High Atherothrombotic Risk Research Articles

Prognostic impact of intravascular imaging in percutaneous coronary intervention according to atherothrombotic risk

Abstract Background Recent randomized controlled trials support intravascular imaging-guided PCI to improve patient prognosis, however, future risk of clinical events in patient with coronary artery disease is not solely determined by lesion characteristics or how these lesions are treated. Objectives Current study investigated whether the effects of intravascular imaging in complex percutaneous coronary invention (PCI) would differ according to atherothrombotic risks. Methods This study was post-hoc analysis of the RENOVATE-COMPLEX-PCI trial that compared intravascular imaging-guided PCI with angiography-guided PCI in patients with complex coronary artery lesions. Study population was stratified according to atherothrombotic risk assessed by Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TRS-2P) (a sum of age≥75 years, diabetes mellitus, hypertension, smoking, peripheral arterial disease, stroke, coronary artery bypass grafting, heart failure, and renal dysfunction) into low-risk (TRS-2P<3) or high-risk (TRS-2P≥3) groups. The primary endpoint was target vessel failure (TVF), a composite of cardiac death, target vessel related myocardial infarction, or clinically driven target vessel revascularization. Results Among the total patients, 1,247 were low-risk and 392 were high-risk. The risk of TVF was significantly higher in the high-risk group than the low-risk group (15.5% vs. 7.2%; hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.51–3.00; P<0.001). The benefits of intravascular imaging-guided PCI over angiography-guided PCI did not differ between the low-risk group (5.6% vs. 10.4%; HR, 0.56; 95% CI, 0.36–0.86) and the high-risk group (14.1% vs. 18.5%; HR, 0.71; 95% CI, 0.41–1.24) without significant interaction (interaction P=0.496). Conclusions Although patients with high atherothrombotic risk had significantly worse clinical outcome than those with low atherothrombotic risk, the prognostic impact of intravascular imaging-guided PCI compared with angiography-guided PCI was similarly observed in both low and high future atherothrombotic risk groups.Structured Graphical Abstract

Generalisability of trials on antithrombotic treatment intensification in patients with cardiovascular disease

ObjectiveAssessment of generalisability of guideline-informing trials on antithrombotic treatment intensification to real-world patients with cardiovascular disease (CVD).MethodsInclusion and exclusion criteria of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS),...

Balancing Benefits and Risks of Long-Term Antiplatelet Therapy in Noncardioembolic Transient Ischemic Attack or Stroke.

Lifelong treatment with antiplatelet drugs is recommended following a transient ischemic attack or ischemic stroke. Bleeding complications may offset the benefit of antiplatelet drugs in patients at increased risk of bleeding and low risk of recurrent ischemic events. We aimed to investigate the net benefit of antiplatelet treatment according to an individuals’ bleeding risk. We pooled individual patient data from 6 randomized clinical trials (CAPRIE [Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events], ESPS-2 [European Stroke Prevention Study-2], MATCH [Management of Atherothrombosis With Clopidogrel in High-Risk Patients], CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance], ESPRIT [European/Australasian Stroke Prevention in Reversible Ischemia Trial], and PRoFESS [Prevention Regimen for Effectively Avoiding Second Strokes]) investigating antiplatelet therapy in the subacute or chronic phase after noncardioembolic transient ischemic attack or stroke. Patients were stratified into quintiles according to their predicted risk of major bleeding with the S2TOP-BLEED score. The annual risk of major bleeding and recurrent ischemic events was assessed per quintile for 4 scenarios: (1) aspirin monotherapy, (2) aspirin-clopidogrel versus aspirin or clopidogrel monotherapy, (3) aspirin-dipyridamole versus clopidogrel, and (4) aspirin versus clopidogrel. Net benefit was calculated for the second, third, and fourth scenario. Thirty seven thousand eighty-seven patients were included in the analyses. Both risk of major bleeding and recurrent ischemic events increased over quintiles of predicted bleeding risk, but risk of ischemic events was consistently higher (eg, from 0.7%/y (bottom quintile) to 3.2%/y (top quintile) for major bleeding on aspirin and from 2.5%/y to 10.2%/y for risk of ischemic events on aspirin). Treatment with aspirin-clopidogrel led to more major bleedings (0.9%–1.7% per year), than reduction in ischemic events (ranging from 0.4% to 0.9/1.0% per year) across all quintiles. There was no clear preference for either aspirin-dipyridamole or clopidogrel according to baseline bleeding risk. Among patients with a transient ischemic attack or ischemic stroke included in clinical trials of antiplatelet therapy, the risk of recurrent ischemic events and of major bleeding increase in parallel. Antiplatelet treatment cannot be individualized solely based on bleeding risk assessment.

Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease.

IL (interleukin)-6 is a pivotal cytokine of innate immunity, which enacts a broad set of physiological functions traditionally associated with host defense, immune cell regulation, proliferation, and differentiation. Following recognition of innate immune pathways leading from the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome to IL-1 to IL-6 and on to the hepatically derived clinical biomarker CRP (C-reactive protein), an expanding literature has led to understanding of the proatherogenic role for IL-6 in cardiovascular disease and thus the potential for IL-6 inhibition as a novel method for vascular protection. In this review, we provide an overview of the mechanisms by which IL-6 signaling occurs and how that impacts upon pharmacological inhibition; describe murine models of IL-6 and atherogenesis; summarize human epidemiological data outlining the utility of IL-6 as a biomarker of vascular risk; outline genetic data suggesting a causal role for IL-6 in systemic atherothrombosis and aneurysm formation; and then detail the potential role of IL-6 inhibition in stable coronary disease, acute coronary syndromes, heart failure, and the atherothrombotic complications associated with chronic kidney disease and end-stage renal failure. Finally, we review anti-inflammatory and antithrombotic findings for ziltivekimab, a novel IL-6 ligand inhibitor being developed specifically for use in atherosclerotic disease and poised to be tested formally in a large-scale cardiovascular outcomes trial focused on individuals with chronic kidney disease and elevated levels of CRP, a population at high residual atherothrombotic risk, high residual inflammatory risk, and considerable unmet clinical need.

Peripheral artery disease in outpatients with a recent history of acute coronary syndrome or at high atherothrombotic risk.

The frequency and implications of peripheral artery disease (PAD) in some risk groups are not entirely characterized in Latin America. We studied PAD prevalence, risk factors, and six-month outcomes in stable outpatients with a history of a recent acute coronary syndrome (ACS), or at high coronary risk. We recruited 830 outpatients in 43 Mexican sites (median age: 64.8 years; 57.8% men). Inclusion criteria were age >18 years, and ACS within 30 days, or age <55 years plus ≥2 major vascular risk factors, or age ≥55 years plus ≥1 vascular risk factors. Patients received standardized assessments at baseline and six-month follow-up for medical history, ankle-brachial index (ABI), and the Edinburgh Claudication Questionnaire (ECQ). ABI <0.8 was found in 10.5%, <0.9 in 22.5%, >1.3 in 4.8%, and >1.4 in 3.6%, without differences according to sex or selection criteria. Positive ECQ was found in 7.6%. ABI <0.9 was directly associated with age, diabetes, ACS, and chronic kidney disease, but inversely associated with BMI >27. The six-month case-fatality and atherothrombotic events rates were 1.6% and 3.6%, respectively. In patients with ABI <0.9 and ABI <0.8, the six-month case-fatality rates were 2.5% (p = 0.27) and 5.4% (p = 0.03), respectively. In a Cox proportional-hazards model, baseline factors associated with death were age ≥65, ABI <0.8, and ACS. Subclinical PAD is more common than symptomatic claudication in high-risk coronary outpatients. Low ABI is associated with reduced short-term survival in patients with recent ACS or at high coronary risk.

3293Atherothrombotic risk and outcomes following guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome:a post-hoc analysis of the TROPICAL-ACS trial

