Net Clinical Outcome Research Articles

Abstract 13112: Benefit of Early Discharge Among Patients With Low-risk Pulmonary Embolism: Focus on Net Clinical Impact

Introduction: Clinical guidelines recommend early discharge of patients with Low Risk Pulmonary Embolism (LRPE). With increasing awareness of the risks of hospital acquired complications (HAC), we sought to measure the overall impact of early discharge of LRPE patients on clinical outcomes and costs within the Veterans Health Administration. Methods: Adult patients with ≥1 inpatient diagnosis for PE (index date) between 10/2011- 6/2015 and continuous enrollment for ≥12 months pre- and 3 months post-index date were included. PE risk stratification was done using the simplified Pulmonary Embolism Stratification Index (sPESI). Propensity score matching (PSM) was used to compare 90-day PE-related outcomes, HAC, healthcare utilization and costs among short versus long length of stay (LOS) LRPE patients. We defined short LOS as ≤2 days, adverse PE events (APE) as recurrent deep vein thrombosis, major bleed, or death, and net clinical benefit as 1 minus the combined rate of APE and HAC. Results: Among 6,746 PE patients, 95.4% were male, 67.7% were white, 22.0% were African American, and 1,918 had a LRPE. Among LRPE patients, only 688 (35.9%) had short LOS. After PSM, 784 LRPE patients were evaluated. There were no differences in APE, but short LOS had fewer HAC (1.5% vs. 13.3%; p<0.0001) and bacterial pneumonias (5.9% vs. 11.7%, p<0.005). Net clinical benefit was higher for short LOS patients (86.9% vs. 78.3%, p=0.0013). Among long LOS, the number of HAC (52) exceeded APE (14 recurrent DVT, 5 bleeds). Short LOS had lower inpatient costs ($2,164 vs. $5,100; p<0.0001) and lower total costs ($9,056 vs. $12,544; p<0.0001) versus long LOS. Conclusions: LRPE patients with short LOS had better net clinical outcomes at lower costs than those with long LOS. Providers should deploy risk stratification strategies and consider early discharge for LRPE patients.

Impact of time to treatment on the effects of bivalirudin vs. glycoprotein IIb/IIIa inhibitors and heparin in patients undergoing primary percutaneous coronary intervention: insights from the HORIZONS-AMI trial.

In the HORIZONS-AMI trial, bivalirudin compared to unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) improved net clinical outcomes in patients undergoing primary percutaneous coronary intervention (PCI) at the cost of an increased rate of acute stent thrombosis. We sought to examine whether these effects are dependent on time to treatment. The interaction between anticoagulation regimen and symptom onset to first balloon inflation time (SBT) on the 30-day and three-year rates of major adverse cardiac events (MACE) was examined in 3,199 randomised patients according to SBT ≤3 hours versus >3 hours. Among patients with an SBT ≤3 hours, bivalirudin resulted in higher 30-day rates of MACE compared to UFH plus a GPI. Non-significant differences were observed in patients with an SBT >3 hours. Similar results were found for MACE at three years and stent thrombosis and reinfarction at 30 days and three years. By multivariable analysis, bivalirudin was an independent predictor of MACE at 30 days and three years in patients with an SBT ≤3 hours, but not in patients with SBT >3 hours. Bivalirudin compared to UFH plus a GPI is associated with an increased rate of stent thrombosis and MACE in patients with short SBTs, but not in those with longer SBTs.

Standard dose versus low dose non–vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: A meta-analysis of contemporary randomized controlled trials

Although randomized controlled trials (RCTs) indicated that standard dose non-vitamin K antagonist oral anticoagulants (NOACs) were more compelling, low dose NOACs are commonly used in clinical practice in Asia. The purpose of this study was to assess the relative therapeutic benefit and risk of standard dose vs low dose NOACs in Asian patients enrolled in contemporary RCTs. We performed a prespecified meta-analysis of 3155 Asian patients with NOACs in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) and ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trials. Efficacy and safety with standard dose vs low dose NOACs were compared by risk ratios (RRs) and 95% confidence intervals (CIs) in a random-effects model. An evidence network incorporating additional Asian patients from ROCKET AF, J- ROCKET AF, and ARISTOTLE was constructed with the Bayesian method. Risks of stroke or systemic embolism and ischemic stroke were significantly reduced with standard dose vs low dose NOACs (RR 0.62, 95% CI 0.45-0.85; and RR 0.55, 95% CI 0.38-0.79, respectively). Rates of major, intracranial, and life-threatening bleeding with 2 dosing regimens were broadly similar (RR 1.31, 95% CI 0.74-2.33; RR 1.54, 95% CI 0.72-3.30; and RR 1.49, 95% CI 0.87-2.55, respectively). Absolute rates of all-cause mortality and the net clinical outcome with standard dose NOACs were lower but not statistically significant (absolute reduction 0.4% per year and 1.1% per year, respectively). Network meta-analyses demonstrated that standard dose NOACs had the most favorable risk-benefit profile among oral anticoagulants. In Asian patients, standard dose NOACs represent a more appealing therapeutic option than low dose NOACs, with a significant reduction in ischemic stroke without an excess of major bleeding.

