Coronary Syndrome-Thrombolysis In Myocardial Infarction Research Articles

Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis.

Atherosclerosis is a leading cause of cardiovascular and neurological ischemic events. Plaque rupture leads to the exposure of highly thrombogenic material with blood and results in the activation of the coagulation cascade, thrombus formation, and embolic events. Although antiplatelets and anticoagulants are used to prevent thromboembolic episodes, bleeding episodes remain the major adverse effect. Decreased ischemic events have been reported while comparing oral rivaroxaban and apixaban with aspirin to improve the therapeutic outcome in several clinical trials, including Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51, Apixaban for Prevention of Acute Ischemic and Safety Events, and GEMINI-ACS-1 phase II clinical trials. However, there were bleeding episodes. Thus, there is an unmet need for better therapeutic strategies. Therefore, the current focus is to target Factors IX, XI, and XII to develop safer and efficient strategies. In this article, we critically reviewed and discussed the limitations of current therapies and the potential of targeting Factors IX, XI, and XII for anticoagulant therapy in atherothrombosis.

Fatal or Irreversible Bleeding and Ischemic Events With Rivaroxaban in Acute Coronary Syndrome

BackgroundNet clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact. ObjectivesA comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact. MethodsIn 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) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding. ResultsRivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: −11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking 2.5 mg orally twice per day. ConclusionsBoth fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965)

The effect of rivaroxaban on myocardial infarction in the ATLAS ACS 2 - TIMI 51 trial.

Rivaroxaban reduces cardiovascular death, myocardial infarction (MI), or stroke in patients following acute coronary syndrome (ACS). We aimed to characterize the specific effects of rivaroxaban on the size and type of MI. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study randomized 15,526 patients with a recent ACS to rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo. An independent clinical events committee adjudicated each MI that occurred during the study and further classified them based on type. Data are presented as two-year Kaplan-Meier event rates and hazard ratios (HRs) and 95% confidence intervals (CI). In total, 665 patients experienced a post-randomization MI. The majority (n=535, 80.5%) were spontaneous (Type 1) events. Rivaroxaban reduced spontaneous MI when compared with placebo (4.4% vs 5.7%, HR 0.80, 95% 0.67-0.95, p=0.01), and there were directionally consistent reductions with both the 2.5 mg BID (4.7% vs 5.7%, HR 0.84, 95% 0.68-1.02, p=0.08) and 5 mg BID doses (4.1% vs 5.7%, HR 0.77, 95% 0.62-0.94, p=0.01) as compared with placebo. Rivaroxaban reduced MI with large elevations in troponin or creatine kinase-MB (CK-MB) fraction (1.8% vs 2.4%, HR 0.73, 95% CI 0.56-0.96, p=0.03) and STEMI events (1.7% vs 2.5%, HR 0.74, 95% CI 0.56-0.99, p=0.04). In patients stabilized and followed after ACS, the majority of MIs that occur are spontaneous and rivaroxaban significantly reduced the incidence of these events. Notably, rivaroxaban reduced MIs with extensive biomarker release and ST-segment elevation.

Relation of T-Wave Alternans to Mortality and Nonsustained Ventricular Tachycardia in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome from the MERLIN-TIMI 36 Trial of Ranolazine Versus Placebo

We explored the utility of T-wave alternans (TWA) in predicting mortality in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Maximum TWA was calculated using Modified Moving Average method from continuous electrocardiographic recordings in patients with left ventricular ejection fraction <40% and ventricular tachycardia (VT) ≥4 beats during index hospitalization or sudden cardiac death during thefollow-up year and age- and sex-matched controls in the Metabolic Efficiency withRanolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. All patients received standard therapy for NSTEACS plus ranolazine (n= 109) or placebo (n= 101). Median follow-up was 1year. Baseline clinical characteristics did not differ between patients with elevated TWA (≥47μV) compared with lower levels. Patients with TWA ≥47μV at admission had increased risk of total mortality (adjusted odds ratio [ORadj] 2.35, p= 0.04) during follow-up and VT ≥4 beats (ORadj 2.70, p= 0.01) during hospitalization with a trend toward increased cardiovascular death risk (ORadj 2.18, p= 0.07) during follow-up. In patients receiving placebo, TWA ≥47μV on day 6 was associated with increased risk of total mortality (OR 4.12, 95% confidence interval 1.25 to 13.64, p= 0.02) and cardiovascular death (OR 4.73, p= 0.01) during follow-up. No deaths occurred among patients with TWA ≥47μV assigned to ranolazine. In conclusion, in patients with NSTEACS and left ventricular ejection fraction <40%, TWA ≥47μV early after admission is associated with increased risk of mortality at 1year and with nonsustained VT during hospitalization. TWA may be useful in risk estimation in patients with NSTEACS. The possibility that TWA may serve as a therapeutic target deserves further exploration.

