Efficacy and safety of bivalirudin in coronary artery disease patients with mild to moderate chronic kidney disease: Meta-analysis.

BACKGROUND: Patients with chronic kidney disease (CKD) have elevated bleeding and ischemic outcomes. We aim to assess the short- and long-term efficacy and safety of bivalirudin compared to heparin plus glycoprotein IIb/IIIa inhibitors (GPIs) in coronary artery disease (CAD) patients with CKD. METHODS: Randomized trials were searched in PubMed, Cochrane, and Embase databases up to January 2017. Among the trials retrieved, efficacy endpoints were defined as mortality, myocardial infarction (MI), repeat revascularization, stent thrombosis, and major adverse cardiac events (MACEs). Safety endpoints were reported as non-coronary artery bypass grafting (CABG) related major bleeding and thrombolysis in myocardial infarction (TIMI) major bleeding. Risk ratio (RR) and 95% confidence interval (CI) were calculated for each outcome using a fixed effect model. RESULTS: Five studies with a total of 3796 patients were included. In short-term follow up (30 days), bivalirudin significantly reduced non-CABG related major bleeding (p=0.0004) and TIMI major bleeding (p=0.007) compared to heparin plus GPIs. No significant differences were observed in rates of mortality, MI, repeat revascularization, stent thrombosis, and MACEs between the two groups in short- and long-term follow up (6 months to 3 years). In patients with ST elevated myocardial infarction (STEMI) with concurrent CKD, the decreased non-CABG related major bleeding (p=0.04) without increasing ischemic events was also observed after short-term follow up. CONCLUSIONS: (1) Bivalirudin is safer than and as effective as heparin plus GPIs in CAD patients with CKD. (2) Impaired renal function does not affect the safety benefits of bivalirudin. (3) Similar efficacy profiles were identified between the two groups after both short- and long-term follow up in the CAD patients with CKD.

Impact of design of coronary stents and length of dual antiplatelet therapies on ischaemic and bleeding events: a network meta-analysis of 64 randomized controlled trials and 102 735 patients.

AIMS: The differential impact on ischaemic and bleeding events of the type of drug-eluting stent [durable polymer stents [DES] vs. biodegradable polymer stents vs. bioresorbable scaffolds (BRS)] and length of dual antiplatelet therapy (DAPT) remains to be defined. METHODS AND RESULTS: Randomized controlled trials comparing different types of DES and/or DAPT durations were selected. The primary endpoint was Major Adverse Cardiovascular Events (MACE) [a composite of death, myocardial infarction (MI), and target vessel revascularization]. Definite stent thrombosis (ST) and single components of MACE were secondary endpoints. The arms of interest were: BRS with 12 months of DAPT (12mDAPT), biodegradable polymer stent with 12mDAPT, durable polymer stent [everolimus-eluting (EES), zotarolimus-eluting (ZES)] with 12mDAPT, EES/ZES with <12 months of DAPT, and EES/ZES with >12 months of DAPT (DAPT > 12 m). Sixty-four studies with 150 arms and 102 735 patients were included. After a median follow-up of 20 months, MACE rates were similar in the different arms of interest. EES/ZES with DAPT > 12 m reported a lower incidence of MI than the other groups, while BRS showed a higher rate of ST when compared to EES/ZES, irrespective of DAPT length. A higher risk of major bleedings was observed for DAPT > 12 m as compared to shorter DAPT. CONCLUSION: Durable and biodegradable polymer stents along with BRS report a similar rate of MACE irrespective of DAPT length. Fewer MI are observed with EES/ZES with DAPT > 12 m, while a higher rate of ST is reported for BRS when compared to EES/ZES, independently from DAPT length. Stent type may partially affect the outcome together with DAPT length.

Validation of the DAPT score in patients randomized to 6 or 12 months clopidogrel after predominantly second-generation drug-eluting stents.

