Marc A. Brouwer

Optimal duration of dual antiplatelet therapy after percutaneous coronary intervention with drug eluting stents: meta-analysis of randomised controlled trials

Objective To assess the benefits and risks of short term (<12 months) or extended (>12 months) dual antiplatelet therapy (DAPT) versus standard 12 month therapy, following percutaneous coronary intervention with drug eluting stents. Design Meta-analysis of randomised controlled trials. Data sources PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major congress proceedings, searched from 1 January 2002 to 16 February 2015. Review methods Trials comparing short term (<12 months) or extended (>12 months) DAPT regimens with standard 12 month duration of therapy. Primary outcomes were cardiovascular mortality, myocardial infarction, stent thrombosis, major bleeding, and all cause mortality. Results 10 randomised controlled trials (n=32 287) were included. Compared to 12 month DAPT, a short term course of therapy was associated with a significant reduction in major bleeding (odds ratio 0.58 (95% confidence interval 0.36 to 0.92); P=0.02) with no significant differences in ischaemic or thrombotic outcomes. Extended versus 12 month DAPT yielded a significant reduction in the odds of myocardial infarction (0.53 (0.42 to 0.66); P<0.001) and stent thrombosis (0.33 (0.21 to 0.51); P<0.001), but more major bleeding (1.62 (1.26 to 2.09); P<0.001). All cause but not cardiovascular death was also significantly increased (1.30 (1.02 to 1.66); P=0.03). Conclusions Compared with a standard 12 month duration, short term DAPT (<12 months) after drug eluting stent implementation yields reduced bleeding with no apparent increase in ischaemic complications, and could be considered for most patients. In selected patients with low bleeding risk and very high ischaemic risk, extended DAPT (>12 months) could be considered. The increase in all cause but not cardiovascular death with extended DAPT requires further investigation.

Aspirin Plus Coumarin Versus Aspirin Alone in the Prevention of Reocclusion After Fibrinolysis for Acute Myocardial Infarction Results of the Antithrombotics in the Prevention of Reocclusion In Coronary Thrombolysis (APRICOT)-2 Trial

Background—Despite the use of aspirin, reocclusion of the infarct-related artery occurs in ≈30% of patients within the first year after successful fibrinolysis, with impaired clinical outcome. This study sought to assess the impact of a prolonged anticoagulation regimen as adjunctive to aspirin in the prevention of reocclusion and recurrent ischemic events after fibrinolysis for ST-elevation myocardial infarction. Methods and Results—At coronary angiography <48 hours after fibrinolytic therapy, 308 patients receiving aspirin and intravenous heparin had a patent infarct-related artery (Thrombolysis In Myocardial Infarction [TIMI] grade 3 flow). They were randomly assigned to standard heparinization and continuation of aspirin alone or to a 3-month combination of aspirin with moderate-intensity coumarin, including continued heparinization until a target international normalized ratio (INR) of 2.0 to 3.0. Angiographic and clinical follow-up were assessed at 3 months. Median INR was 2.6 (25 to 75th percentiles 2.1 to 3.1). Reocclusion (≤TIMI grade 2 flow) was observed in 15% of patients receiving aspirin and coumarin compared with 28% in those receiving aspirin alone (relative risk [RR], 0.55; 95% CI 0.33 to 0.90;P <0.02). TIMI grade 0 to 1 flow rates were 9% and 20%, respectively (RR, 0.46; 95% CI, 0.24 to 0.89;P <0.02). Survival rates free from reinfarction and revascularization were 86% and 66%, respectively (P <0.01). Bleeding (TIMI major and minor) was infrequent: 5% versus 3% (P =NS). Conclusions—As adjunctive to aspirin, a 3-month-regimen of moderate-intensity coumarin, including heparinization until the target INR is reached, markedly reduces reocclusion and recurrent events after successful fibrinolysis. This conceptual study provides a mechanistic rationale to further investigate the role of prolonged anticoagulation after fibrinolytic therapy.

Manual vs. integrated automatic load-distributing band CPR with equal survival after out of hospital cardiac arrest. The randomized CIRC trial