The Role of Rivaroxaban in Atrial Fibrillation and Acute Coronary Syndromes

Rivaroxaban, a direct factor Xa inhibitor, is a novel oral anticoagulant approved for stroke prevention in patients with nonvalvular atrial fibrillation and also approved in Europe (but not in the United States) to prevent recurrent ischemic events in patients with recent acute coronary syndromes. Advantages of rivaroxaban over oral anticoagulants such as warfarin are the lack of need for ongoing monitoring, a fixed-dose regimen, and fewer drug and food interactions. Drawbacks include a lack of an antidote and the absence of a widely available method to reliably monitor the anticoagulant effect. In patients at risk of stroke due to atrial fibrillation, rivaroxaban was noninferior compared to warfarin in preventing stroke/systemic embolism in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and was associated with a similar risk of major bleeding; the incidence of intracranial hemorrhage was 33% lower with rivaroxaban. Concerns raised about the trial were the adequacy of warfarin management and the increase in event rate at the end of the trial. The drug acquisition cost of rivaroxaban is higher than that of warfarin although decision-analytic models suggest that it is cost effective in atrial fibrillation. In patients with recent acute coronary syndrome, low-dose rivaroxaban reduced mortality and the composite end point of death from cardiovascular causes, myocardial infarction and stroke, but this was accompanied by an increased risk of intracranial hemorrhage and major bleeding in the Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI) 51 trial. Thus, rivaroxaban appears to be a valuable addition to the therapeutic armamentarium in atrial fibrillation although caution should be exercised, given the limited experience in combination with novel oral antiplatelet agents. The role of rivaroxaban as part of a modern regimen in acute coronary syndrome continues to be evaluated.

Prognostic Performance of Multiple Biomarkers in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome: Analysis From the MERLIN–TIMI 36 Trial (Metabolic Efficiency With Ranolazine for Less Ischemia in Non−ST-Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36)

The aim of this study was to assess the prognostic performance of C-terminal provasopressin (copeptin), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. We measured copeptin, MR-proADM, and MR-proANP concentrations in 4,432 patients with NSTE-ACS who were randomized to treatment with ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36) trial and followed up for 1 year. A high concentration (quartile 4 vs. quartiles 1 to 3) of each biomarker identified an increased risk of CV death or HF(copeptin: 13.2% vs. 5.0%, p < 0.001; MR-proADM: 15.8% vs. 4.1%, p < 0.001; MR-proANP: 17.7% vs. 3.5%, p < 0.001)as well as CV death, HF, and myocardial infarction individually (all p ≤ 0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratio: copeptin, 1.71; MR-proADM, 1.96; MR-proANP, 2.20; all p ≤ 0.001).These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year(all categorical NRI >10%, p < 0.001), and maintained independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus BNP, cTnI, ST2, PAPP-A, and MPO (each p≤0.01) [corrected]. Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS that perform as well as or better than established and other emerging biomarkers and warrant further investigation of application for therapeutic decision making. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).

Clinical Features, Use of Evidence‐Based Therapies, and Cardiovascular Outcomes Among Patients With Chronic Kidney Disease Following Non–ST‐Elevation Acute Coronary Syndrome

Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular events following acute coronary syndrome (ACS). The underlying pathobiology and optimal treatments for this population continue to be evaluated. Patients with CKD will receive fewer evidence-based therapies and experience high rates of adverse cardiovascular events in both the short- and long term. The MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36) trial randomized non-ST-elevation ACS patients to ranolazine or placebo, with no exclusion for renal dysfunction (except dialysis). We conducted a prespecified analysis among 6543 patients based on the degree of CKD. Patients with worse renal function were older with more comorbidities (P < 0.0001 for each). They were less likely to receive evidence-based cardiovascular medicines (P < 0.04 for each). Rates of an early invasive management strategy varied based on renal function; however, among patients with the highest TIMI risk scores, the rates of an early invasive management strategy were similar regardless of glomerular filtration rate (GFR) (Pinteraction = 0.005). Lower GFR was associated with increased rates of cardiovascular disease or myocardial infarction in the short and long term, even after adjustment (GFR <30 vs ≥90 mL/min/1.73 m(2) ; hazard ratio [HR]: 3.24 [95% confidence interval {CI}: 1.26-8.38] through 7 days and HR: 2.12 [95% CI: 1.33-3.39] through 1 year). The effect of ranolazine vs placebo on clinical outcomes was similar among those with and without CKD (Pinteraction = not significant). Following ACS, patients with renal dysfunction had more cardiovascular risk factors but were less likely to receive evidence-based medical therapies. A strong graded, independent relationship between the degree of CKD and poor clinical outcomes was observed over time. Continued efforts to optimize ACS treatment strategies in patients with CKD are warranted.

Inducible Fast Ventricular Tachycardia After ST-Segment–Elevation Myocardial Infarction

Although our understanding of sudden cardiac death (SCD) is far from complete, at least part of SCD post–myocardial infarction (MI) is because of ventricular tachycardia (VT) that degenerates to ventricular fibrillation. Because of the poor outcome of resuscitative efforts, considerable effort has been directed at risk stratification to guide interventions to prevent and to protect patients from this syndrome. Several clinical and laboratory variables (structural, arrhythmic, and autonomic) have been associated with poor outcome; how to use these to determine which patients are likely to have SCD, for which we have an established primary prevention treatment strategy, versus non-SCD remains elusive. Article see p 884 Ventricular ectopy was first recognized as a predictor of death in 1969; ventricular ectopy recorded on a standard ECG in outpatients were associated with a 6-fold increase in sudden death.1 For patients with early post-MI, Lown et al2 postulated that an electric catastrophe is more likely when ventricular premature beats occur early in the cycle, in salvos of ≥2, when they are multiform, or with a frequency >5/min. Ruberman et al3 showed that complex premature beats were associated with a risk of sudden coronary death 3× that for men free of these findings. A graded prognostic importance of ventricular premature beats and left ventricular dysfunction was described in the Myocardial Post-Infarction Program.4 The risk of nonsustained VT lasting 4 to 7 beats in the setting of acute coronary syndromes persists today as shown in the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) study.5 Programmed electric stimulation (PES) arose as a way of mimicking spontaneous ectopy and subjecting it to formal study. The pioneering work of Wellens, Josephson and others suggested that inducibility indicated reentry as a mechanism of VT …

Anticoagulation in heart failure: current status and future direction

Despite therapeutic advances, patients with worsening heart failure (HF) requiring hospitalization have unacceptably high post-discharge mortality and re-admission rates soon after discharge. Evidence suggests a hypercoagulable state is present in patients with HF. Although thromboembolism as a direct consequence of HF is not frequently clinically recognized, it may contribute to mortality and morbidity. Additionally, many patients with HF have concomitant disorders conferring additional thrombotic risk, including atrial fibrillation (AF) and coronary artery disease (CAD). Acute coronary syndrome (ACS), a known consequence of coronary thrombosis, is a common precipitating factor for worsening HF. Coronary thrombosis may also cause sudden death in patients with HF and CAD. Because data are largely derived from observational studies or trials of modest size, guideline recommendations on anticoagulation for HF vary between organizations. The recently presented Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial of HF patients in sinus rhythm suggested anticoagulation reduces the risk of stroke, although rates of the combined primary endpoint (death, ischemic stroke, or intracerebral hemorrhage) were similar for acetylsalicylic acid and warfarin. Newer oral anticoagulants dabigatran, apixaban, and rivaroxaban have successfully completed trials for the prevention of stroke in patients with AF and have shown benefits in the subpopulation of patients with concomitant HF. Positive results of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial of rivaroxaban in ACS are also encouraging. These data suggest there is a need to assess the potential role for these newer agents in the management of patients hospitalized for HF who continue to have a high post-discharge event rate despite available therapies.