The DAPT score is a recently-proposed decision tool for guiding optimal duration of dual antiplatelet therapy (DAPT). It showed modest accuracy in prior derivation and validation cohorts of patients with ≥12 months DAPT. This study was aimed to evaluate the validity of the DAPT score in a cohort of patients with 6 or 12 months DAPT after implantation of predominantly second-generation drug-eluting stents. We analyzed data of patients enrolled in the ISAR-SAFE trial. Patients were classified into low (<2) or high (≥2) DAPT score groups. Primary ischaemic (all-cause death, myocardial infarction, definite stent thrombosis or stroke) and bleeding (TIMI major or minor) outcomes were analyzed in the low and high DAPT score groups. Data of 3976 patients were available for DAPT score calculation. 2407 patients (60.5 %) were classified in the low DAPT score group and 1569 patients (39.5 %) in the high DAPT score group. In the low DAPT score group there were no significant differences between 6 and 12 months DAPT regarding ischaemic (1.0 % vs. 1.4 %, HR=0.74, 95 % CI, 0.35-1.57; p=0.43) or bleeding outcomes (0.3 % vs. 0.8 %, HR=0.44, 95 % CI, 0.13-1.42; p=0.17). In the high DAPT score group there were also no significant differences between 6 and 12 months DAPT regarding ischaemic (1.9 % vs. 1.8 %, HR=1.02, 95 % CI, 0.49-2.14; p=0.96) or bleeding (0.3 % vs. 0.5 %, HR=0.51, 95 % CI, 0.09-2.78; p=0.44) outcomes. In conclusion, the DAPT score failed to show a differential treatment effect in patients receiving 6 or 12 months DAPT after contemporary drug-eluting stent implantation.

Outcomes of ≤6-month versus 12-month dual antiplatelet therapy after drug-eluting stent implantation: A meta-analysis and meta-regression.

BACKGROUND: The benefit of ≤6-month compared with 12-month dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) placement remains controversial. We performed a meta-analysis and meta-regression of ≤6-month versus 12-month DAPT in patients undergoing PCI with DES placement. METHODS: We conducted electronic database searches of randomized controlled trials (RCTs) comparing DAPT durations after DES placement. For studies with longer follow-up, outcomes at 12 months were identified. Odds ratios and 95% confidence intervals were computed with the Mantel-Haenszel method. Fixed-effect models were used; if heterogeneity (I) > 40 was identified, effects were obtained with random models. RESULTS: Nine RCTs were included with total n = 19,224 patients. No significant differences were observed between ≤6-month compared with 12-month DAPT in all-cause mortality (OR 0.87; 95% confidence interval (CI): 0.69-1.11), cardiovascular (CV) mortality (OR 0.89; 95% CI: 0.66-1.21), non-CV mortality (OR 0.85; 95% 0.58-1.24), myocardial infarction (OR 1.10; 95% CI: 0.89-1.37), stroke (OR 0.97; 95% CI: 0.67-1.42), stent thrombosis (ST) (OR 1.37; 95% CI: 0.89-2.10), and target vessel revascularization (OR 0.95; 95% CI: 0.77-1.18). No significant difference in major bleeding (OR 0.72; 95% CI: 0.49-1.05) was observed, though the all-bleeding event rate was significantly lower in the ≤6-month DAPT group (OR 0.76; 95% CI: 0.59-0.96). In the meta-regression analysis, a significant association between bleeding events and non-CV mortality with 12-month DAPT was found, as well as between ST and mortality in addition to MI with ≤6-month DAPT. CONCLUSION: DAPT for ≤6 months is associated with similar mortality and ischemic outcomes but less bleeding events compared with 12-month DAPT after PCI with DES.

Six Versus Twelve Months Clopidogrel Therapy After Drug-Eluting Stenting in Patients With Acute Coronary Syndrome: An ISAR-SAFE Study Subgroup Analysis.

