Use and outcomes of dual antiplatelet therapy for acute coronary syndrome in patients with chronic kidney disease: insights from the Canadian Observational Antiplatelet Study (COAPT).

Chronic kidney disease (CKD) increases the risk of adverse outcomes in acute coronary syndrome (ACS). The optimal regimen of dual antiplatelet therapy (DAPT) post-percutaneous coronary intervention (PCI) in CKD poses a challenge due to the increased bleeding and clotting tendencies, particularly since patients with CKD were underrepresented in randomized controlled trials. We examined the practice patterns of DAPT prescription stratified by the presence of CKD. The multicentre prospective Canadian Observational Antiplatelet Study (COAPT) enrolled patients with ACS between December 2011 and May 2013. The present study is a subgroup analysis comparing type and duration of DAPT and associated outcomes among patients with and without CKD (eGFR < 60 ml/min/1.73 m2, calculated by CKD-EPI). Patients with CKD (275/1921, 14.3%) were prescribed prasugrel/ticagrelor less (18.5% vs 25.8%, p = 0.01) and had a shorter duration of DAPT therapy versus patients without CKD (median 382 vs 402 days, p = 0.003). CKD was associated with major adverse cardiovascular events (MACE) at 12 months (p < 0.001) but not bleeding when compared to patients without CKD. CKD was associated with MACE in both patients on prasugrel/ticagrelor (p = 0.017) and those on clopidogrel (p < 0.001) (p for heterogeneity = 0.70). CKD was associated with increased bleeding only among patients receiving prasugrel/ticagrelor (p = 0.007), but not among those receiving clopidogrel (p = 0.64) (p for heterogeneity = 0.036). Patients with CKD had a shorter DAPT duration and were less frequently prescribed potent P2Y12 inhibitors than patients without CKD. Overall, compared with patients without CKD, patients with CKD had higher rates of MACE and similar bleeding rates. However, among those prescribed more potent P2Y12 inhibitors, CKD was associated with more bleeding than those without CKD. Further studies are needed to better define the benefit/risk evaluation, and establish a more tailored and evidence-based DAPT regimen for this high-risk patient group.

Marital status and outcomes after myocardial infarction: Observations from the Canadian Observational Antiplatelet Study (COAPT).

While divorced or living alone, patients with stable cardiovascular disease are at increased risk for adverse cardiovascular events. The importance of marital status following a myocardial infarction (MI) is less clear. We hypothesized that marital status may affect cardiovascular outcomes following MI. We analyzed outcomes among patients with MI who underwent percutaneous coronary intervention from the Canadian Observational Antiplatelet Study (COAPT). Marital status was categorized into 3 groups: married/common-law patients living together; never married; and divorced, separated, or widowed patients. Patients were followed for 15 months and our primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of mortality, repeat acute MI, stroke, or urgent coronary revascularization. Multivariable logistic regression models were performed, with married/common-law patients living together considered the reference group. Among 2100 patients included in analyses, 1519 (72.3%) were married/common-law patients living together, 358 (17.1%) were separated/divorced/widowed, and 223 (10.6%) patients were never married. Dual antiplatelet therapy use after 15 months was similar across groups (75.4%, 77.8%, and 73.6%, respectively). The risk of MACE after 15 months was similar among married patients living together (12.7%; referent) compared with patients who were never married (13.9%; adjusted odds ratio: 1.09, 95% confidence interval: 0.58-2.07, P = 0.79) and patients separated/divorced/widowed (14.3%; adjusted odds ratio: 0.71, 95% confidence interval: 0.40-1.25, P = 0.23). Similarly, the risk of individual endpoints, including mortality, was similar across the 3 groups. Among patients stabilized following an MI, we found no association between marital status and 15-month outcomes.

Duration of dual antiplatelet therapy and associated outcomes following percutaneous coronary intervention for acute myocardial infarction: contemporary practice insights from the Canadian Observational Antiplatelet Study.