Rivaroxaban Improves Outcomes in Patients with Acute Coronary Syndromes

Results from the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51 [ATLAS ACS 2-TIMI 51; NCT00809965] Trial showed that rivaroxaban significantly reduced the risk of cardiovascular death, myocardial infarction, and stroke in acute coronary syndrome patients.

Myocardial Ischemia and Ventricular Tachycardia on Continuous Electrocardiographic Monitoring and Risk of Cardiovascular Outcomes After Non–ST-Segment Elevation Acute Coronary Syndrome (from the MERLIN-TIMI 36 Trial)

Among patients with non-ST-segment elevation acute coronary syndromes, recurrent ischemia and ventricular arrhythmias detected on continuous electrocardiographic monitoring remain common events that are associated with worse outcomes. The relative clinical significance of both events together is not well described. We determined the risk associated with ischemia (≥1 mm ST depression lasting ≥1 minutes) and ventricular tachycardia (VT) (≥4 beats) detected on 7-day continuous electrocardiographic monitoring in 6,355 patients with non-ST-segment elevation acute coronary syndromes from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction (MERLIN-TIMI) 36 trial. The patients were categorized into 4 groups according to the presence or absence of VT and ischemia. Cardiovascular death, sudden cardiac death (SCD), myocardial infarction, and recurrent ischemia were assessed during a median follow-up of 348 days. A total of 60.0% patients had no VT or ischemia, 20.0% had VT alone, 14.7% had ischemia alone, and 5.3% had both. The patients with either VT or ischemia were at increased risk of cardiovascular outcomes. The combination of ischemia and VT identified a particularly high-risk population for cardiovascular death (10.1% vs 3.0%, p <0.001), SCD (7.8% vs 0.9%, p <0.001), and myocardial infarction (15.4% vs 6.2%, p <0.001) compared to patients with neither. The addition of arrhythmia and ischemia significantly improved the clinical model for predicting cardiovascular death or SCD (p <0.001). In patients with both ischemia and VT, 66.6% of SCD occurred within 90 days of the non-ST-segment elevation acute coronary syndromes. In conclusion, in >6,300 patients with non-ST-segment elevation acute coronary syndromes, the presence of myocardial ischemia or VT alone, and particularly in combination, was independently associated with poor cardiovascular outcomes and thus provides incremental improvement in early risk stratification.

Response to Letters Regarding Article, “Relationship Between Nonsustained Ventricular Tachycardia After Non-ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death: Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial”

We thank Dr Madias for his insightful comments regarding the limitations of current clinical risk stratification for sudden cardiac death after an acute coronary syndrome and the great clinical need for the development of more sophisticated tools. With over 40 000 days of continuous electrocardiogram monitoring, the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 Trial (MERLIN-TIMI 36) is a rich database for future research, and we are currently investigating whether specific morphological features may identify a subset of more lethal ventricular arrhythmias. We appreciate Dr Madias's suggestions for additional analyses and have embarked on an evaluation of novel electrocardiogram techniques, such as heart …

Letter by Madias Regarding Article, “Relationship Between Nonsustained Ventricular Tachycardia After Non-ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death: Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial”

To the Editor: I read with great interest the important study by Scirica et al,1 published in the August 3, 2010 issue of Circulation , that reported on a possible role of 4- to 7-beat or ≥8-beat nonsustained ventricular tachycardia (NSVT) episodes from ambulatory continuous electrocardiogram recordings (cECG) of 7 days in duration after the randomization of patients with non-ST-segment elevation acute coronary syndrome in predicting 1-year sudden cardiac death (SCD), using the database of Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). This …

Letter by Ayalloore and LeLorier Regarding Article, “Relationship Between Nonsustained Ventricular Tachycardia After Non-ST-Elevation Acute Coronary Syndrome and Sudden Cardiac Death: Observations From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial”

To The Editor: The strategy of suppressing ventricular ectopy by pharmaceutical means in the peri-infarct period has been fraught with disappointment and has tinted our view of the approach, as can be seen in the accompanying editorial by Patton.1 The Cardiac Arrhythmia Suppression Trial showed that premature ventricular beat suppression did not prevent sudden cardiac death, but rather increased the risk secondary to the proarrhythmic effects of the antiarrhythmic drugs used.2 Several other trials have reaffirmed these results. In the European Myocardial …

G-protein beta3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16 trial.

Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity. To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction (OPUS-TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55-1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58-4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.

Is there an acceptable ceiling for bleeding for an antithrombotic drug dose to be tested in a phase 3 trial?

This editorial refers to ‘Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial’†, by M. Sabatine, published in the Lancet , 2009;374:787–795. The SEPIA-ACS1 TIMI 42 (Study to Evaluate the Pharmacodynamics, the Safety and Tolerability, and the Pharmacokinetics of Several Intravenous Regimens of the Factor Xa Inhibitor Otamixaban (XRP0673), in Comparison to Intravenous Unfractionated Heparin-Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction) trial is a well performed trial. It tested otamixaban, which is a short-acting i.v. direct factor Xa inhibitor with a half-life of 30 min, compared with unfractionated heparin (UFH) plus eptifibatide in patients with non-ST elevation acute coronary syndrome (NSTEACS). The trial identified a signal for reduction in ischaemic events with otamixaban but also a signal associated with increased bleeding. This is an important study with a high rate of angiography (98%) and guideline-recommended medications. The trial was a large dose-ranging trial in 3241 patients with NSTEACS following a dose-ranging trial in 947 patients undergoing non urgent percutaneous coronary intervention (PCI; SEPIA PCI trial).1 This is to be compared with a previous era when small numbers of patients were investigated in order to select a dose for a phase III trial, e.g. in GUSTO2 <100 patients were tested with the streptokinase–tissue plasminogen activator (tPA) combination, and in GUSTO IIa <50 patients were tested with the hirudin dose that was evaluated in GUSTO IIa.3 The patients enrolled in SEPIA-ACS14 were at …

Ischemia Detected on Continuous Electrocardiography After Acute Coronary Syndrome: Observations From the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 36) Trial

The purpose of this study was to assess the relationship between ischemia detected on continuous electrocardiographic (cECG) recording and cardiovascular outcomes after acute coronary syndrome (ACS).The small size of prior studies evaluating cECG prevented full evaluation of the risk associated with ischemia across subpopulations and compared with other methods of risk stratification. Ranolazine, a new antianginal agent, reduces ischemic symptoms in patients with chronic angina and after ACS but the anti-ischemic effect, as detected by cECG, is not known.In all, 6,560 patients hospitalized with non-ST-segment elevation ACS were randomly assigned to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 36) trial. The cECG was performed for 7 days after randomization. Outcomes were followed for a median of 348 days. Clinical events that occurred during cECG recording were excluded from analysis.A total of 6,355 (97%) patients had cECG recordings evaluable for ischemia analysis. Patients with >or=1 episode of ischemia on cECG (n = 1,271, 20%) were at increased risk of cardiovascular death (7.7% vs. 2.7%, p < 0.001), MI (9.4% vs. 5.0%, p < 0.001), and recurrent ischemia (17.5% vs. 12.3%, p < 0.001). The relationship with cardiovascular death was independent of baseline characteristics or elevated biomarkers (adjusted hazard ratio: 2.46, p < 0.001). Ischemia on cECG was associated with significantly worse outcomes in several subgroups. Ranolazine did not reduce the rate of ischemia detected on cECG (19.9% vs. 21.0%, hazard ratio: 0.93, p = 0.21).In more than 6,300 patients with ACS, ischemia detected on cECG occurred frequently and was strongly and independently associated with poor cardiovascular outcomes, including cardiovascular death. Continuous ECG monitoring to detect ischemia after ACS may help to identify patients at increased risk. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes [MERLIN]; NCT00099788).

Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes (MERLIN TIMI-36) study

Ranolazine is a piperazine derivative believed to reduce anginal symptoms by preventing ischemia-mediated sodium and calcium overload in myocardial cells through inhibition of the late sodium current (late INa). Three small studies demonstrated the antianginal efficacy of ranolazine alone and in combination with βblockers or calcium channel blockers on conventional end points such as total exercise duration and time to ischemia/angina on a treadmill; however, questions of safety related to QT prolongation, efficacy in women and potential utility in higher risk populations remained. Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (MERLIN-TIMI) 36 was a large randomized, double-blind, placebo-controlled trial, which evaluated the efficacy and safety of ranolazine initiated acutely and continued as chronic therapy following a non-ST-segment elevation acute coronary syndrome event. A total of 6560 patients were randomized 1:1 to ranolazine or placebo; the primary efficacy end point of the trial was a composite of cardiovascular death, myocardial infarction or recurrent ischemia. The key safety end points were death from any cause and symptomatic documented arrhythmia. Although statistically significant differences between the ranolazine and placebo groups were not reached in the primary efficacy analysis or in the major secondary outcome end point analyses (cardiovascular death, myocardial infarction or severe recurrent ischemia), the individual component of recurrent ischemia was significantly reduced by ranolazine, and ranolazine was demonstrated to be safe.

Serum Blood Urea Nitrogen as an Independent Marker of Subsequent Mortality Among Patients With Acute Coronary Syndromes and Normal to Mildly Reduced Glomerular Filtration Rates

We hypothesized that elevated blood urea nitrogen (BUN) would be associated with adverse outcomes independent of serum creatinine (sCr)-based estimates of kidney function in patients with acute coronary syndromes (ACS). Although lower glomerular filtration rates (GFR) have prognostic significance among patients with ACS, estimates of GFR based on sCr may perform less accurately among patients with milder kidney dysfunction. In this population in particular, BUN, which can reflect increased proximal tubular reabsorption in addition to decreased GFR, may have independent prognostic value. Data were drawn from 9,420 patients with unstable coronary syndromes from Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI)-16, a trial that excluded patients with sCr >1.6 mg/dl or estimated creatinine clearance <40 ml/min. Patients with elevated BUN were older, had a higher prevalence of comorbidities, and had higher heart rates, lower systolic blood pressures, and an abnormal Killip class more often on admission. In univariate analyses, as well as in stratified and multivariable analyses including sCr-based estimates of GFR as a covariate, a stepwise increase in mortality occurred with increasing BUN (multivariable hazard ratio with BUN 20 to 25 mg/dl 1.9, 95% confidence interval 1.3 to 2.6; with BUN >/=25 mg/dl 3.2 [95% confidence interval 2.2 to 4.7]) compared with BUN </=20 mg/dl. A higher BUN was also associated with increased mortality among strata of troponin-I, B-type natriuretic peptide, and C-reactive protein concentrations. Among patients with unstable coronary syndromes and predominantly normal or mildly reduced GFR, an elevated BUN is associated with increased mortality, independent of sCr-based estimates of GFR and other biomarkers.

Validated risk score predicts the development of congestive heart failure after presentation with unstable angina or non-ST–elevation myocardial infarction: results from OPUS-TIMI 16 and TACTICS-TIMI 18

Background Few data are available about development of congestive heart failure (CHF) in patients with unstable angina/non-ST–elevation myocardial infarction (UA/NSTEMI). We developed and validated a risk score to predict which patients will develop CHF. Methods A subset of 4681 patients from the Orbofiban in Patients With Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI 16) trial with UA/NSTEMI and without a history of CHF were included in this analysis and stratified according to the development of CHF at 10 months. A risk score was created from significant variables and validated in the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI 18) trial. B-type natriuretic peptide (BNP) was then added to the initial multivariate analysis and validated in the TACTICS-TIMI 18 trial. Results The incidence of CHF at 30 days was 4.9%, and at 10 months it was 5.6%. Significant variables on multivariate analysis included age >65 years, heart rate >100 beats/min, history of diabetes mellitus, lateral electrocardiographic changes, and history of angiographically confirmed coronary artery disease. The risk of CHF increased 10-fold across the number of risk factors ( P < .001). When validated in the TACTICS-TIMI 18 trial, the risk score was significantly associated with CHF at 6 months ( P = .01). The median BNP value doubled across the number of risk factors ( P <.001 for trend). The addition of BNP to the risk score improved its discriminatory capacity. Conclusions In patients with UA/NSTEMI, a simple clinical risk score can aid in assessing the risk of developing CHF. BNP adds to the predictive capacity of this risk score. This score may assist in identifying patients who warrant more careful monitoring and therapy for CHF prevention inhospital and during follow-up.