Should a prolonged duration of dual anti-platelet therapy be recommended to patients with diabetes mellitus following percutaneous coronary intervention? A systematic review and meta-analysis of 15 studies.

BackgroundThis study aimed to compare the adverse clinical outcomes associated with a short and a prolonged duration of Dual Anti-Platelet Therapy (DAPT) in patients with Diabetes Mellitus (DM) after undergoing Percutaneous Coronary Intervention (PCI).MethodsMedline/PubMed, EMBASE and the Cochrane library were searched for studies comparing the short and prolonged DAPT use in patients with DM. Adverse outcomes were considered as the clinical endpoints in this analysis. Odds Ratios (OR) with 95 % Confidence Intervals (CI) were used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3.ResultsFifteen studies with a total number of 25,742 patients with DM were included in this current analysis which showed no significant differences in primary endpoints, net clinical outcomes, myocardial infarction and stroke with OR: 1.03, 95 % CI: 0.65–1.64; P = 0.90, OR: 0.96, 95 % CI: 0.69–1.34; P = 0.81, OR: 0.85, 95 % CI: 0.70–1.04; P = 0.12 and OR: 0.94, 95 % CI: 0.65–1.36; P = 0.75 respectively. Revascularization was also similar between these 2 groups of patients with DM. However, even if mortality favored prolonged DAPT use, with OR: 0.87, 95 % CI: 0.76–1.00; P = 0.05, the result only approached significance. Also, stent thrombosis insignificantly favored a prolonged DAPT duration with OR: 0.56, 95 % CI: 0.27–1.17; P = 0.12. Thrombolysis In Myocardial Infarction (TIMI) defined major and minor bleeding were not significantly different in these diabetic patients with OR: 0.91, 95 % CI: 0.60–1.37; P = 0.65 and OR: 1.08, 95 % CI: 0.62–1.91; P = 0.78 respectively. However, bleeding defined by the Bleeding Academic Research Consortium (BARC) classification was significantly higher with a prolonged DAPT use in these diabetic patients with OR: 1.92, 95 % CI: 1.58–2.34; P < 0.00001.ConclusionFollowing PCI, a prolonged DAPT use was associated with similar adverse clinical outcomes but with a significantly increased BARC defined bleeding compared to a short term DAPT use in these patients with DM. However, even if mortality and stent thrombosis favored a prolonged DAPT use, these outcomes only either reached statistical significance or were insignificant respectively, showing that a clear decision about recommending a prolonged duration of DAPT to patients with DM might not be possible at this moment, warranting further research in this particular subgroup.

Efficacy and safety of short-term dual- versus mono-antiplatelet therapy in patients with ischemic stroke or TIA: a meta-analysis of 10 randomized controlled trials

Stroke is still a primary disease for death and disability all over the world. The optimal antiplatelet therapy for treatment of stroke is under controversy. We performed a meta-analysis to justify whether short-term (≤1year) dual-antiplatelet therapy (DAPT) has advantages over mono-antiplatelet therapy. We systematically searched the databases of Cochrane library, Pubmed and Embase up to July 2016. Randomized controlled trials (RCTs) comparing DAPT with mono-antiplatelet therapy were included in our meta-analysis. Totally ten trials involving 8969 patients were satisfied with our inclusion criteria. At the end of follow-up, DAPT is associated with a significant reduction in recurrent stroke [risk ratio (RR) 0.65, 95% confidence interval (CI) 0.56-0.76, P<0.00001] and the net clinical outcome (ischemic stroke (IS) recurrence plus major bleeding) (RR 0.67, 95% CI 0.58-0.79, P<0.00001). In terms of safety outcomes of major bleeding (RR 1.44, 95% CI 0.72-2.88, P=0.30) and intracranial hemorrhage (RR 1.29, 95% CI 0.56-2.93, P=0.55), DAPT has a homologous safety profile compared with mono-antiplatelet therapy. The subgroup analysis according to different races, antiplatelet combinations or initiation time produced similar outcomes as comprehensive outcomes. Given short-term treatment regimen, DAPT can be superior to mono-antiplatelet therapy in treating IS or transient ischemic attack (TIA). No matter in acute or non-acute phase of IS, short-term DAPT has more efficacy than mono-antiplatelet therapy and has equivalent safety as mono-antiplatelet therapy.