In patients presenting with acute coronary syndrome (ACS) the optimal duration of dual-antiplatelet therapy after drug-eluting stent (DES) implantation remains unclear. At 6 months after intervention, patients receiving clopidogrel were randomly assigned to either a further 6-month period of placebo or clopidogrel. The primary composite endpoint was death, myocardial infarction, stent thrombosis, stroke, or major bleeding 9 months after randomization. The ISAR-SAFE trial was terminated early due to low event rates and slow recruitment. 1601/4000 (40.0%) patients presented with ACS and were randomized to 6 (n = 794) or 12 months (n = 807) clopidogrel. The primary endpoint occurred in 14 patients (1.8%) receiving 6 months of clopidogrel and 17 patients (2.2%) receiving 12 months; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.41-1.68, P = 0.60. There were 2 (0.3%) cases of stent thrombosis in each group; HR 1.00, 95% CI 0.14-7.09, P = >0.99. Major bleeding occurred in 3 patients (0.4%) receiving 6 months clopidogrel and 5 (0.6%) receiving 12 months; HR 0.60, 95% CI 0.15-2.49, P = 0.49. There was no significant difference in net clinical outcomes after DES implantation in ACS patients treated with 6 versus 12 months clopidogrel. Ischaemic and bleeding events were low beyond 6-months.

Association of progression or regression of coronary artery atherosclerosis with long-term prognosis.

BACKGROUND: The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically proven coronary artery disease. METHODS: The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. RESULTS: Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), the group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=.004 for 0.1 mm reduction in mean MLD). CONCLUSIONS: Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.

Increased bleeding risk during percutaneous coronary interventions by arterial hypertension.

OBJECTIVES: We aimed to assess the association between arterial hypertension and bleeding in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: The impact of arterial hypertension on bleeding risk of patients with coronary artery disease undergoing PCI is unknown. METHODS: This study included 14,180 patients who underwent PCI. Bleeding was defined using the Bleeding Academic Research Consortium (BARC) criteria. Arterial hypertension was defined as treatment with antihypertensive drugs or a systolic blood pressure >140 mm Hg and/or diastolic blood pressure value >90 mm Hg documented on at least 2 occasions. The primary outcome was bleeding rate within 30 days of PCI. RESULTS: Overall, 11,066 patients (78.0%) had arterial hypertension. Bleeding events occurred in 1,232 patients with arterial hypertension and 278 patients without arterial hypertension (11.1% vs 8.9%; odds ratio [OR] = 1.28, 95% confidence interval [CI] 1.11-1.46, P < 0.001). Access-site bleeding occurred in 730 patients with arterial hypertension and 175 patients without arterial hypertension (6.6% vs 5.6%: OR = 1.19 [1.01-1.41], P = 0.049). Non-access-site bleeding occurred in 502 patients with and 103 patients without arterial hypertension (4.5% vs 3.3%; OR = 1.39 [1.12-1.72], P = 0.003). After adjustment, arterial hypertension was significantly associated with any bleeding (adjusted OR = 1.41 [1.19-1.67], P < 0.001), access-site bleeding (adjusted OR = 1.36 [1.10-1.68], P = 0.005) and non-access-site bleeding (adjusted OR = 1.42 [1.09-1.83], P = 0.008). A history of arterial hypertension increased the risk of non-access-site bleeding (P = 0.002), whereas systolic blood pressure at the time of PCI increased the risk of access site bleeding (P = 0.018). CONCLUSIONS: Arterial hypertension is associated with increased risk of bleeding during PCI procedures. © 2015 Wiley Periodicals, Inc.

Impact of Dabigatran versus Phenprocoumon on ADP Induced Platelet Aggregation in Patients with Atrial Fibrillation with or without Concomitant Clopidogrel Therapy (the Dabi-ADP-1 and Dabi-ADP-2 Trials).