Abstract Background A de-escalation of P2Y12-inhibitor treatment guided by platelet function testing (PFT) has been identified as a safe and alternative treatment strategy in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). However, no specific data are available on the efficacy of such strategy in patients with high atherothrombotic risk (ATR). Purpose To investigate the safety and efficacy of guided de-escalation of P2Y12-inhibitor treatment in patients with low- vs. high-ATR. Methods The TROPICAL-ACS trial randomized 2,610 biomarker-positive ACS patients 1:1 to either conventional treatment with prasugrel for 12 months (control group) or to a PFT guided de-escalation treatment strategy (guided de-escalation group). The primary endpoint was defined as the composite of cardiovascular mortality (CVM), myocardial infarction (MI), stroke, and clinically overt bleeding (bleeding ≥ grade 2 according to the BARC criteria). The ischemic endpoint was defined as the composite of CVM, MI or stroke. We used semi-parametric Cox regression analysis and interaction testing to assess the effect of low- vs. high-ATR on the primary and ischemic endpoints. High-ATR was defined as one of the following: (i) age ≥65 years or (ii) age &lt;65 and either history of peripheral artery disease or at least two of the following risk-factors: diabetes mellitus, current smoking or renal dysfunction. Results Patients with high- (n=990) versus low-ATR (n=1,620) exhibited a higher risk for the primary endpoint (11.0% vs. 6.7%; HR 1.67; 95% CI 1.28–2.18; p&lt;0.001). Guided de-escalation was non-inferior to conventional treatment for the primary endpoint in both patients with high- (10.5% vs. 11.5%; pnon-inferiority = 0.029; Figure 1A) and low-ATR (5.6% vs. 7.7%; pnon-inferiority=0.001; Figure 1B). Moreover, there was no significant interaction in the prognostic value of guided de-escalation between high- and low-ATR groups for both the primary (HR 0.90 [0.61–1.32]; p=0.586 in patients with high-ART vs. 0.71 [0.48–1.04; p=0.082 in patients with low-ATR; pinteraction= 0.394) and combined ischemic endpoints (HR 0.83 [0.44–1.56]; p=0.567 in patients with high-ATR vs. 0.68 [0.35–1.34]; p=0.262 in patients with low-ATR; pinteraction =0.666). Kaplan-Meier curves Conclusion A guided DAPT de-escalation strategy appears to be safe and effective in ACS patients regardless of the atherothrombotic risk. Further studies are needed for refining antiplatelet treatment strategies in ACS patients with varying levels of atherothrombotic risk. Acknowledgement/Funding Klinikum der Universität München, Roche Diagnostics, Eli Lilly, and Daiichi Sankyo.

Are risk factors of cerebral small vessel disease differ from those in patients with high atherothrombotic risk without cerebrovascular disease?

Knowledge of risk factors for cerebral small vessel disease (CSVD) may generate hypothesis regarding possible targets for prevention. Our aim was to evaluate if atherothrombotic risk factors differ between patients with CSVD and with subjects without cerebrovascular disease but with high cardiovascular (CVD) risk. A single-center, cohort study was performed in consecutive patients with different CSVD manifestations. The study group consisted of 205 patients: 52 with lacunar stroke (LS), 20 with subcortical hemorrhagic stroke (HS), 50 with vascular dementia (VaD), 28 with vascular parkinsonism (VaP) and 55 controls (CG) with high CVD risk (35 with atherosclerotic CVD, 20 with 10-year risk of CVD with SCORE?5). Logistic regression was used to analyze the influence of clinical and laboratory data on the occurrence of CSVD. Mean age, sex distribution, prevalence of smoking, hyperlipidemia, peripheral artery disease and obesity were similar in CSVD and CG. The factors significantly associated with CSVD compared to controls were diabetes mellitus, polymetabolic syndrome, elevated systolic blood pressure, low levels of eGFR, HDL, albumin and high uric acid, fibrinogen, fasting glucose, HbA1c and intima medic thickness (p&lt;0.05). Hypertension, chronic kidney disease and elevated fasting blood glucose were related to LS and HS (p&lt;0.1). Diabetes was significantly associated with LS and VaD while smoking and low total cholesterol were related to HS (p&lt;0.1). The study confirms that risk factors profile for CSVD differs from subjects with proatherogenic profile without history of cerebrovascular disease. Our results also support that unique risk factors profiles exist for different manifestations of the CSVD.