Atherothrombotic Risk Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart Disease and Previous Myocardial Infarction.

Patients with stable ischemic heart disease and previous myocardial infarction (MI) vary in their risk for recurrent cardiovascular events. Atherothrombotic risk assessment may be useful to identify high-risk patients who have the greatest potential to benefit from more intensive secondary preventive therapy such as treatment with vorapaxar. We identified independent clinical indicators of atherothrombotic risk among 8598 stable, placebo-treated patients with a previous MI followed up for 2.5 years (median) in TRA 2°P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50]. The efficacy and safety of vorapaxar (SCH 530348; MK-5348) were assessed by baseline risk among patients with previous MI without prior stroke or transient ischemic attack for whom there is a clinical indication for vorapaxar. End points were cardiovascular death, MI, or ischemic stroke and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding. The 9 independent risk predictors were age, diabetes mellitus, hypertension, smoking, peripheral arterial disease, previous stroke, previous coronary bypass grafting, heart failure, and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rate of cardiovascular death/MI/ischemic stroke and the individual components (P for trend <0.001 for all). High-risk patients (≥3 risk indicators; 20% of population) had a 3.2% absolute risk reduction in cardiovascular disease/MI/ischemic stroke with vorapaxar, and intermediate-risk patients (1-2 risk indicators; 61%) had a 2.1% absolute risk reduction (P<0.001 each), translating to a number needed to treat of 31 and 48. Bleeding increased across risk groups (P for trend<0.01); however, net clinical outcome was increasingly favorable with vorapaxar across risk groups. Fatal bleeding or intracranial hemorrhage was 0.9% with both treatments in high-risk patients. Stratification of baseline atherothrombotic risk can assist with therapeutic decision making for vorapaxar use for secondary prevention after MI. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00526474.

Comparison between Fondaparinux and Low-Molecular-Weight Heparin in Patients with Acute Coronary Syndrome: A Meta-Analysis

Objective: A number of studies have evaluated the efficacy and safety of fondaparinux versus low-molecular-weight heparin (LMWH) in patients with acute coronary syndrome (ACS), but the findings were not consistent across these studies. Methods: Electronic databases and article references were searched for studies that assessed fondaparinux versus LMWH in ACS patients. Results: Six studies met the inclusion criteria. There was a lower risk of major adverse cardiac events (MACE) with fondaparinux-based regimens both in randomized controlled trials (RCT; risk ratio, RR: 0.91, p = 0.04) and observational studies (RR: 0.85, p < 0.0001). Mortality decreased in fondaparinux-treated patients in RCT (RR: 0.84, p = 0.02), but not in observational studies (RR: 1.44, p = 0.64). For the analysis of myocardial infarction (MI), recurrent ischemia and stroke, none of the studies showed significant results. In addition, fondaparinux lowered the risk of major bleeding in RCT (RR: 0.62, p < 0.0001) and observational studies (RR: 0.65, p < 0.0001). The net clinical outcome also favored fondaparinux over LMWH in RCT (RR: 0.82, p < 0.0001) and observational studies (RR: 0.84, p < 0.0001). Conclusions: Among ACS patients, a fondaparinux-based regimen presented advantages regarding MACE and major bleeding, and a net clinical benefit compared with LMWH, although the benefit is minimal regarding MACE. For death, MI, recurrent ischemia and stroke, fondaparinux has not shown significant benefits.