BACKGROUND: A relevant number of patients receive triple therapy with clopidogrel, aspirin, and oral anticoagulation. Clopidogrel's efficacy on ADP induced platelet function may be influenced by concomitant antithrombotic therapies. Data regarding the effect of dabigatran on platelet function is limited to in vitro studies and healthy individuals. METHODS: The "Dabi-ADP-1" and "Dabi-ADP-2" trials randomized patients with atrial fibrillation to either dabigatran or phenprocoumon for a 2-week period. In Dabi-ADP-1 (n = 70) patients with clopidogrel therapy were excluded and in Dabi-ADP-2 (n = 46) patients had to be treated concomitantly with clopidogrel. The primary endpoint was ADP-induced platelet aggregation between dabigatran and phenprocoumon at 14 days. Secondary endpoints were ADPtest HS-, TRAP-, and COL-induced platelet aggregation. RESULTS: There was no significant difference regarding the primary endpoint between both groups in either trial (Dabi-ADP-1: Dabigatran: 846 [650-983] AU × min versus phenprocoumon: 839 [666-1039] AU × min, P = 0.90 and Dabi-ADP-2: 326 [268-462] versus 350 [214-535], P = 0.70) or regarding the secondary endpoints, ADPtest HS-, TRAP-, and COL-induced platelet aggregation. CONCLUSION: Dabigatran as compared to phenprocoumon has no impact on ADP-induced platelet aggregation in atrial fibrillation patients neither with nor without concomitant clopidogrel therapy.

Long-Term Efficacy and Safety of Paclitaxel-Eluting Balloon for the Treatment of Drug-Eluting Stent Restenosis: 3-Year Results of a Randomized Controlled Trial.

OBJECTIVES: This study sought to investigate the long-term comparative efficacy and safety of paclitaxel-eluting balloon (PEB), paclitaxel-eluting stent (PES), or balloon angioplasty (BA) for the treatment of drug-eluting stent restenosis. BACKGROUND: The optimal treatment of drug-eluting stent restenosis remains unknown. Although PEB has shown encouraging results, the long-term clinical efficacy and safety of PEB remains poorly defined. METHODS: A total of 402 patients with clinically significant restenosis in limus-eluting stents were randomly assigned to receive PEB (n = 137), PES (n = 131), or BA (n = 134). For this analysis, PEB versus PES and PEB versus BA were compared. The primary efficacy and safety endpoints were target lesion revascularization and the composite of death or myocardial infarction. RESULTS: At a median follow-up of 3 years, the risk of target lesion revascularization was comparable with PEB versus PES (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 0.91 to 2.33; p = 0.11) and lower with PEB versus BA (HR: 0.51, 95% CI: 0.34 to 0.74; p < 0.001). The risk of death/myocardial infarction tended to be lower with PEB versus PES (HR: 0.55, 95% CI: 0.28 to 1.07; p = 0.08), due to a lower risk of death (HR: 0.38, 95% CI: 0.17 to 0.87; p = 0.02). The risk of death/myocardial infarction was similar with PEB versus BA (HR: 0.96, 95% CI: 0.46 to 2.0; p = 0.91). CONCLUSIONS: At 3 years, the use of PEB as compared with PES to treat patients with limus-eluting stent restenosis has similar efficacy and safety. PEB remains superior to BA. The sustained efficacy without trade-off in safety supports the role of PEB as treatment option for patients with drug-eluting stent restenosis. (Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis: 3 Treatment Approaches [ISAR-DESIRE 3]; NCT00987324).

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

BACKGROUND: Patients 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. OBJECTIVES: The 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. METHODS: In 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. RESULTS: The 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). CONCLUSIONS: Six 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).

ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting.