Aims: There is a paucity of real-world, contemporary data of practice patterns and clinical outcomes following dual-antiplatelet therapy (DAPT) in acute myocardial infarction (AMI) patients treated with percutaneous coronary intervention (PCI). Methods and results: The Canadian Observational Antiplatelet Study was a prospective, multicentre, cohort study examining adenosine diphosphate receptor antagonist use following PCI for AMI. We compared practice patterns, patient characteristics, and clinical outcomes in relation to DAPT duration (<6 weeks, 6 weeks to <6 months, 6 to <12, and ≥12 months). The primary outcome was the composite of non-fatal AMI, unplanned coronary revascularization, stent thrombosis, new or worsening heart failure, cardiogenic shock, or stroke. We identified 2034 patients with AMI treated with PCI. DAPT duration was <6 weeks in 5.2% of patients; 6 weeks to <6 months in 7.0%; 6 to <12 months in 12.6%; and ≥12 months in 75.3%. Patients who discontinued DAPT early had higher GRACE risk scores. Overall, mortality rate at 15 months was 2.5%. Compared with a duration of DAPT of ≥12 months, discontinuation of DAPT <6 weeks (P < 0.0001) and 6 weeks to <6 months (P = 0.02), but not 6 months to <12 months (P = 0.06), were independently associated with a higher incidence of the primary outcome among survivors. Conclusion: One-in-four patients with AMI treated with PCI discontinued DAPT prior to the guideline-recommended 12-month duration. Patients in whom DAPT was discontinued early were at higher baseline risk and had higher rates of non-fatal ischaemic events during follow up.

Longitudinal treatment patterns with ADP receptor inhibitors after myocardial infarction: Insights from the Canadian Observational AntiPlatelet sTudy.

BACKGROUND: After myocardial infarction (MI) treated with percutaneous coronary intervention (PCI), guidelines recommend dual antiplatelet therapy (DAPT) with aspirin and an ADP receptor inhibitor (ADPri) for at least 1year. However, whether real-world Canadian practice patterns reflect this recommendation is unknown. METHODS: We studied 2175 MI patients treated with PCI and discharged from 26 Canadian hospitals between 12/2011 and 05/2013 in the Canadian Observational Antiplatelet sTudy (COAPT). Hierarchical Cox proportional hazard regression modeling was used to determine baseline demographic and clinical factors associated with duration of ADPri therapy post-discharge. RESULTS: At index-hospitalization discharge, 1597 (73%) patients were treated with clopidogrel, 220 (10%) with prasugrel, and 358 (17%) with ticagrelor. ADPri was discontinued prior to 1year in 474 (21.8%) patients; discontinuation rates were lowest for patients discharged on prasugrel (17.7%), compared with clopidogrel (22.5%) or ticagrelor (21.0%), (log rank test, p=0.03). In addition to regional variability, factors associated with shorter ADPri duration included older age, low body weight, Killip III/IV heart failure, atrial fibrillation, ticagrelor on discharge, and bare metal stent use, while longer ADPri duration was associated with history of prior MI. CONCLUSIONS: One in five PCI-treated MI patients did not complete Canadian guideline-recommended 1-year course of ADPri treatment. Premature ADPri discontinuation was most strongly associated with factors that increase the risk of bleeding. Further study is required to assess the clinical implications of premature ADPri discontinuation on patient outcomes.

Baseline characteristics, adenosine diphosphate receptor inhibitor treatment patterns, and in-hospital outcomes of myocardial infarction patients undergoing percutaneous coronary intervention in the prospective Canadian Observational AntiPlatelet sTudy (COAPT).

BACKGROUND: Contemporary use of dual antiplatelet therapy and consistency with guideline recommendations in acute coronary syndrome patients undergoing percutaneous coronary intervention (PCI) have not been well characterized. METHODS: The COAPT was a prospective, observational, multicenter, longitudinal study of patients with myocardial infarction (MI) undergoing PCI. Baseline characteristics, treatment patterns, processes of care, factors associated with switching to and from novel adenosine diphosphate receptor inhibitors (ADPris), and in-hospital outcomes are described. RESULTS: Among 2,179 MI patients undergoing PCI during their index hospitalization, 1,328 (60.9%) had ST elevation. Initial ADPri use included clopidogrel in 1,812 (83.2%), prasugrel in 125 (5.7%), and ticagrelor in 242 (11.1%). At discharge, 1,597 patients (73.4%) were prescribed clopidogrel, 220 (10.1%) prasugrel, and 358 (16.5%) ticagrelor. Switching between ADPri therapies during the index hospitalization occurred in 15.3%, 22.4%, and 25.2% of patients initially started on clopidogrel, prasugrel, and ticagrelor, respectively. Most switches over the 15-month study period occurred during the index admission (16.8% of patients vs 4.4% switches postdischarge). Major adverse cardiovascular events occurred in 7.5% of patients during the index hospitalization. In-hospital bleeding events occurred in 6.0% of patients and most were mild. CONCLUSIONS: Despite randomized trial evidence and guideline recommendations, only a minority of Canadian MI patients undergoing PCI initially received or were discharged on one of the newer ADPri agents. These findings suggest an opportunity to improve upon the appropriate selection of the ADPris at index hospitalization and discharge in Canadian MI patients undergoing PCI.

Ischemic and bleeding events in patients with myocardial infarction undergoing percutaneous coronary intervention who require oral anticoagulation: Insights from the Canadian observational AntiPlatelet sTudy.