Vorapaxar in the secondary prevention of atherothrombosis

Dual antiplatelet therapy with aspirin, a platelet cyclooxygenase-1 inhibitor and P2Y12 receptor blockers, remains the major drug strategy to prevent ischemic event occurrence in patients with acute coronary syndromes and in patients undergoing coronary stenting, but there some limitations that can be overcome by targeting novel targets. Unlike direct thrombin inhibitors that bind directly to thrombin, targeting the platelet thrombin receptor, protease activated receptor (PAR)-1, may offer a better choice for the attenuation of atherosclerosis progression, thrombus-mediated ischemic events and restenosis without interfering with primary hemostasis. Vorapaxar – a synthetic analogue of himbacine, is a high affinity and highly selective PAR-1 antagonist that can effectively inhibit thrombin-induced platelet aggregation. In the TRACER trial, the addition of vorapaxar to standard therapy in patients with non-stent thrombosis-elevation- acute coronary syndromes did not significantly reduce the primary composite end point occurrence of cardiovascular (CV) death, myocardial infarction (MI), stroke, hospitalization for ischemia, or urgent revascularization, but significantly increased the GUSTO moderate and severe bleeding (p < 0.001) and intracranial hemorrhage (ICH). In the TRA 2°P-TIMI 50 trial, in patients with a history of MI and peripheral arterial disease (PAD) (67% of the total population), the end point of CV death, MI, or stroke was significantly (20%) reduced with vorapaxar whereas GUSTO moderate or severe bleeding was increased (1.5-fold), but not ICH or fatal bleeding and the net clinical outcome favoring the vorapaxar therapy. Based on these favorable results, the FDA approved vorapaxar for the reduction of thrombotic cardiovascular events in patients with prior MI or with PAD for long term therapy. A careful patient selection is needed to balance efficacy versus safety. At this time, patients with high risk for recurrent ischemic event occurrence such as patients with diabetes mellitus and previous MI can be safely treated with vorapaxar for long-term therapy.

Abstract 17338: Development of a TIMI Risk Score for Stable Ischemic Heart Disease

Patients (pts) with stable ischemic heart disease (SIHD) who have had a prior myocardial infarction (MI) demonstrate a range of residual risk for recurrent CV events. A risk prediction tool may be useful to identify high risk pts who have the greatest potential for benefit from intensive treatment. Methods: The integer-based TIMI Risk Score for SIHD (Prior MI) was derived in 8,200 placebo-treated pts who were stable with a history of MI (2 wks to 12 mo) in the TRA 2°P-TIMI 50 trial. The score was developed to predict CV death, MI or ischemic stroke (CVD/MI/iCVA; n=676 events, median 2.5y follow-up). The score was validated in 8,274 vorapaxar-treated pts from the trial. Differential efficacy and safety (GUSTO severe bleeding) response to randomized treatment was assessed among pts with prior MI without a history of TIA or stroke for whom there is a clinical indication for vorapaxar. Results: The risk score predictors were age, CHF, smoking, diabetes mellitus, hypertension, prior stroke, peripheral arterial disease, family history of CAD, prior CABG, and eGFR (Fig 1a). The TIMI Risk Score showed a strong graded relationship with the rate of CVD/MI/iCVA as well as the individual components (p-trend&lt;0.001 for all), a pattern that was confirmed in the validation cohort (p&lt;0.001). In pts eligible for clinical use, those at intermediate (score 2-3) and high (score ≥4) risk had a 2.4% and 3.6% absolute risk reduction in CVD/MI/iCVA with vorapaxar, translating to a number needed to treat (NNT) of 41 and 28 in the intermediate and high risk groups (Fig 1b). Bleeding increased across risk groups (Fig 1b); however, net clinical outcome was increasingly favorable with vorapaxar with an increasing TIMI Risk Score. ICH was 0.5 vs 0.6% and fatal bleeding was 0.3 vs 0.5% with vorapaxar vs placebo in those with a score ≥4. Conclusions: The TIMI Risk Score for SIHD (Prior MI) identifies a strong gradient of increasing risk for recurrent CV events and may be useful as a basis for therapeutic decision-making.