Dual Antiplatelet Therapy Cessation and Adverse Events After Drug-Eluting Stent Implantation in Patients at High Risk for Atherothrombosis (from the PARIS Registry)

The impact of dual antiplatelet therapy (DAPT) cessation after percutaneous coronary intervention with drug eluting stent implantation in patients at high atherothrombotic risk remains unclear. We aimed to characterize the risk for adverse events, and its relation with the mode of DAPT cessation in patients at high atherothrombotic risk (HATR). Considering patients treated with drug-eluting stents among those enrolled in the Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients registry, we defined subjects with prior myocardial infarction (MI), prior stroke or peripheral vascular disease at HATR, while patients without any of these conditions were classified as atherothrombotic risk (LATR). DAPT cessation-modes were defined as physician-recommended discontinuation, temporary interruption, and disruption due to bleeding or poor compliance. Compared to patients with LATR (n = 2867; 68.2%), patients with HATR (n = 1340; 31.8%) were older with a higher prevalence of cardiovascular risk factors. Over 2 years, HATR patients had lower rates of physician-recommended discontinuation (32.5% vs 39.4%; p = 0.002) and trend for disruption (11.5% vs 13.7%, p = 0.051), though no significant difference in the rate of DAPT interruption. Patients with HATR had higher 2-year rates of cardiac death, MI, or stent thrombosis compared with those at LATR (8.7% vs 4.0%; adjusted hazard ratio [aHR]: 1.80; 95% confidence interval [CI]: 1.36-2.39; p < 0.0001). Disruption of DAPT was associated with greater risk for cardiac death, MI, or stent thrombosis in both HATR (aHR: 1.86; 95% CI: 1.05 to 3.46) and LATR (aHR: 2.84; 95% CI: 1.68 to 4.80) patients (pinteraction = 0.40). The degree of atherothrombotic risk influences the pattern and mode of DAPT cessation with less discontinuation among patients considered HATR. Atherothrombotic risk status does not influence the association between DAPT cessation and cardiac risk.

Early time course of major bleeding on antiplatelet therapy after TIA or ischemic stroke.

ObjectiveTo study the early time course of major bleeding and its subtypes in patients with cerebral ischemia on dual and single antiplatelet therapy.MethodsWe performed a post hoc analysis on individual patient data from 6 randomized clinical trials (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events [CAPRIE], Second European Stroke Prevention Study [ESPS-2], Management of Atherothrombosis With Clopidogrel in High-Risk Patients [MATCH], Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [CHARISMA], European/Australasian Stroke Prevention in Reversible Ischaemia Trial [ESPRIT], and Prevention Regimen for Effectively Avoiding Second Strokes [PRoFESS]) including 45,195 patients with a TIA or noncardioembolic ischemic stroke. We studied incidence rates of bleeding per antiplatelet regimen stratified by time from randomization (≤30, 31–90, 91–180, 181–365, >365 days). We calculated incidence rates per trial and pooled estimates with random-effects meta-analysis. We performed Poisson regression to assess differences between time periods with adjustment for age and sex.ResultsThe incidence of major bleeding on aspirin plus clopidogrel and aspirin plus -dipyridamole was highest in the first 30 days, 5.8 and 4.9 per 100 person-years, respectively, and was significantly higher than at 31 to 90 days (rate ratio 1.98, 95% confidence interval 1.16–3.40 for aspirin plus clopidogrel; rate ratio 1.94, 95% confidence interval 1.24–3.03 for aspirin plus dipyridamole). Incidence rates on aspirin and clopidogrel monotherapy were 2.8 and 2.5 per 100 person-years, respectively, in the first 30 days, with no significant change over time. The time course was similar for gastrointestinal bleeds. There was no early excess of intracranial hemorrhage in patients on either dual or single antiplatelet therapy.ConclusionDual antiplatelet therapy is associated with high early risks of major and gastrointestinal bleeding that decline after the first month in trial cohorts.

Risk of vascular events in different manifestations of cerebral small vessel disease: A 2-year follow-up study with a control group

Background and purposeNatural course of cerebral small vessel disease (CSVD) has not yet been thoroughly studied. The aim of the single center study was to establish risk of vascular events or death in different manifestations of CSVD. Methods150 consecutive, functionally independent patients with marked MRI features of CSVD and with recent lacunar stroke (n = 52, LS), deep hemorrhagic stroke (n = 20, HS), vascular parkinsonism (n = 28, VaP), vascular dementia (n = 50, VaD) and 55 controls (CG) with high atherothrombotic risk free of cerebrovascular events were prospectively recruited and followed for 24 months. ResultsMean age and sex distribution were similar in CSVD and CG but patients with CSVD were less likely to have CAD (19% vs 40%, p = 0.02) and tended to have higher prevalence of diabetes (54% vs 37%, p = 0.11). The risk of vascular events or death was increased in any patients with moderate to severe white matter lesions at baseline MRI (HR 2.0; 95% CI 0.85–7.2), in CSVD (4.56; 95% CI 1.3–14.9) vs CG, regardless of its clinical manifestation: LS or HS (HR 4.70; 95% CI 1.3–16.2) and VaD or VaP (HR 4.59; 95% CI 1.3–15.7). Adjustment for confounders did not change the results substantially. ConclusionsPatients with symptomatic CSVD regardless of the clinical (acute or chronic) manifestation had more than fourfold the risk of vascular events or death in 24 months of observation compared with controls with high atherothrombotic risk free of cerebrovascular events.