OBJECTIVE To compare integrated automated load distributing band CPR (iA-CPR) with high-quality manual CPR (M-CPR) to determine equivalence, superiority, or inferiority in survival to hospital discharge. METHODS Between March 5, 2009 and January 11, 2011 a randomized, unblinded, controlled group sequential trial of adult out-of-hospital cardiac arrests of presumed cardiac origin was conducted at three US and two European sites. After EMS providers initiated manual compressions patients were randomized to receive either iA-CPR or M-CPR. Patient follow-up was until all patients were discharged alive or died. The primary outcome, survival to hospital discharge, was analyzed adjusting for covariates, (age, witnessed arrest, initial cardiac rhythm, enrollment site) and interim analyses. CPR quality and protocol adherence were monitored (CPR fraction) electronically throughout the trial. RESULTS Of 4753 randomized patients, 522 (11.0%) met post enrollment exclusion criteria. Therefore, 2099 (49.6%) received iA-CPR and 2132 (50.4%) M-CPR. Sustained ROSC (emergency department admittance), 24h survival and hospital discharge (unknown for 12 cases) for iA-CPR compared to M-CPR were 600 (28.6%) vs. 689 (32.3%), 456 (21.8%) vs. 532 (25.0%), 196 (9.4%) vs. 233 (11.0%) patients, respectively. The adjusted odds ratio of survival to hospital discharge for iA-CPR compared to M-CPR, was 1.06 (95% CI 0.83-1.37), meeting the criteria for equivalence. The 20 min CPR fraction was 80.4% for iA-CPR and 80.2% for M-CPR. CONCLUSION Compared to high-quality M-CPR, iA-CPR resulted in statistically equivalent survival to hospital discharge.

Uninterrupted Dabigatran versus Warfarin for Ablation in Atrial Fibrillation

BACKGROUND Catheter ablation of atrial fibrillation is typically performed with uninterrupted anticoagulation with warfarin or interrupted non–vitamin K antagonist oral anticoagulant therapy. Uninterrupted anticoagulation with a non–vitamin K antagonist oral anticoagulant, such as dabigatran, may be safer; however, controlled data are lacking. We investigated the safety of uninterrupted dabigatran versus warfarin in patients undergoing ablation of atrial fibrillation. METHODS In this randomized, open‐label, multicenter, controlled trial with blinded adjudicated end‐point assessments, we randomly assigned patients scheduled for catheter ablation of paroxysmal or persistent atrial fibrillation to receive either dabigatran (150 mg twice daily) or warfarin (target international normalized ratio, 2.0 to 3.0). Ablation was performed after 4 to 8 weeks of uninterrupted anticoagulation, which was continued during and for 8 weeks after ablation. The primary end point was the incidence of major bleeding events during and up to 8 weeks after ablation; secondary end points included thromboembolic and other bleeding events. RESULTS The trial enrolled 704 patients across 104 sites; 635 patients underwent ablation. Baseline characteristics were balanced between treatment groups. The incidence of major bleeding events during and up to 8 weeks after ablation was lower with dabigatran than with warfarin (5 patients [1.6%] vs. 22 patients [6.9%]; absolute risk difference, ‐5.3 percentage points; 95% confidence interval, ‐8.4 to ‐2.2; P<0.001). Dabigatran was associated with fewer periprocedural pericardial tamponades and groin hematomas than warfarin. The two treatment groups had a similar incidence of minor bleeding events. One thromboembolic event occurred in the warfarin group. CONCLUSIONS In patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin. (Funded by Boehringer Ingelheim; RE‐CIRCUIT ClinicalTrials.gov number, NCT02348723.)

Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review

Background Clopidogrel as an adjunct to aspirin has improved outcomes after acute coronary syndromes, but laboratory studies suggest a reduced antiplatelet effect when proton pump inhibitors (PPIs) are co-administered. Despite corroborating data from retrospective studies, new clinical data fuel the controversy on this issue. Purpose Systematic review of the impact of the addition of PPIs to clopidogrel on platelet function and cardiovascular outcome. Data sources PubMed, Web-of-Science, Cochrane Database and reference lists of related articles. Study selection Published articles on controlled studies addressing the addition of PPIs to clopidogrel. Platelet function studies describe patients as well as healthy volunteers. Clinical studies concern patients using clopidogrel for acute coronary syndromes or because of stent implantation for stable coronary disease. Data extraction Two investigators independently reviewed the identified articles for eligibility, and one author extracted the data. Data synthesis In 70% (7/10) of the laboratory studies examining healthy volunteers on clopidogrel, addition of PPIs resulted in a significant reduction in platelet inhibition. For patients, this was observed in 11/18 (61%) studies. The 33 clinical studies showed significant heterogeneity in observed outcomes, with risk ratios for major adverse cardiovascular events varying from 0.64 to 4.58 in the case of PPI use, which was randomly allocated in only two studies. Consequently, imbalances between prognosticators at baseline and PPI prescription bias markedly contributed to the variability in results. Conclusions Despite indications of reduced antiplatelet activity ex vivo in the case of PPI administration in clopidogrel users, data on the clinical consequences are controversial. With the accumulating evidence from better designed, prospective clinical studies, an adverse effect of PPI use on clinical outcome in patients on clopidogrel cannot be substantiated. This review challenges the validity of conclusions based on quantitative analyses of predominantly non-randomised data.