Abstract 17169: The Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial

Background: Edoxaban (edox), an oral factor Xa inhibitor with 50% renal clearance, was non-inferior to warfarin for prevention of thromboembolic events and significantly reduced bleeding in pts with AF. However, a detailed analysis of the impact of creatinine clearance (CrCl) on clinical outcomes with edox has not been described. Purpose: We evaluated the safety, efficacy and net clinical outcome of edox vs warfarin (warf) across the range of baseline CrCl in the ENGAGE AF-TIMI 48 trial. Methods: 14,071 AF pts at moderate-to-high risk of stroke were randomized to edox 60mg QD or warf. Severe renal dysfunction (CrCl&lt;30ml/min) was exclusionary and a CrCl 30-50 resulted in a 50% dose reduction of edox (30mg QD). Endpoints of stroke or systemic embolism (SSE), ISTH major bleeding (MB) and the primary net clinical outcome of SSE/MB and all-cause mortality (ACM) were evaluated by intention-to-treat analysis by the pre-specified singular CrCl cutpoint of 50ml/min and additional exploratory cutpoints. Results: The relative risk of SSE with edox vs warf in the pre-specified analysis in those with CrCl≤50 (HR 0.87, 0.65-1.18) was similar to those with CrCl&gt;50 (HR 0.87, 0.72-1.04; p-int=0.94). Evaluation by more granular, exploratory cutpoints demonstrated higher rates of SSE (Fig 1a; p-int&lt;0.001) and ischemic stroke (p-int=0.05) with edox vs warf in the upper range of CrCl, but lower rates of bleeding were observed at all levels of CrCl with edox (Fig 1a; p-int=0.39). For the net clinical outcome (SSE/MB/ACM), there was no significant difference between edox and warf at higher levels of renal function due to the preserved effect on bleeding and mortality (Fig 1b; p-int 0.17). An on-treatment analysis with plasma drug levels will be shown. Conclusion: While there is a trend towards decreasing efficacy with increasing CrCl for edox compared to well-managed warfarin, the overall safety and net clinical benefit of edox compared to warfarin is consistent across renal function groups.

A systematic review on the role of bivalirudin in patients undergoing percutaneous coronary interventions: primus inter pares or a falling star?

Intracoronary thrombosis triggered by ruptured or eroded atherosclerotic plaques constitutes the predominant underlying cause of acute coronary syndromes (ACS). Thrombin is considered a central enzyme in hemostasis and thrombosis, and a well-established target for anticoagulant therapies. Bivalirudin was introduced in the clinical practice as a promising, reversible, direct thrombin inhibitor with a predictable anticoagulant effect. Initial randomized clinical trials demonstrated that bivalirudin compared with heparin on top of a glycoprotein IIb/IIIa inhibitor was associated with a significant reduction of major bleeding and favorable net clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The HORIZON-AMI trial even indicated mortality benefit in bivalirudin-treated patients. Thereby, the 2011 and 2012 European Society of Cardiology Guidelines on the management of non-ST-segment elevation ACS and ST-segment elevation myocardial infarction positioned bivalirudin as the anticoagulant of choice in the PCI setting. Further randomized studies, better reflecting routine clinical practice, revealed significantly increased rates of stent thrombosis and myocardial infarction in the bivalirudin arm. Additionally, these findings were corroborated in the subsequent meta-analyses. Speculations that excessive occurrence of stent thrombosis and myocardial infarction may be caused by too short duration of post PCI bivalirudin infusion did not find confirmation in the latest MATRIX trial. In this systematic review, we aim to assess the efficacy and safety of bivalirudin therapy in patients undergoing PCI and to formulate recommendations on the bivalirudin use for clinicians. In our opinion, the research evidence and pharmacoeconomic considerations strongly support the use of bivalirudin in PCI patients at high risk of bleeding complications, while in other situations old and inexpensive UFH or enoxaparin remain the first line antithrombotic drugs.

Rivaroxaban: An Evaluation of its Cardiovascular Benefit-Risk Profile Across Indications Based on Numbers Needed to Treat or Harm, and on Clinically Meaningful Endpoint Comparisons.

The decision to prescribe anticoagulant therapy must consider the balance between reducing the risk of thromboembolic events and increasing the risk of bleeding. Although assessments of net clinical outcomes with oral anticoagulants are not new, this article presents an evaluation of benefit–risk by considering only events of substantial and comparable clinical relevance (i.e., events with serious long-term sequelae likely to have irreversible consequences, including death). This is based on the concept of the number of patients who need to be treated to elicit one beneficial [number needed to treat (NNT)] or harmful [number needed to harm (NNH)] event. The approach is illustrated using data from phase III trials of rivaroxaban, selected because it has the broadest range of approved indications of the novel oral anticoagulants. For example, in the ATLAS ACS 2 TIMI 51 trial of rivaroxaban plus standard antiplatelet therapy following an acute coronary syndrome event, the current analysis demonstrates that 63 patients need to be treated (over 24 months) to prevent one all-cause mortality event compared with placebo (NNT = 63). Conversely, 500 patients need to be treated to cause one additional intracranial hemorrhage (NNH = 500). The most relevant and clinically meaningful assessment of benefit–risk may therefore be achieved by focusing only on events of greatest concern to patients and physicians, namely those with (potentially) long-lasting, severe consequences. Although there are clear limitations to this type of analysis, rivaroxaban appears to demonstrate a broadly favorable benefit–risk profile across multiple clinical indications.

