patients also had higher risks of cardiovascular death [aIRR 2.5 (2.1-3.0)], ischaemic stroke [aIRR 1.4 (1.2-1.6)], and MI [aIRR 1.9 (1.7-2.1)]. CONCLUSION: In this all-comers CAG cohort, 15% were eligible for combined aspirin and rivaroxaban treatment. COMPASS eligible patients had up to 2.5-fold higher rates of cardiovascular events than non-eligible patients. The higher incidence of ischaemic events in COMPASS eligible patients highlights an unmet need for additional preventive measures.

The ABO locus is associated with increased platelet aggregation in patients with stable coronary artery disease.

BACKGROUND: Genome-wide association studies of patients with coronary artery disease (CAD) suggest that several risk loci increase the risk of CAD and myocardial infarction (MI) equally. In contrast, the ABO locus is stronger associated with MI than with CAD, but the underlying mechanisms are unknown. PURPOSE: To investigate the association between the ABO risk variant and platelet activation and aggregation. Moreover, to explore the effects of other CAD-associated risk variants. METHODS: We included 879 stable CAD patients receiving low-dose aspirin. All patients were genotyped for 45 genome-wide significant CAD risk variants, including rs495828 at the ABO locus. A genetic risk score (GRS) was calculated to assess the combined risk of all genetic variants. Serum soluble P-selectin (sP-selectin) and thromboxane B2 were used as measures of platelet activation, and platelet aggregation was assessed by multiple electrode aggregometry (MEA) using arachidonic acid and collagen as agonists and VerifyNow. RESULTS: The rs495828 CAD risk allele was associated with higher MEA platelet aggregation; arachidonic acid: 14.9% (6.7-23.7%, p = 0.0002) higher AUC (Area Under aggregation Curve) per risk allele, and collagen: 13.1% (5.8%-20.9%, p = 0.0003). Conversely, sP-selectin levels were 7.5% (3.1%-11.7%, p = 0.001) lower per risk allele. Rs495828 genotypes were not associated with aggregation assessed by VerifyNow (p = 0.30) or S-thromboxane B2 levels (p = 0.98). None of the remaining variants or the GRS were associated with platelet activation or aggregation. CONCLUSIONS: The ABO risk allele was associated with increased platelet aggregation as assessed by MEA. This finding may contribute to explain the increased MI risk in ABO risk variant carriers.

Effect of remote ischaemic conditioning on platelet aggregation and platelet turnover.

Remote ischaemic conditioning (RIC) is a new beneficial treatment for patients with ST-elevation myocardial infarction. RIC may inhibit thrombus formation and, therefore, we investigated whether RIC affects platelet aggregation and turnover. 30 healthy male volunteers were subjected to intervention on day 1 (sham intervention, no aspirin), day 2 (RIC, no aspirin), and day 16 (RIC, treated 7 days with aspirin 75 mg/day). RIC was performed as four cycles of 5 min interchangeable inflation and deflation using an automated cuff. Blood samples were collected 5 min before, as well as 5 and 45 min after RIC. Platelet aggregation was measured by Multiplate® using collagen (COLtest), adenosine diphosphate (ADPtest), and arachidonic acid (ASPItest) as agonists. Platelet turnover was evaluated by flow cytometry. Serum thromboxane B2 was determined by ELISA to confirm aspirin compliance. We found no significant change in platelet aggregation at visit 1 (COLtest: p = 0.32; ADPtest: p = 0.24; ASPItest: p = 0.07), visit 2, except for ADP-induced platelet aggregation evaluated 5 min after RIC (COLtest: p = 0.39; ADPtest: p = 0.02; ASPItest: p = 0.39), or visit 3 (COLtest: p = 0.48; ADPtest: p = 0.61; ASPItest: p = 0.90). Platelet turnover was not influenced by RIC, neither on nor off aspirin (all p-values > 0.07). (1) RIC did not affect platelet aggregation in healthy young men. (2) RIC did not affect platelet turnover in healthy young men. (3) Aspirin did not influence the effect of RIC on platelet aggregation and turnover. (4) Future studies exploring the effect of RIC on platelet aggregation and turnover in patients with ischaemic heart disease are warranted.