BACKGROUND: Since the introduction of newer, more potent P2Y12 receptor inhibitors (P2Y12ris), practice patterns and associated clinical outcomes in patients with myocardial infarction (MI) undergoing percutaneous coronary intervention (PCI) and also requiring oral anticoagulation (OAC) have not been fully characterized. METHODS: The Canadian Observational Antiplatelet Study was a prospective, multicenter, longitudinal, observational study (26 hospitals, December 2011 to May 2013) describing P2Y12ri treatment patterns and outcomes in patients with ST-elevation and non-ST-elevation MI undergoing PCI. We describe the clinical characteristics, treatment patterns, bleeding, and ischemic outcomes over the 15-month follow-up within and between the subgroups of patients discharged on either dual-antiplatelet therapy (DAPT) (acetyl salicylic acid [ASA]+P2Y12ri) or triple therapy (ASA+P2Y12ri+OAC). RESULTS: Of the 2,034 patients at discharge, 86% (n = 1,757) were on DAPT, whereas 14% (n = 277) were on triple therapy (50% warfarin, 50% non-vitamin K OAC [NOAC]). The frequency of newer P2Y12ri use (prasugrel or ticagrelor) was similar in the DAPT and triple therapy groups (28% vs 26%, respectively). In the triple therapy group, NOAC use was higher in those receiving a new P2Y12ri compared to those receiving clopidogrel (75% vs 41%, respectively, P < .0001). The unadjusted and adjusted events of major cardiovascular event (MACE) and bleeding were higher in the triple therapy group. For patients on triple therapy, the bleeding or MACE events were not significantly different between those on clopidogrel versus those on ticagrelor or prasugrel. CONCLUSION: In this observational study of MI patients requiring PCI, 1 in 8 were discharged on triple antithrombotic therapy, of whom 26% were on newer P2Y12ris. Patients on triple therapy had higher risk at baseline, with higher unadjusted and adjusted MACE and bleeding events compared to those on DAPT alone. Among triple therapy-treated patients, there was no difference in the MACE and bleeding events regardless of the P2Y12ri used.

Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial.

BACKGROUND: Adding a prasugrel loading dose (LD) to a clopidogrel LD could be desirable because clopidogrel may fail to provide adequate levels of platelet inhibition in patients with acute coronary syndrome undergoing percutaneous coronary intervention. METHODS AND RESULTS: The pharmacodynamic response of prasugrel 60 mg ld alone was compared with prasugrel 60 mg or 30 mg added 24 hours to clopidogrel 600 mg in Transferring From Clopidogrel Loading Dose To Prasugrel Loading Dose In Acute Coronary Syndrome Patients study: a multicenter, randomized, double-blind, double-dummy, 3-arm, parallel, active-comparator controlled study. Two hundred eighty-two patients were randomized to 3 LD strategies: placebo plus prasugrel 60 mg, clopidogrel 600 mg plus prasugrel 60 mg, or clopidogrel 600 mg plus prasugrel 30 mg. Platelet function was assessed using VerifyNow P2Y12 Reaction Units (PRU) immediately before prasugrel LD, and 2, 6, 24, and 72 hours after prasugrel LD in 149 patients with evaluable platelet function studies. At 6 hours after the prasugrel 60 mg LD, the least squares mean (95% confidence interval) difference between placebo/prasugrel 60 mg and clopidogrel 600 mg/prasugrel 60 mg (primary outcome) was 22.2 (-11.0 to 55.5; P=0.19; least squares mean PRU 57.9 versus 35.6, respectively). For clopidogrel 600 mg/prasugrel 30 mg (least squares mean PRU, 53.9), the difference was 3.9 (-28.2 to 36.1; P=0.81) versus placebo/prasugrel 60 mg. No significant differences in PRU were observed at any time point across the 3 groups. There were few bleeding events observed regardless of treatment. CONCLUSIONS: Platelet reactivity with prasugrel 60 mg LD added to clopidogrel 600 mg LD was not significantly different compared with prasugrel 60 mg LD alone in acute coronary syndrome patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01115738.

Early drotrecogin alpha (activated) administration in severe sepsis is associated with lower mortality: a retrospective analysis of the Canadian ENHANCE cohort.

INTRODUCTION: Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy. METHODS: Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored. RESULTS: Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day. CONCLUSIONS: These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age. TRIAL REGISTRATION: Previous trial registration number: NCT00568893.

A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry.