State transition model: vorapaxar added to standard antiplatelet therapy to prevent thrombosis post myocardial infarction or peripheral artery disease

Objective: To evaluate long-term health benefits and risks of adding vorapaxar (VOR) to the standard care antiplatelet therapy (SC) of aspirin and/or clopidogrel, among a population with a recent myocardial infarction (MI) and/or peripheral artery disease (PAD).Research design and methods: In a state-transition model, patients transition between health states (event-free, recurrent MI, stroke, death), while at risk of experiencing non-transition-related revascularization and non-fatal bleeding events. Risk equations developed from the TRA 2°P-TIMI 50 trial’s patient-level data were used to predict cardiovascular (CV) outcomes over longer time horizons. Additional sources, including trials and US-based observational studies, informed the inputs for short-term CV risk, non-CV death, and health-related quality of life. Survival and quality-adjusted life-years (QALYs) were estimated over a lifetime horizon, discounted at 3% per year.Results: Within a cohort of 7361 patients with recent MI and/or PAD, VOR + SC relative to SC alone yielded 176 fewer CV events (MIs, strokes, or CV deaths), but 27 more major bleeding events. VOR + SC was associated with increased life expectancy and health benefits (19.93 undiscounted life-years [LYs], 9.57 discounted QALYs vs. 19.61 undiscounted LYs, 9.41 discounted QALYs). The results were most sensitive to scenarios varying time of vorapaxar initiation, and the assumptions in the 90 day period post-MI. Additional analyses showed that add-on vorapaxar provides consistent incremental benefits in high-risk subgroups.Conclusion: This study contributes to the growing literature on secondary prevention add-on therapy, as results from these modeling analyses suggest that adding vorapaxar to SC for patients at high atherothrombotic risk can provide long-term health benefits.

Longer-term oral antiplatelet use in stable post-myocardial infarction patients: Insights from the long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) observational study

ObjectiveTo describe contemporary patient characteristics and treatment patterns, including antithrombotic management, of post-myocardial infarction (MI) stable coronary artery disease (CAD) patients at high atherothrombotic risk from different geographical regions. MethodsPatients ≥50years with prior MI 1–3years ago and ≥1 risk factor (age ≥65years, diabetes, 2nd prior MI >1yr ago, multivessel CAD, creatinine clearance 15–<60ml/min) were enrolled by 369 physicians (96% cardiologists) in 25 countries (2013–14) in the prospective TIGRIS study (NCT01866904). Results9225 patients were enrolled (median 1.8years) post-MI: 52% with prior ST-elevation MI, median age 67years, 24% women, 67% Caucasian, 55% had ≥2 additional qualifying risk factors, 14% current smokers, 67% overweight/obese, 34% with blood pressure ≥140/90mmHg. 81% underwent percutaneous coronary intervention (PCI; 66% with drug-eluting stents) for the index MI. 75% of patients had been discharged on dual antiplatelet therapy (DAPT; acetylsalicylic acid [ASA]+ADP receptor inhibitor [ADPri]), mainly clopidogrel (75%). 63% had discontinued antiplatelet treatment (60% ADPri) around 1year, most commonly by physician recommendation (90%). At enrolment, 97% were taking an antithrombotic drug, most commonly ASA (88%), with 27% on DAPT (median duration 1.6years); continued DAPT >1year was highest (39%) in Asia-Pacific and lowest (12%) in Europe. ConclusionsDespite guideline recommendations, 1 in 4 post-MI patients did not receive DAPT for ~1year. In contrast to guideline recommendations supporting newer ADPris, clopidogrel was mainly prescribed. Prior to recent RCT data supporting DAPT >1year post-MI/PCI, >1 in 4 patients have continued on DAPT, though with substantial international variability.

