Impact of triple therapy in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention

Background and Purpose: Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) can be challenging since they have a higher thromboembolic and bleeding risk than younger patients. The current study aimed to assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplate- let therapy: aspirin plus clopidogrel) in patients > 75 years of age with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Methods: A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1- year of follow-up. Results: Five hundred and eighty-five patients, 289 (49%) of whom were > 75 years of age (79.6 ± 3.4 years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge who had a higher thromboembolic risk (CHA 2 DS 2 VASc score: 4.23 ± 1.51 vs 3.76 ± 1.40, p = 0.007 and a higher bleeding risk (HAS-BLED > 3: 88.6% vs 79.2%, p = 0.02) than those on DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01 - 0.70, p = 0.004). Major bleeding events occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = 0.002; HR 5.2, 95% CI: 1.53 - 17.57, p = 0.008). The overall mortality rate was similar in both treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12 - 0.86, p = 0.02). Conclusions In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associ- ated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding

Safety and efficacy of the supreme biodegradable polymer sirolimus-eluting stent in patients with diabetes mellitus

Patients with diabetes mellitus (DM) have worse outcomes following percutaneous coronary intervention than nondiabetic patients. The novel Supreme DES is a biodegradable polymer sirolimus-eluting stent designed to synchronize early drug delivery, limiting the potential for long-term inflammatory response. The purpose of this study was to evaluate the safety and efficacy of the Supreme DES in patients with DM. Methods This is a prespecified analysis of the diabetic subgroup from the PIONEER III randomized (2:1), controlled trial, comparing the Supreme DES with a durable polymer everolimus-eluting stent (DP-EES). The primary safety and efficacy composite endpoint was target lesion failure at 1 year, a composite of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Results The PIONEER III trial randomized 1629 patients, of which 494 (30.3%) had DM with 331 (398 lesions) randomly assigned to Supreme DES and 163 (208 lesions) to DP-EES. Among patients with DM, target lesion failure at 1 year was 6.1% (20/331) with Supreme DES vs 3.7% (6/163) with DP-EES (hazard ratio = 1.65; 95% confidence interval = 0.66-4.10, P = .28). The composite of cardiac death or target vessel myocardial infarction was 3.3% (11/331) with Supreme DES and 3.7% (6/163) with DP-EES (hazard ratio = 0.90; 95% confidence interval = 0.33-2.44, P = .83). There were no significant differences in other secondary endpoints. Conclusions This prespecified substudy of the PIONEER III trial demonstrated the relative safety and efficacy of the novel Supreme DES when compared with commercially available DP-EES in diabetics at 1 year. Longer term follow-up will be required to ensure continued safety and efficacy of the Supreme DES

Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events : The ODYSSEY OUTCOMES Trial

The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial compared alirocumab with placebo, added to high-intensity or maximum-tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio: 0.87; 95% confidence interval: 0.82 to 0.93) and death (hazard ratio: 0.83; 95% confidence interval: 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS

A controlled trial of rivaroxaban after transcatheter aortic-valve replacement

Background: whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. Methods: we randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. Results: after a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). Conclusions: in patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.)

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Effects of triple therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention regarding thromboembolic risk stratification

Background: the effects of dual antiplatelet therapy (DAPT) and triple therapy (TT: DAPT plus oral anticoagulation) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) regarding to CHA2DS2-VASc score remain undefined.We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score. Methods and results: in a prospective multicenter registry, 585 patients (75.2% male, 73.2 ± 8.2 years) with AF undergoing PCI were followed up during 1 year. Of them, 157 (26.8%) had a CHA2DS2-VASc=1, and 428 (73.2%) had a CHA2DS2-VASc ≥2. TT was prescribed in 51.6% with CHA2DS2-VASc=1 and in 55.5% with CHA2DS2-VASc ≥ 2. Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT (1.2% vs. 1.3%, P=0.73), but more total (19.5% vs. 6.9%, P=0.01) and a tendency to more major (4.9% vs. 0%, P=0.06) bleeding. However, patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate (1.7% vs. 5.3%, P=0.03) and a trend towards more bleeds (21.8% vs. 15.6%, P=0.06), with an excess of major bleeding (8.4% vs. 3.1%, P=0.01). Rates of major adverse cardiac events (MACE) in both CHA2DS2-VASc subgroups were similar, irrespective of treatment. In a Cox multivariate analysis, TT was associated to major bleeding, but not with MACE. Conclusions: in patients with AF and CHA2DS2-VASc=1 undergoing PCI, the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism

Impact of triple therapy in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention

Background and Purpose: Selecting an ideal antithrombotic therapy for elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) can be challenging since they have a higher thromboembolic and bleeding risk than younger patients. The current study aimed to assess the efficacy and safety of triple therapy (TT: oral anticoagulation plus dual antiplate- let therapy: aspirin plus clopidogrel) in patients > 75 years of age with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). Methods: A prospective multicenter study was conducted from 2003 to 2012 at 6 Spanish teaching hospitals. A cohort study of consecutive patients with AF undergoing PCI and treated with TT or dual antiplatelet therapy (DAPT) was analyzed. All outcomes were evaluated at 1- year of follow-up. Results: Five hundred and eighty-five patients, 289 (49%) of whom were > 75 years of age (79.6 ± 3.4 years; 33% women) were identified. TT was prescribed in 55.9% of patients at discharge who had a higher thromboembolic risk (CHA 2 DS 2 VASc score: 4.23 ± 1.51 vs 3.76 ± 1.40, p = 0.007 and a higher bleeding risk (HAS-BLED > 3: 88.6% vs 79.2%, p = 0.02) than those on DAPT. Therefore, patients on TT had a lower rate of thromboembolism than those on DAPT (0.6% vs 6.9%, p = 0.004; HR 0.08, 95% CI: 0.01 - 0.70, p = 0.004). Major bleeding events occurred more frequently in patients on TT than in those on DAPT (11.7% vs 2.4%, p = 0.002; HR 5.2, 95% CI: 1.53 - 17.57, p = 0.008). The overall mortality rate was similar in both treatment groups (11.9% vs 13.9%, p = 0.38); however, after adjustment for confounding variables, TT was associated with a reduced mortality rate (HR 0.33, 95% CI: 0.12 - 0.86, p = 0.02). Conclusions In elderly patients with AF undergoing PCI, the use of TT compared to DAPT was associ- ated with reduced thromboembolism and mortality rates, although a higher rate of major bleeding

Effects of triple therapy in patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention regarding thromboembolic risk stratification

Background: the effects of dual antiplatelet therapy (DAPT) and triple therapy (TT: DAPT plus oral anticoagulation) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) regarding to CHA2DS2-VASc score remain undefined.We compare the effect of TT vs. DAPT in this setting regarding the CHA2DS2-VASc score. Methods and results: in a prospective multicenter registry, 585 patients (75.2% male, 73.2 ± 8.2 years) with AF undergoing PCI were followed up during 1 year. Of them, 157 (26.8%) had a CHA2DS2-VASc=1, and 428 (73.2%) had a CHA2DS2-VASc ≥2. TT was prescribed in 51.6% with CHA2DS2-VASc=1 and in 55.5% with CHA2DS2-VASc ≥ 2. Patients with CHA2DS2-VASc=1 receiving TT had a similar thromboembolism rate to those on DAPT (1.2% vs. 1.3%, P=0.73), but more total (19.5% vs. 6.9%, P=0.01) and a tendency to more major (4.9% vs. 0%, P=0.06) bleeding. However, patients with CHA2DS2-VASc ≥ 2 receiving TT had a lower thromboembolism rate (1.7% vs. 5.3%, P=0.03) and a trend towards more bleeds (21.8% vs. 15.6%, P=0.06), with an excess of major bleeding (8.4% vs. 3.1%, P=0.01). Rates of major adverse cardiac events (MACE) in both CHA2DS2-VASc subgroups were similar, irrespective of treatment. In a Cox multivariate analysis, TT was associated to major bleeding, but not with MACE. Conclusions: in patients with AF and CHA2DS2-VASc=1 undergoing PCI, the use of TT involves a high risk of bleeding without a significant benefit in preventing thromboembolism

Bivalirudin for patients with acute coronary syndromes

Background: Current guidelines for patients with moderate- or high-risk acute coronary syndromes recommend an early invasive approach with concomitant antithrombotic therapy, including aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors. We evaluated the role of thrombin-specific anticoagulation with bivalirudin in such patients. Methods: We assigned 13,819 patients with acute coronary syndromes to one of three antithrombotic regimens: unfractionated heparin or enoxaparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin alone. The primary end points were a composite ischemia end point (death, myocardial infarction, or unplanned revascularization for ischemia), major bleeding, and the net clinical outcome, defined as the combination of composite ischemia or major bleeding. Results: Bivalirudin plus a glycoprotein IIb/IIIa inhibitor, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with noninferior 30-day rates of the composite ischemia end point (7.7% and 7.3%, respectively), major bleeding (5.3% and 5.7%), and the net clinical outcome end point (11.8% and 11.7%). Bivalirudin alone, as compared with heparin plus a glycoprotein IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia end point (7.8% and 7.3%, respectively; P = 0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% vs. 5.7%; P<0.001; relative risk, 0.53; 95% CI, 0.43 to 0.65) and the net clinical outcome end point (10.1% vs. 11.7%; P = 0.02; relative risk, 0.86; 95% CI, 0.77 to 0.97). Conclusions: In patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment with glycoprotein IIb/IIIa inhibitors, bivalirudin was associated with rates of ischemia and bleeding that were similar to those with heparin. Bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding. (ClinicalTrials.gov number, NCT00093158.