Background Atrial fibrillation (AF) is associated with high rates of morbidity and mortality. Patients with AF carry a fivefold increased risk of stroke and the risk of death from AF-related stroke ...is doubled. Current management is often inadequate, leaving patients at risk for a potentially fatal or disabling event. The purpose of the GARFIELD registry is to evaluate the management and outcomes of patients with newly diagnosed non-valvular AF at risk for stroke. Design The GARFIELD registry is an observational, multicenter, prospective study of patients with newly diagnosed AF and one or more additional risk factors for stroke. The aim is to enroll 55,000 patients at >1,000 centers in 50 countries. Enrollment will take place in five independent, sequential, prospective cohorts. An additional retrospective validation cohort of 5,000 patients with established AF and at least one additional risk factor for stroke will be conducted in parallel with cohort one. The study started in December 2009, with a planned recruitment period of 4 years and a minimum of 2-year follow-up for each patient. Summary The GARFIELD registry will provide valuable insights into the clinical management and related outcomes of AF patients throughout many regions of the world and across the spectrum of healthcare systems. By capturing data from unselected patients treated in everyday practice, the registry has the potential to identify best practices as well as deficiencies in available treatment options for specific patient populations and to describe how therapeutic strategies, patient care, and outcomes will evolve over time.
Study objective Mechanical chest compression devices have been developed to facilitate continuous delivery of high-quality cardiopulmonary resuscitation (CPR). Despite promising hemodynamic data, ...evidence on clinical outcomes remains inconclusive. With the completion of 3 randomized controlled trials, we conduct a meta-analysis on the effect of in-field mechanical versus manual CPR on clinical outcomes after out-of-hospital cardiac arrest. Methods With a systematic search (PubMed, Web of Science, EMBASE, and the Cochrane Libraries), we identified all eligible studies (randomized controlled trials and nonrandomized studies) that compared a CPR strategy including an automated mechanical chest compression device with a strategy of manual CPR only. Outcome variables were survival to hospital admission, survival to discharge, and favorable neurologic outcome. Results Twenty studies (n=21,363) were analyzed: 5 randomized controlled trials and 15 nonrandomized studies, pooled separately. For survival to admission, the pooled estimate of the randomized controlled trials did not indicate a difference (odds ratio 0.94; 95% confidence interval 0.84 to 1.05; P =.24) between mechanical and manual CPR. In contrast, meta-analysis of nonrandomized studies demonstrated a benefit in favor of mechanical CPR (odds ratio 1.42; 95% confidence interval 1.21 to 1.67; P <.001). No interaction was found between the endorsed CPR guidelines (2000 versus 2005) and the CPR strategy ( P =.27). Survival to discharge and neurologic outcome did not differ between strategies. Conclusion Although there are lower-quality, observational data that suggest that mechanical CPR used at the rescuer’s discretion could improve survival to hospital admission, the cumulative high-quality randomized evidence does not support a routine strategy of mechanical CPR to improve survival or neurologic outcome. These findings are irrespective of the endorsed CPR guidelines during the study periods.
Objectives The aim of this study was to evaluate the relative frequency of access and nonaccess site bleeding, the association of these events with 1-year mortality, and the impact of randomized ...antithrombotic therapy. Background Post-percutaneous coronary intervention (PCI) bleeding has been strongly associated with subsequent mortality. The extent to which access versus nonaccess site bleeding contributes to this poor prognosis and the role of antithrombotic therapies remains poorly understood. Methods The incidence and impact of Thrombolysis In Myocardial Infarction (TIMI) major/minor 30-day bleeding and randomized antithrombotic therapy were examined in a combined dataset from the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events), Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY), and HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trials in 17,393 PCI patients. Results The TIMI major/minor bleeding occurred in 5.3% of patients, 61.4% of which (3.3%) were nonaccess site bleeds. After multivariable adjustment, TIMI bleeding was associated with an increased risk of 1-year mortality (hazard ratio HR: 3.17, 95% confidence interval CI: 2.51 to 4.00, p < 0.0001). The HR of a nonaccess site bleed was approximately 2-fold that of an access site bleed: HR: 3.94, 95% CI: 3.07 to 5.15, p < 0.0001 versus HR: 1.82, 95% CI: 1.17 to 2.83, p = 0.008, respectively. Randomization to bivalirudin versus heparin + a glycoprotein IIb/IIIa inhibitor resulted in 38% and 43% relative reductions in TIMI major/minor and TIMI major bleeding, respectively (p < 0.0001 for both), with significant reductions in both access and nonaccess site bleeding. Conclusions Nonaccess site bleeding after PCI is common, representing approximately two-thirds of all TIMI bleeding events, and is associated with a 4-fold increase in 1-year mortality. Use of bivalirudin rather than heparin + a glycoprotein IIb/IIIa inhibitor significantly decreases both nonaccess site as well as access site bleeding events by approximately 40%.
In their report, Steinberg et al. (1) nicely demonstrate that despite the advantage of uniform non-vitamin K antagonist oral anticoagulants (NOAC) dosing, off-label treatment occurs in approximately ...13% of patients, which is related to adverse outcomes.
Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of ...complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.
Objectives The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 ...(Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 51) trial. Background Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. Methods The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. Results Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio HR: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). Conclusions Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965 )
The Impact of Renal Dysfunction on Outcomes in the ExTRACT–TIMI 25 Trial Keith A. A. Fox, Elliott M. Antman, Gilles Montalescot, Stefan Agewall, Bhupathi SomaRaju, Freek W. A. Verheugt, Jose ...Lopez-Sendon, Hanoch Hod, Sabina A. Murphy, Eugene Braunwald The ExTRACT–TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis In Myocardial Infarction 25) trial provided the opportunity to evaluate the risk of varying degrees of renal dysfunction on outcomes in patients with ST-segment elevation myocardial infarction. A powerful and direct relationship was observed between the severity of renal dysfunction and death, stroke, intracranial hemorrhage, and major and minor bleeding (p < 0.001 for each comparison). There was a progressive increase in the magnitude of the treatment benefit with enoxaparin (death or nonfatal MI, p < 0.01) with better renal function. Future studies should take account of renal dysfunction in assessing the balance between efficacy and safety of antithrombotic regimens.
Background Concomitant use of proton-pump inhibitors (PPIs) has been implicated in diminished antiplatelet response to clopidogrel and an increased risk of ischemic events, but primarily among ...patients undergoing percutaneous coronary intervention. We sought to examine the potential influence of interactions between PPIs and clopidogrel versus prasugrel on platelet reactivity and clinical outcomes after acute coronary syndromes (ACS) in patients managed medically without revascularization. Methods This analysis from the TRILOGY ACS trial focused upon the 7,243 ACS patients aged <75 years who were managed without revascularization, randomized to clopidogrel or prasugrel, and followed for a median of 17 months. Proton-pump inhibitor type and use were assessed at each study visit, and 2,049 of the patients in this cohort underwent serial platelet reactivity assessments. Results Proton-pump inhibitor use (23%) was similar between the clopidogrel and prasugrel groups at baseline and throughout the study. Median on-treatment platelet reactivity values were consistently lower with prasugrel versus clopidogrel irrespective of PPI use. For the primary end point (composite of cardiovascular death, myocardial infarction MI, or stroke), PPI use modified the unadjusted treatment effect of prasugrel versus clopidogrel (interaction P = .02). After adjusting for differences in baseline characteristics, this treatment effect modification was attenuated for the composite end point (interaction P = .06) but was significant for the MI component end point (interaction P = .01). Similarly, among patients on a PPI, the frequency of MI was significantly lower with prasugrel versus clopidogrel (hazard ratio = 0.61; 95% CI 0.42-0.88). These findings were similar by PPI type (omeprazole and pantoprazole). Conclusions Among ACS patients managed without revascularization, use of PPIs did not result in a differential antiplatelet response between prasugrel versus clopidogrel but was associated with a lower incidence of MI with prasugrel. These hypothesis-generating findings suggest that factors besides platelet reactivity may underlie the differential risk of MI observed by treatment assignment with PPI use.
After acute coronary syndrome (ACS), long-term dual antiplatelet therapy with acetylsalicylic acid and a P2Y12 platelet receptor antagonist is the standard of care for secondary prevention. Despite ...the introduction of more potent P2Y12 receptor antagonists, the risk of a recurrent vascular event within 12 months remains at approximately 10%, indicating a need for improved secondary prevention strategies. A recent phase III trial found that addition of a third antiplatelet agent, vorapaxar, in patients with atherosclerosis might benefit those who have previously experienced a myocardial infarction, although a trial in patients with ACS found this strategy led to increased bleeding without significant efficacy improvement. Previously, data from patients with ACS given vitamin K antagonists in addition to acetylsalicylic acid demonstrated significant reductions in vascular events, but this was associated with an unacceptable bleeding risk. As expected, phase II trials of newer oral anticoagulants in addition to dual antiplatelet therapy also found increased bleeding risk, with only the direct factor Xa inhibitors apixaban and rivaroxaban continuing to phase III. The phase III trial of full-dose apixaban was stopped early for safety concerns, because the major bleeding rates were significantly increased with minimal improvement in efficacy. However, the phase III trial of low-dose rivaroxaban demonstrated a significantly reduced incidence of recurrent vascular events without an increased risk of fatal bleeding. In conclusion, these trials underline the potential importance of optimal dose selection in phase III studies and suggest that the long-term use of low-dose anticoagulation, together with dual antiplatelet therapy, might have a role in secondary prevention after ACS.
Both fibrin and platelets are involved in the formation of thrombi. Because recently formed thrombi are mainly composed of fibrin and aggregated platelets, vasoactive mediators such as thromboxane A2 ...released from platelets may occlude coronary vessels. Cardiologists mainly see patients with symptomatic heart disease, who are beyond primary prevention, but there may be patients without coronary disease who see a cardiologist for other reasons, such as atypical chest pain, arrhythmia, or heart failure and who are at risk for coronary events. ...there is a clear role for the practicing cardiologists in that risk factors should be collected and appropriate prophylactic therapy instituted.
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