BACKGROUND: In patients receiving aspirin, the optimal duration of clopidogrel therapy after drug-eluting stent (DES) implantation remains unclear. METHODS: This multicentre, randomized, double-blind, placebo-controlled trial tested the hypothesis that in patients undergoing DES implantation, 6 months of clopidogrel is non-inferior to 12 months in terms of clinical outcomes. At 6 months after DES implantation, patients on clopidogrel were randomly assigned to either a 6-month period of placebo or an additional 6-month period of clopidogrel. The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, and thrombolysis in myocardial infarction major bleeding at 9 months after randomization. RESULTS: Owing to slow recruitment and low event rates, the trial was stopped prematurely after enrolment of 4005 of 6000 planned patients. Of 4000 patients included in the final analysis, 1997 received 6 months of clopidogrel and 2003 received 12 months. The primary endpoint occurred in 29 patients (1.5%) assigned to 6 months of clopidogrel and 32 patients (1.6%) assigned to 12 months, observed difference -0.1%, upper limit of one-sided 95% confidence interval (CI) 0.5%, limit of non-inferiority 2%, Pfor noninferiority <0.001. Stent thrombosis was observed in five patients (0.3%) assigned to 6 months of clopidogrel and three patients (0.2%) assigned to 12 months; hazard ratio (HR) 1.66, 95% CI: 0.40-6.96, P = 0.49. Thrombolysis in myocardial infarction major bleeding was observed in 4 patients (0.2%) assigned to 6 months clopidogrel and 5 patients (0.3%) assigned to 12 months; HR 0.80, 95% CI: 0.21-2.98, P = 0.74. CONCLUSIONS: In the present trial, characterized by low event rates, we did not observe a significant difference in net clinical outcome between 6 and 12 months of clopidogrel therapy after DES implantation. However, the results of the trial must be considered in view of its premature termination and lower than expected event rates. The trial is registered with ClinicalTrials.gov, Identifier: NCT00661206.

Comparison of vascular closure devices vs manual compression after femoral artery puncture: the ISAR-CLOSURE randomized clinical trial.

IMPORTANCE: The role of vascular closure devices (VCD) for the achievement of hemostasis in patients undergoing transfemoral coronary angiography remains controversial. OBJECTIVE: To compare outcomes with the use of 2 hemostasis strategies after diagnostic coronary angiography performed via transfemoral access-a VCD-based strategy with 2 types of devices, an intravascular device and an extravascular device, vs standard manual compression. The primary hypothesis to be tested was that femoral hemostasis achieved through VCD is noninferior to manual compression in terms of vascular access-site complications. A secondary objective was the comparison of the 2 types of VCD. DESIGN, SETTING, AND PARTICIPANTS: Randomized, large-scale, multicenter, open-label clinical trial. We enrolled 4524 patients undergoing coronary angiography with a 6 French sheath via the common femoral artery from April 2011 through May 2014 in 4 centers in Germany. Last 30-day follow-up was performed in July 2014. INTERVENTIONS: After angiography of the access site, patients were randomized to hemostasis with an intravascular VCD, extravascular VCD, or manual compression in a 1:1:1 ratio. MAIN OUTCOMES AND MEASURES: Primary end point: the composite of access site-related vascular complications at 30 days after randomization with a 2% noninferiority margin. Secondary end points: time to hemostasis, repeat manual compression, and VCD failure. An α-level of .025 was chosen for primary and secondary comparisons. RESULTS: Of the 4524 enrolled patients, 3015 were randomly assigned to a VCD group (1509 received intravascular VCD and 1506 received extravascular VCD) and 1509 patients were randomly assigned to the manual compression group. Before hospital discharge, duplex sonography of the access site was performed in 4231 (94%) patients. The primary end point was observed in 208 patients (6.9%) assigned to receive a VCD and 119 patients (7.9%) assigned to manual compression (difference, -1.0% [1-sided 97.5% CI, 0.7%]; P for noninferiority<.001). Time to hemostasis was significantly shorter in patients with VCD (1 minute [interquartile range {IQR}, 0.5-2.0]), vs manual compression (10 minutes [IQR, 10-15]; P < .001). Time to hemostasis was significantly shorter among patients with intravascular VCD (0.5 minute [IQR, 0.2-1.0]), vs extravascular VCD (2.0 minutes [IQR, 1.0-2.0]; P <.001) and closure device failure was also significantly lower among those with intravascular vs extravascular VCD (80 patients [5.3%], vs 184 patients [12.2%]; P < .001). CONCLUSIONS AND RELEVANCE: In patients undergoing transfemoral coronary angiography, VCDs were noninferior to manual compression in terms of vascular access-site complications and reduced time to hemostasis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01389375.