Vascular parkinsonism and vascular dementia are associated with an increased risk of vascular events or death.

IntroductionThe natural course of vascular parkinsonism (VaP) and dementia (VaD) due to cerebral small vessel disease (SVD) is not well known. The aim of this single-center study was to evaluate the long-term risk of vascular events, death and dependency in patients with VaP or VaD and to compare it with patients without cerebrovascular disease but with high atherothrombotic risk.Material and methodsSeventy-eight consecutive, functionally independent patients with MRI features of SVD and with recently diagnosed VaD (n = 50) and VaP (n = 28) and 55 controls (control group – CG) with high 10-year risk of total cardiovascular disease (SCORE ≥ 5%) were prospectively recruited and followed for 24 months.ResultsPatients with SVD had lower prevalence of coronary artery disease compared with the CG (20.5% vs. 40%; p = 0.02) but similar prevalence of other atherothrombotic risk factors including mean age (73.7 ±7.3 vs. 72 ±5.9 years, p = 0.09). All outcomes were worse in SVD patients than controls. Thirty-one percent of SVD patients (34% of VaD vs. 25% of VaP, p = 0.45) experienced vascular events or died compared to 6% of controls (p < 0.01). After adjustments for potential confounders (age, sex, vascular risk factors), patients with VaP (HR = 7.5; 95% CI: 1.6–33; p < 0.01) and VaD (HR = 8.7; 95% CI: 2.1–35; p < 0.01) had higher risk of vascular events or death and death or dependency (respectively; HR = 3.9; 95% CI: 0.83–18.8; p = 0.07 and HR = 4.7, 95% CI: 1.1–19.7; p = 0.03).ConclusionsPatients with VaP or VaD due to SVD had significantly higher risk of vascular events, death and dependency compared to controls with high cardiovascular risk and without cerebrovascular disease.

Safety and Efficacy of New-Generation Drug-Eluting Stents in Women at High Risk for Atherothrombosis: From the Women in Innovation and Drug-Eluting Stents Collaborative Patient-Level Pooled Analysis.

The safety and efficacy of new-generation drug-eluting stents (DES) in women with multiple atherothrombotic risk (ATR) factors is unclear. We pooled patient-level data for women enrolled in 26 randomized trials. Study population was categorized based on the presence or absence of high ATR, which was defined as having history of diabetes mellitus, prior percutaneous or surgical coronary revascularization, or prior myocardial infarction. The primary end point was major adverse cardiovascular events defined as a composite of all-cause mortality, myocardial infarction, or target lesion revascularization at 3 years of follow-up. Out of 10,449 women included in the pooled database, 5333 (51%) were at high ATR. Compared with women not at high ATR, those at high ATR had significantly higher risk of major adverse cardiovascular events (15.8% versus 10.6%; adjusted hazard ratio: 1.53; 95% confidence interval: 1.34-1.75; P=0.006) and all-cause mortality. In high-ATR risk women, the use of new-generation DES was associated with significantly lower risk of 3-year major adverse cardiovascular events (adjusted hazard ratio: 0.69; 95% confidence interval: 0.52-0.92) compared with early-generation DES. The benefit of new-generation DES on major adverse cardiovascular events was uniform between high-ATR and non-high-ATR women, without evidence of interaction (Pinteraction=0.14). At landmark analysis, in high-ATR women, stent thrombosis rates were comparable between DES generations in the first year, whereas between 1 and 3 years, stent thrombosis risk was lower with new-generation devices. Use of new-generation DES even in women at high ATR is associated with a benefit consistent over 3 years of follow-up and a substantial improvement in very-late thrombotic safety.

Comparison of bleeding time changes in essential hypertension patients on losartan or amlodipine: a prospective observational study