Duration of dual antiplatelet therapy following drug-eluting coronary stents: Longer or shorter?

Article history: Received 27 August 2015 Accepted 21 September 2015 Available online 26 September 2015 net clinical outcomes compared with patients assigned 12 months of DAPT after percutaneous coronary intervention (PCI) with a DES, according to new data from the ISAR-SAFE study [5]. At the same time, the ITALIC trial showed that rates of bleeding and of thrombotic events were not significantly different for the six-month versus 24-month long DAPT after PCI with new generation DES in good aspirin responders [6]. All in all, the optimal duration of DAPT after DES implantation re-

Novel antiplatelet agents in cardiovascular medicine.

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker, particularly clopidogrel, has been the standard of therapy for secondary prevention in patients with acute coronary syndromes and patients treated with percutaneous coronary intervention. More potent P2Y12 inhibitors such as ticagrelor and prasugrel are associated with better pharmacodynamic effect and improved clinical outcomes but are associated with an increased risk of bleeding compared to clopidogrel. In addition, the observation of treatment failure in ~10% of high-risk patients treated with aspirin and a potent P2Y12 inhibitor is another major concern. Personalized antiplatelet therapy based on therapeutic winnow concept for P2Y12 receptor blocker may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome. New class of agents like vorapaxar has been approved by the FDA to reduce thrombotic events in patients with a history of myocardial infarction or with peripheral arterial disease. In addition, new P2Y12 receptor and protease-activated receptor (PAR)-1 receptor antagonists and agents targeting intracellular signaling downstream from G protein-coupled receptors are among the novel strategies under investigation to prevent arterial ischemic event occurrences.

Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial

BackgroundPatients receiving oral anticoagulation (OAC) who undergo drug-eluting stent (DES) implantation require additional dual antiplatelet therapy with aspirin and clopidogrel. Such triple therapy confers an elevated bleeding risk, and its optimal duration is not known. ObjectivesThe goal of this study was to evaluate whether shortening the duration of clopidogrel therapy from 6 months to 6 weeks after DES implantation was associated with a superior net clinical outcome in patients receiving concomitant aspirin and OAC. MethodsIn this randomized, open-label trial, we enrolled patients receiving OAC who underwent DES implantation at 3 European centers between September 2008 and December 2013. A total of 614 patients receiving concomitant aspirin and OAC were randomized to either 6-week clopidogrel therapy (n = 307) or 6-month clopidogrel therapy (n = 307). The primary endpoint was a composite of death, myocardial infarction (MI), definite stent thrombosis, stroke, or Thrombolysis In Myocardial Infarction (TIMI) major bleeding at 9 months. ResultsThe primary endpoint occurred in 30 patients (9.8%) in the 6-week group compared with 27 patients (8.8%) in the 6-month group (hazard ratio [HR]: 1.14; 95% CI: 0.68 to 1.91; p = 0.63). There were no significant differences for the secondary combined ischemic endpoint of cardiac death, MI, definite stent thrombosis, and ischemic stroke (12 [4.0%] vs. 13 [4.3%]; HR: 0.93; 95% CI: 0.43 to 2.05; p = 0.87) or the secondary bleeding endpoint of TIMI major bleeding (16 [5.3%] vs. 12 [4.0%]; HR: 1.35; 95% CI: 0.64 to 2.84; p = 0.44). ConclusionsSix weeks of triple therapy was not superior to 6 months with respect to net clinical outcomes. These results suggest that physicians should weigh the trade-off between ischemic and bleeding risk when choosing the shorter or longer duration of triple therapy. (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE]; NCT00776633)

Comparison of short- and medium-term clinical outcomes between transradial approach and transfemoral approach in a high-volume PCI heart center in China.