Pre-hospital triage for primary angioplasty: direct referral to the intervention center versus interhospital transport.

OBJECTIVES We sought to study the impact of direct referral to an intervention center after pre-hospital diagnosis of ST-segment elevation myocardial infarction (STEMI) on treatment intervals and outcome. BACKGROUND Primary angioplasty has become the preferred reperfusion strategy in STEMI. Ambulance diagnosis and direct referral to an intervention center is an attractive treatment option that has not been studied extensively. METHODS Consecutive pre-hospital patients with STEMI, who were referred to our intervention center for primary angioplasty between 2005 and 2007, were studied. After pre-hospital diagnosis, patients were either directly transported to our center or referred through a nonintervention center. The catheterization laboratory was activated before transport to the intervention center. RESULTS Of the 581 patients referred, 454 (78%) came with direct transport and 127 (22%) through a nonintervention center. Direct transport was associated with a higher proportion of patients treated within the 90-min time window of the STEMI guidelines: 82% versus 23% (p < 0.01). Patients directly transported had a significantly shorter median symptom-to-balloon time of 149 min (Interquartile range: 118 to 197 min) versus 219 min (interquartile range: 178 to 315 min), p < 0.01, a higher post-procedural Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 rate (92% vs. 84%; p = 0.03), and a lower 1-year mortality rate (7% vs. 13%; p = 0.03). Direct transport to the intervention center was independently associated with the symptom-to-balloon time, which in turn was an independent predictor of post-procedural TIMI flow grade 3, a strong prognosticator of outcome. CONCLUSIONS After ambulance-based diagnosis of STEMI, direct transport to an intervention center with pre-hospital notification of the catheterization laboratory more than triples the proportion of patients treated within the time window of the guidelines. Time to balloon was an independent predictor of post-procedural TIMI flow grade 3, which underscores the need to reduce treatment delays.

Adverse long-term effects of reocclusion after coronary thrombolysis

OBJECTIVES This study sought to assess the long-term clinical consequences of reocclusion after coronary thrombolysis. BACKGROUND After acute myocardial infarction successfully treated with thrombolysis, reocclusion occurs in approximately 30% of patients and leads to poorer in-hospital outcome. However, the long-term effects of reocclusion are unknown. METHODS Three hundred patients with no history of coronary surgery and with a patent infarct-related artery at coronary angiography within 48 h after thrombolysis were enrolled in the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT) trial. At a mean (+/- SD) of 77 +/- 23 days after thrombolysis, 248 patients (87%) underwent follow-up angiography. Reocclusion was observed in 71 (29%) of 248 patients. To compare outcome between 71 patients with and 177 without reocclusion an analysis of event-free survival, defined as a clinical course without death, reinfarction and revascularization, was performed. RESULTS Over a 3-year follow-up period, event-free survival was significantly better in patients without reocclusion: At 1 year it was 63% for patients with and 83% for those without reocclusion (p < 0.001). In the first year, two or more cardiac-related events occurred in 24% of patients with and 6% of those without reocclusion (p < 0.001). Patients with reocclusion had a markedly higher reinfarction and revascularization rate. At 1 year the reinfarction rate was 23% for patients with and 5% for those without reocclusion (p < 0.001). CONCLUSIONS This analysis shows the adverse influence of reocclusion on long-term clinical outcome in relation to reinfarction and need for revascularization. To further optimize prognosis after thrombolysis, prevention of reocclusion should become a main priority. Future research should focus on the criteria and timing of elective revascularization procedures in the prevention of coronary reocclusion.

The C50T polymorphism of the cyclooxygenase-1 gene and the risk of thrombotic events during low-dose therapy with acetyl salicylic acid.

Aspirin prevents thrombotic events by inhibiting platelet cyclooxygenase-1 (COX-1), thus reducing thromboxane A2 formation and platelet aggregation. The C50T polymorphism of COX-1 is associated with an impaired inhibition of both thromboxane production and in-vitro platelet aggregation by aspirin. We studied whether this polymorphism is also associated with the risk of clinical thrombotic events in patients using aspirin. We included 496 patients admitted to our Coronary Care Unit for various indications treated with aspirin 80 mg daily. Genotyping for the C50T polymorphism demonstrated that 86.7% of the patients had the common genotype, and 13.3% had the variant (12.5% heterozygous, 0.8% homozygous). Baseline variables were well balanced, except that patients with the common genotype more frequently used aspirin prior to admission compared to those patients with the variant genotype. The composite primary endpoint of myocardial infarction, stroke, and/or cardiovascular death occurred in 98 patients (19.8%). Myocardial infarction occurred in 9.6% of patients, stroke in 1.6%, and cardiovascular death in 12.1%. The unadjusted hazard ratio (95% CI) for the primary endpoint for patients with the variant versus the common genotype was 1.07 (0.62-1.85), p = 0.8. The adjusted hazard ratio was 0.86 (0.49-1.50), p = 0.6. In prior laboratory studies the COX-1 C50T polymorphism was associated with an impaired inhibitory effect of aspirin on thromboxane production and platelet function. However, in this cohort of patients using low-dose aspirin for secondary prevention the polymorphism was not associated with a higher risk of atherothrombotic events.