Background: Hypertension leads to vascular damage due to high pressure exerted on arteriolar wall and also promotes atherothrombosis in large and medium sized blood vessels. Thrombosis is an extension of haemostasis and platelets have a crucial role in the formation of atherothrombosis. Increased platelet activity is a risk factor in hypertensive patients and leads to cardio- and cerebrovascular events and target organ damage. Anti-platelet aggregatory treatment in these high risk patients have become a crucial step in their treatment. Recent data indicate that angiotensin II type 1 blockers or AT1 receptor blockers (ARBs) like Losartan and dihydropyridine class of L-type calcium channel antagonist like Amlodipine have anti- platelet activity. These two classes of drugs are frequently administered in hypertensive either alone and in combinations. This study aims to compare the anti-platelet activity of Losartan and Amlodipine. Anti-platelet activity in addition to anti-hypertensive activity of these drugs would be beneficial in treating hypertensive who are at high risk of atherosclerosis and atherothrombosis, if they are selectively prescribed these agents. Methods: This was an observational study. Sixty (n=60) patients diagnosed with essential hypertension, attending medicine outpatient department of a tertiary care hospital were enrolled in the study. Out of them thirty (n=30) were patients who were prescribed losartan. Rest of the patients (n=30) were ones prescribed amlodipine. It was ensured that the patients of both the groups were on respective medication for at least one month. Another thirty (n=30) normotensive subjects acted as control. The bleeding time was evaluated for all three groups using Duke method of bleeding time estimation. Results: Data was analysed using SPSS software version 20. One way ANOVA was used to analyse the data. This was followed by post hoc Tukey’s test. The mean bleeding time(in minutes) of Losartan group was 2.583±0.263 SD, Amlodipine group was 2.214±0155 SD and control group was 1.998±0.198 SD. Statistically significant p value of &lt;0.001 was observed in losartan and amlodipine groups. Conclusions: Our study shows that the mean bleeding time of Losartan group and amlodipine group were significantly higher than that of Control group. It was further observed that the mean bleeding time of losartan was higher than that of amlodipine group indicating a better antiplatelet action by losartan than amlodipine. Additional antiplatelet activity could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk.

β-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial.

The long-term efficacy of β-blockers in patients with and without myocardial infarction (MI) is controversial. This is post hoc analysis from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial of 4772 patients with prior MI, 7804 patients with known atherothrombosis, and 2101 patients with risk factors alone but without heart failure. Primary outcome was a composite of nonfatal MI, stroke, or cardiovascular mortality. The cohorts were divided into 2 groups based on baseline β-blocker use. In the propensity score-matched prior MI cohort, after 28 months of follow-up, β-blocker use was associated with a 31% lower risk of the primary outcome (70 [7.1%] versus 100 [10.2%]; hazards ratio, 0.69; 95% confidence interval, 0.50-0.94; P=0.021), driven by a lower risk of recurrent MI (33 [3.4%] versus 48 [4.9%]; hazards ratio, 0.62; 95% confidence interval, 0.39-1.00; P=0.049) with no difference in mortality (52 [5.3%] versus 66 [6.7%]; P=0.20). In the known atherothrombotic disease and the risk factors alone cohorts, β-blocker use was not associated with lower ischemic outcomes, whereas a trend toward a higher risk of stroke (3.5% versus 1.5%; hazards ratio, 2.13; 95% confidence interval, 0.92-4.92; P=0.079) was observed in the risk factors alone cohort. This higher stroke risk was significant in the regression model adjusted to the propensity score (hazards ratio, 2.69; 95% confidence interval, 1.33-5.44; P=0.006) and in the multivariable models. β-blocker use in patients with prior MI but no heart failure was associated with a lower composite cardiovascular outcome driven by lower risk of recurrent MI with no difference in mortality. However, β-blocker use was not associated with lower cardiovascular events in those without MI, with a suggestion of inferior outcome with regard to stroke risk. http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Antithrombotic effects of losartan in patients with hypertension complicated by atrial fibrillation: 4A (Angiotensin II Antagonist of platelet Aggregation in patients with Atrial fibrillation), a pilot study

Angiotensin receptor blockers (ARBs) are widely used for the treatment of hypertension. It has been reported that the ARB losartan has antiplatelet, anticoagulant and profibrinolytic effects experimentally. These properties could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk. To examine the antithrombotic effects of losartan in hypertension, 20 consecutive patients with hypertension complicated by atrial fibrillation (AF) were enrolled in this study. The patients were treated with losartan 50 mg for 8 weeks followed by 100 mg for 4 weeks. Blood samples were obtained from each patient at 0 (pretreatment), 8 and 12 weeks after initiating treatment. Platelet aggregability, plasma levels of tissue factor (TF) and type 1 plasminogen activator inhibitor (PAI-1) activity levels were measured. The area under the curve for small platelet aggregability decreased from 100 to 42.8% at 12 weeks (P<0.0001). TF levels (ng ml(-1)) and PAI-1 activity (IU ml(-1); mean±s.d.) also changed from 14.2±3.6 to 10.9±4.5 at 12 weeks (P=0.0299) and from 11.7±3.6 to 8.5±3.1 at 12 weeks (P=0.0122), respectively. Losartan inhibited platelet activity and coagulation factors in a dose- and time-dependent manner in patients with hypertension complicated by AF, whereas the fibrinolytic capacity was increased. The use of losartan could be advantageous in the treatment of hypertensive patients with high atherothrombotic risk.