BackgroundTransradial approach (TRA) outweighed transfemoral approach (TFA) in acute coronary syndrome patients because the former has better short-term outcomes in high-volume percutaneous coronary intervention (PCI) centers. Our study was one of the limited studies specifically in comparing the short- and medium-term effects of TRA and those of TFA in patients undergoing elective PCIs.MethodsA total of 21,242 patients who underwent elective PCI with stent implantation were included. Using propensity score methodology, 1,634 patient pairs were matched. Major clinical outcomes and PCI-related complications between TRA and TFA were compared.ResultsIn the propensity score-matched patients, the rates of in-hospital net adverse clinical events, which included death, myocardial infarction (MI), target vessel revascularization (TVR), stroke, and major bleeding, were much lower with TRA than with TFA (1.8% vs. 3.9%, P < 0.001). This difference was mainly due to the lower rate of major bleeding (0.6% vs. 1.8%, P < 0.001) and the decreased rate of MI (1.1% vs. 1.9%, P = 0.060). PCI-related dissection and thrombosis were similar between the TRA and TFA groups (both P > 0.05). Meanwhile, one-year incidence rates of major adverse cardiovascular events, which included death, MI, and TVR, were also similar (4.1% vs. 4.9%, P = 0.272) in TRA and TFA. Multivariable regression analyses showed that TRA was an independent predictor of the low rate of in-hospital net adverse clinical events (odds ratio, 0.53; 95% confidence interval, 0.40 to 0.71), but not of major adverse cardiovascular events at one-year follow-up (hazard ratio, 1.01; 95% confidence interval, 0.96 to 1.06).ConclusionsIn patients undergoing elective PCI, TRA patients had lower rates of in-hospital net adverse clinical outcomes compared with TFA patients. TRA might be recommended as a routine approach in high-volume PCI hospitals for elective PCIs.

Vorapaxar in patients with diabetes mellitus and previous myocardial infarction: findings from the thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events-TIMI 50 trial.

Vorapaxar reduces cardiovascular death, myocardial infarction (MI), or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus (DM) are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis. We examined the efficacy of vorapaxar in patients with and without DM who qualified for the trial with a previous MI. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, the analysis (n=16 896) excluded such patients. The primary end point of cardiovascular death, MI, or stroke occurred more frequently in patients with DM than in patients without DM (rates in placebo group: 14.3% versus 7.6%; adjusted hazard ratio, 1.47; P<0.001). In patients with DM (n=3623), vorapaxar significantly reduced the primary end point (11.4% versus 14.3%; hazard ratio, 0.73 [95% confidence interval, 0.60-0.89]; P=0.002) with a number needed to treat to avoid 1 major cardiovascular event of 29. The incidence of moderate/severe bleeding was increased with vorapaxar in patients with DM (4.4% versus 2.6%; hazard ratio, 1.60 [95% confidence interval, 1.07-2.40]). However, net clinical outcome integrating these 2 end points (efficacy and safety) was improved with vorapaxar (hazard ratio, 0.79 [95% confidence interval, 0.67-0.93]). In patients with previous MI and DM, the addition of vorapaxar to standard therapy significantly reduced the risk of major vascular events with greater potential for absolute benefit in this group at high risk of recurrent ischemic events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.

Bivalirudin Versus Heparin With or Without Glycoprotein IIb/IIIa Inhibitors in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention

In the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) treated with bivalirudin had lower bleeding and mortality rates, but higher acute stent thrombosis rates compared with heparin+ a glycoprotein IIb/IIIa inhibitor (GPI). Subsequent changes in primary PCI, including the use of potent P2Y12 inhibitors, frequent radial intervention, and pre-hospital medication administration, were incorporated into the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, which assigned 2,218 patients to bivalirudin versus heparin ± GPI before primary PCI. The goal of this study was to examine the outcomes of procedural anticoagulation with bivalirudin versus heparin ± GPI for primary PCI, given the evolution in primary PCI. Databases from HORIZONS-AMI and EUROMAX were pooled for patient-level analysis. The Breslow-Day test evaluated heterogeneity between trials. A total of 5,800 patients were randomized to bivalirudin (n= 2,889) or heparin ± GPI (n= 2,911). The radial approach was used in 21.3% of patients, prasugrel/ticagrelor was used in 18.1% of patients, and GPI was used in 84.8% of the control group. Bivalirudin compared with heparin ± GPI resulted in reduced 30-day rates of major bleeding (4.2% vs. 7.8%; relative risk [RR]: 0.53; 95% confidence interval [CI]: 0.43 to 0.66; p< 0.0001), thrombocytopenia (1.4% vs. 2.9%, RR: 0.48; 95% CI: 0.33 to 0.71; p= 0.0002), and cardiac mortality (2.0% vs. 2.9%; RR: 0.70; 95% CI: 0.50 to 0.97; p= 0.03), with nonsignificantly different rates of reinfarction, ischemia-driven revascularization, stroke, and all-cause mortality. Bivalirudin resulted in increased acute (<24 h) stent thrombosis rates (1.2% vs. 0.2%; RR: 6.04; 95% CI: 2.55 to 14.31; p< 0.0001), with nonsignificantly different rates of subacute stent thrombosis. Composite net adverse clinical events were lower with bivalirudin (8.8% vs. 11.9%; RR: 0.74; 95% CI: 0.63 to 0.86; p< 0.0001). There was no significant heterogeneity between the 2 trials for these outcomes, and results were consistent across major subgroups. Despite increased acute stent thrombosis, primary PCI with bivalirudin improved 30-day net clinical outcomes, with significant reductions in major bleeding, thrombocytopenia, and transfusions comparedwith heparin ± GPI, results that were consistent with evolution in PCI technique and pharmacotherapy. (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966) (European Ambulance Acute Coronary Syndrome Angiography [EUROMAX]; NCT01087723).