Antiplatelet treatment for coronary heart disease

Platelets play an essential role in the pathogenesis of acute coronary syndromes (ACS).1 Therefore an important part of the treatment of ACS, and of primary and secondary preventive measures in coronary heart disease, consists of antiplatelet treatment. Over the years antiplatelet treatment has evolved, and currently several types of antiplatelet drugs are available, each with their specific pharmacological target and with their specific clinical indications. Although antiplatelet treatment is beneficial for vascular patients as a group, some individual patients appear to derive less benefit. In this context the term antiplatelet-drug resistance has been introduced. To date, however, no definite cause, definition, or treatment has been determined for this phenomenon. These issues will be discussed in this article. In the case of vascular endothelial damage, the first haemostatic reaction is vasoconstriction. Thereafter, the platelets come into action and the coagulation system is activated. Through disruption of the endothelial layer of the vessel wall, tissue factor is exposed, initiating the coagulation cascade, resulting in thrombin formation. Also subendothelial collagen and Von Willebrand factor are exposed to the flowing blood. Following this event, platelets start to adhere to collagen and Von Willebrand factor through their respective receptors, forming a platelet monolayer covering the damaged part of the vessel wall. This monolayer serves as a base for thrombin generation and platelet aggregation. Adhered platelets undergo shape change, form podocytes, and start to secrete thromboxane A2 (TXA-2) and their granule contents, such as adenosine diphosphate (ADP). Through their specific receptors on the platelet surface, thrombin, TXA-2, ADP and other substances help recruit and further activate platelets at the site of endothelial damage. Activated platelets express the glycoprotein IIb/IIIa receptor, which is the receptor for fibrinogen. This receptor is essential for irreversible aggregation for which fibrinogen serves as the glue between the platelets (fig 1). …

Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post hoc analysis of the ARISTOTLE trial

Objective To determine whether the treatment effect of apixaban versus warfarin differs with increasing numbers of concomitant drugs used by patients with atrial fibrillation. Design Post hoc analysis performed in 2015 of results from ARISTOTLE (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation)—a multicentre, double blind, double dummy trial that started in 2006 and ended in 2011. Participants 18 201 ARISTOTLE trial participants. Interventions In the ARISTOTLE trial, patients were randomised to either 5 mg apixaban twice daily (n=9120) or warfarin (target international normalised ratio range 2.0-3.0; n=9081). In the post hoc analysis, patients were divided into groups according to the number of concomitant drug treatments used at baseline (0-5, 6-8, ≥9 drugs) with a median follow-up of 1.8 years. Main outcome measures Clinical outcomes and treatment effects of apixaban versus warfarin (adjusted for age, sex, and country). Results Each patient used a median of six drugs (interquartile range 5-9); polypharmacy (≥5 drugs) was seen in 13 932 (76.5%) patients. Greater numbers of concomitant drugs were used in older patients, women, and patients in the United States. The number of comorbidities increased across groups of increasing numbers of drugs (0-5, 6-8, ≥9 drugs), as did the proportions of patients treated with drugs that interact with warfarin or apixaban. Mortality also rose significantly with the number of drug treatments (P<0.001), as did rates of stroke or systemic embolism (1.29, 1.48, and 1.57 per 100 patient years, for 0-5, 6-8, and ≥9 drugs, respectively) and major bleeding (1.91, 2.46, and 3.88 per 100 patient years, respectively). Relative risk reductions in stroke or systemic embolism for apixaban versus warfarin were consistent, regardless of the number of concomitant drugs (Pinteraction=0.82). A smaller reduction in major bleeding was seen with apixaban versus warfarin with increasing numbers of concomitant drugs (Pinteraction=0.017). Patients with interacting (potentiating) drugs for warfarin or apixaban had similar outcomes and consistent treatment effects of apixaban versus warfarin. Conclusions In the ARISTOTLE trial, three quarters of patients had polypharmacy; this subgroup had an increased comorbidity, more interacting drugs, increased mortality, and higher rates of thromboembolic and bleeding complications. In terms of a potential differential response to anticoagulation therapy in patients with atrial fibrillation and polypharmacy, apixaban was more effective than warfarin, and is at least just as safe. Trial registration ARISTOTLE trial, ClinicalTrials.gov NCT00412984.