The relationship between CYP2C19 polymorphisms and ischaemic and bleeding outcomes in stable outpatients: the CHARISMA genetics study

Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. This study is registered with ClinicalTrials.gov number, NCT00050817.

Platelet Function Testing and Genotyping Improve Outcome in Patients Treated With Antithrombotic Agents

The only reason P2Y12 inhibitors are administered in addition to aspirin is to improve the prevention of thrombosis. The clinical efficacy of adding clopidogrel to aspirin as a secondary prevention strategy in patients with high-risk coronary artery disease is well established.1 There are no effects of clopidogrel on any receptor other than P2Y12 to explain the magnitude of the clinical benefit. All of the established clinical effects are attributed to reduced platelet responsiveness to ADP.2 Therefore, the patient with inadequate P2Y12 inhibition determined by ex vivo testing logically has an increased risk for thrombosis. Persistent ischemic event occurrence and the irrefutable demonstration of clopidogrel antiplatelet response variability are 2 potent arguments against the widely practiced nonselective or one-size-fits-all strategy of administering clopidogrel therapy. Observational studies conducted in thousands of patients have led to an international consensus that high on-treatment platelet reactivity (HPR) to ADP is a major risk factor for post–percutaneous coronary intervention (PCI) ischemic event occurrence.3,4 Moreover, the recent 2011 American and European guidelines have given a Class IIb recommendation for platelet function testing or genotyping if the results of testing may alter management.5–7 Furthermore, the Society of Thoracic Surgeons gave a Class IIb recommendation for platelet function testing to determine the timing of surgery in patients on clopidogrel therapy (Level of Evidence C).8 These recommendations for personalizing antiplatelet therapy are unprecedented and acknowledge that a large body of data has accrued demonstrating the relation of HPR to ischemic risk in the PCI-treated patient. Finally, the evidence of diminished effectiveness of clopidogrel in poor metabolizers (those having 2 loss-of-function [LoF] cytochrome P450 [ CYP ] 2C19 alleles) has been recognized by the Food and Drug Administration (FDA) boxed warning about treatment with clopidogrel.9 Response by Krishna …

Leukocyte-Derived Microparticles in Vascular Homeostasis

Leukocyte-derived microparticles (LMPs) may originate from neutrophils, monocytes/macrophages, and lymphocytes. They express markers from their parental cells and harbor membrane and cytoplasmic proteins as well as bioactive lipids implicated in a variety of mechanisms, maintaining or disrupting vascular homeostasis. When they carry tissue factor or coagulation inhibitors, they participate in hemostasis and pathological thrombosis. Both proinflammatory and anti-inflammatory processes can be affected by LMPs, thus ensuring an appropriate inflammatory response. LMPs also play a dual role in the endothelium by either improving the endothelial function or inducing an endothelial dysfunction. LMPs are implicated in all stages of atherosclerosis. They circulate at a high level in the bloodstream of patients with high atherothrombotic risk, such as smokers, diabetics, and subjects with obstructive sleep apnea, where their prolonged contact with the vessel wall may contribute to its overall deterioration. Numbering microparticles, including LMPs, might be useful in predicting cardiovascular events. LMPs modify the endothelial function and promote the recruitment of inflammatory cells in the vascular wall, necessary processes for the progression of the atherosclerotic lesion. In addition, LMPs favor the neovascularization within the vulnerable plaque and, in the ruptured plaque, they take part in coagulation and platelet activation. Finally, LMPs participate in angiogenesis. They might represent a novel therapeutic tool to reset the angiogenic switch in pathologies with altered angiogenesis. Additional studies are needed to further investigate the role of LMPs in cardiovascular diseases. However, large-scale studies are currently difficult to set up because microparticle measurement still requires elaborate techniques which lack standardization.