OBJECTIVE: To determine the location of acquisition, timing, and outcomes associated with severe sepsis in community and teaching hospital critical care units. DESIGN: Prospective, observational study. SETTING: Twelve Canadian community and teaching hospital critical care units. PATIENTS: All patients admitted between March 17, 2003, and November 30, 2004 to the study critical care units with at least a 24-hr length of stay or severe sepsis identified during the first 24 hrs. INTERVENTIONS: Daily monitoring for severe sepsis. MEASUREMENTS AND MAIN RESULTS: We recorded data describing characteristics of patients, infections, systemic responses, and organ dysfunction. Severe sepsis occurred in 1238 patients (overall rate, 19.0%; range, 8.2%-35.3%). Hospital mortality was 38.1% (95% confidence interval [CI]: 35.4-40.8). Median intensive care unit length of stay was 10.3 days (interquartile range: 5.5, 17.9). Variables associated with mortality in multivariable analysis included age (odds ratio [OR] by decade 1.50; 95% CI: 1.36-1.65), acquisition location of severe sepsis (with community as the reference-hospital [OR: 1.69; CI: 1.16-2.46], early intensive care unit [OR: 2.15; CI: 1.42-3.25], late intensive care unit [OR: 2.65; CI: 1.82-3.87]), late intensive care unit (OR: 2.65; CI: 1.82-3.87), any comorbidity (OR: 1.42; CI: 1.04-1.93), chronic renal failure (OR: 2.03; CI: 1.10-3.76), oliguria (OR: 1.34; CI: 1.02-1.76), thrombocytopenia (OR: 2.12; CI: 1.43-3.13), metabolic acidosis (OR: 1.54; CI: 1.13-2.10), Multiple Organ Dysfunction Score (OR: 1.15; CI: 1.09-1.21) and Acute Physiology and Chronic Health Evaluation II predicted risk (OR: 3.75; CI: 2.08-6.76). CONCLUSION: These data confirm that sepsis is common and has high mortality in general intensive care unit populations. Our results can inform healthcare system planning and clinical study designs. Modifiable variables associated with worse outcomes, such as nosocomial infection (hospital acquisition), and metabolic acidosis indicate potential targets for quality improvement initiatives that could decrease mortality and morbidity.

A long-term follow-up study investigating health-related quality of life and resource use in survivors of severe sepsis: comparison of recombinant human activated protein C with standard care.

INTRODUCTION: Recombinant human activated protein C (APC) therapy has been shown to reduce short-term mortality in patients with severe sepsis. However, survivors of sepsis may have long-term complications affecting health-related quality of life (HRQoL) and resource utilization. The objective of this study was to evaluate prospectively the effect of APC on long-term HRQoL and resource utilization compared with a nonrandomized control group that received standard care. METHODS: This was an observational cohort study at nine Canadian intensive care units. Patients with severe sepsis who survived to 28 days were recruited. Patients who received APC formed the treatment group and those that did not formed the standard care group. Patients who did not receive APC because of central nervous system bleeding risk were excluded from the standard care group. HRQoL (determined using the 36-item Short Form) and resource use were recorded at 28 days, and 3, 5 and 7 months. RESULTS: One hundred patients were enrolled (64 in the standard care group and 36 in the APC group), with 70 patients completing all follow-up visits. Over the 6 months of follow up, APC-treated patients exhibited statistically significantly better scores for the physical component score (P = 0.04) and trends toward improvements in physical functioning (P = 0.12), role physical (P = 0.10) and bodily pain (P = 0.14) as compared with standard care patients. Shorter hospital length of stay was observed for the APC group (36 days versus 48 days; P = 0.05). CONCLUSION: These findings challenge earlier assumptions suggesting equivalent HRQoL and resource use in APC-treated and standard care patients who survive severe sepsis.

Patient characteristics and costs of severe sepsis and septic shock in Quebec.

BACKGROUND: We investigated the cost of health care resources for the treatment of severe sepsis and/or septic shock patients. MATERIALS AND METHODS: One hundred retrospective chart abstractions from patients with severe sepsis or septic shock were included. The average cost, per episode, through day 28, as well as an analysis of a patient subset through 1 year was calculated. Mean values for all abstracted patient's costs and outcomes, as well as analyses of the survivor and nonsurvivor populations, were undertaken. Data from the Canadian Institute for Health Information and recent published literature were used to estimate the number of severe sepsis cases, and the resulting burden of illness for Quebec. RESULTS: The mean cost for all patients abstracted was $11,474 per episode of care ($1,064/day). The survivors had a mean cost for their treatment of $16,228 per episode of care ($877/day). The total cost per episode was $7,584 per nonsurvivor ($1,724/day). An average cost of $27,481 for survivors after day 28 through 1 year was calculated. The burden of severe sepsis was estimated to be $36.4 to $72.9 million per year, but higher if costs beyond day 28 are included. CONCLUSIONS: The cost of severe sepsis is a significant burden to the Quebec health care system.