Abstract 16185: Medicare Budget Implications of Left Atrial Appendage Closure for Stroke Risk Reduction in Non-Valvular Atrial Fibrillation

Introduction: Strokes associated with atrial fibrillation (AF) are estimated to cost Medicare $8 billion annually. Advancements in stroke prevention are aimed at improving clinical outcomes and reducing healthcare costs. This analysis quantifies the budget impact to Medicare and Medicare beneficiaries of left atrial appendage closure (LAAC) with the Watchman Device compared to warfarin, the standard of care, and rivaroxaban, the most commonly prescribed new oral anticoagulant in the US, for stroke risk reduction in non-valvular AF. Methods: A budget impact model was developed from a Medicare perspective using 2.3-year data from PROTECT AF and relative risks from ROCKET AF. The model captured all costs of treatment and associated complications. Costs for stroke included acute, direct costs as well as long-term disability costs. Cost data were from 2014 US DRGs. Medicare deductibles and co-insurance rates were used in the patient analysis. Results: In addition to better net clinical outcomes (table), LAAC is cost neutral to Medicare relative to warfarin and rivaroxaban by year 5, and one third less costly than both by year 10. Treatment-related complications comprised 33% of LAAC total costs compared to 65% for rivaroxaban and 87% for warfarin at year 5. Patient out-of-pocket costs for LAAC were lower than warfarin and rivaroxaban at 2 and 3 years, respectively. Conclusions: Upfront LAAC procedural costs are offset by ongoing therapy and complication costs associated with warfarin and rivaroxaban. LAAC with Watchman represents an opportunity for improved clinical outcomes and substantial savings to both Medicare and Medicare beneficiaries.

Abstract 19119: Concomitant Use of Antiplatelet Therapy with Edoxaban or Warfarin in Patients with Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial

BACKGROUND: Patients with atrial fibrillation (AF) who receive both antiplatelet (AP) and anticoagulant therapy are at markedly higher risk of bleeding. The ENGAGE AF-TIMI 48 trial showed that both the high- (HD) and low-dose (LD) regimens of the once-daily factor Xa inhibitor edoxaban (Edox) were as effective as well-managed warfarin (Warf) (median TTR 68.4%) in preventing stroke or systemic embolism (SEE) with significant reductions in major bleeding and cardiovascular mortality. In this study, we assessed the relative efficacy and safety of Edox as compared with Warf in patients with and without concomitant use of AP therapy. METHODS: This was a randomized, double-blind, double-dummy trial comparing HD (60 mg daily, reduced to 30mg in patients with anticipated increased drug exposure) and LD (30 mg daily, reduced to 15mg) Edox with Warf. Dual AP therapy was prohibited while receiving study drug. Cox proportional hazards models were performed stratified by AP use at 3 months with treatment as a covariate. RESULTS: Of the 21,105 patients, 4,912 (23%) were receiving AP therapy at 3 months (92% aspirin). Patients who received concomitant AP therapy had higher rates of major bleeding compared to patients who did not (Fig). Both Edox regimens had similar relative efficacy in preventing stroke or SEE compared with Warf regardless of concomitant AP use (P int &gt;0.10 for both) with consistent reductions in major bleeding (HD Edox vs. Warf: P int =0.91; LD Edox vs. Warf: P int =0.59). In patients randomized to LD Edox, AP therapy was associated with a further reduction in the net clinical outcome of death, stroke, SEE, or major bleeding (P int =0.02) compared with Warf. CONCLUSIONS: Regardless of concomitant AP therapy, both doses of Edox significantly reduced bleeding compared to well-managed Warf. The safety profile of Edox may be particularly attractive in patients with AF who receive a combination of AP and anticoagulant therapy because of higher absolute risk of bleeding.