Activated partial thromboplastin time measurement is not associated with clinical outcomes in patients with high-risk non-ST-segment elevation acute coronary syndromes treated with unfractionated heparin.

Our objective was to determine the association of activated partial thromboplastin time (aPTT) with recurrent ischemic events and non-coronary artery bypass surgery-related thrombolysis in myocardial infarction major bleeding. We studied 4,985 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) participating in SYNERGY, a prospective, randomized, international trial designed to emulate contemporary practice wherein unfractionated heparin (UFH) is given intravenously and titrated according to a weight-adjusted dosing nomogram to a target aPTT of 1.5-2 times the upper limit of normal (approximately 50-70 s). Aspirin was administered to 95% of patients, clopidogrel to 63%, and glycoprotein IIb/IIIa receptor inhibitors to 58%. More than 90% of patients underwent early coronary angiography, and 69% were revascularized. Used as a time-dependent covariate, aPTT was evaluated as a predictor of time to ischemic or major hemorrhagic events in proportional hazards regression models. Using discrete variable analysis, aPTT was categorized as persistently below a lower threshold of anticoagulation (<50 vs. ≥50 s) for recurrent ischemic events and above an upper threshold (>70 vs. ≤70 s) for major hemorrhagic events. UFH treatment lasted a median of 42 (30, 78) h. At >6-12 (n = 3,021), >12-24 (n = 3,406), and >24-48 (n = 2,497) h, 34, 41, and 46% of patients achieved the target aPTT range, respectively. Both before and after adjusting for baseline predictors of anticoagulant response and risk score (age, hypertension, diabetes, smoking, ST depression, and renal function), no significant relationship between aPTT values and recurrent ischemic events or major bleeding was found. No relationship was observed between clinical outcomes and aPTT values persistently above or below the designated thresholds. Measurements of aPTT were not associated with clinical outcomes among patients with NSTE ACS treated with UFH. The required intensity of anticoagulation for benefit may be relatively modest when UFH is administered concomitantly with dual or triple platelet-directed therapy, particularly in patients undergoing early coronary revascularization.

A Head-to-Head Comparison of a Free Fatty Acid Formulation of Omega-3 Pentaenoic Acids Versus Icosapent Ethyl in Adults With Hypertriglyceridemia: The ENHANCE-IT Study.

Background MAT9001 is an omega-3 free fatty acid (FFA) formulation containing mainly eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA). Compared with icosapent ethyl (EPA-ethyl esters [EE]), EPA+DPA-FFA previously showed enhanced triglyceride lowering and higher plasma EPA when both were administered once daily with a very-low fat diet. This trial compared pharmacodynamic responses and plasma omega-3 levels following twice daily dosing, with meals, of EPA+DPA-FFA and EPA-EE in hypertriglyceridemic subjects consuming a Therapeutic Lifestyle Changes diet. Methods and Results This open-label, randomized, 2-way crossover trial, with 28-day treatment periods separated by ≥28-day washout, was conducted at 8 US centers and included 100 subjects with fasting triglycerides 1.70 to 5.64 mmol/L (150-499 mg/dL) (median 2.31 mmol/L [204 mg/dL]; 57% women, average age 60.3 years). The primary end point was least squares geometric mean percent change from baseline plasma triglycerides. In the 94 subjects with analyzable data for both treatment periods, EPA+DPA-FFA and EPA-EE reduced least squares geometric mean triglycerides from baseline: 20.9% and 18.3%, respectively (P=not significant). EPA+DPA-FFA reduced least squares geometric mean high-sensitivity C-reactive protein by 5.8%; EPA-EE increased high-sensitivity C-reactive protein by 8.5% (P=0.034). EPA+DPA-FFA increased least squares geometric mean plasma EPA, DPA, and total omega-3 (EPA+docosahexaenoic acid+DPA) concentrations by 848%, 177%, and 205%, respectively, compared with corresponding changes with EPA-EE of 692%, 140%, and 165% (all P<0.001). EPA+DPA-FFA increased docosahexaenoic acid by 1.7%; EPA-EE decreased docosahexaenoic acid by 3.3% (P=0.011). Lipoprotein cholesterol and apolipoprotein responses did not differ between treatments. Conclusions EPA+DPA-FFA raised plasma EPA, DPA, and total omega-3 significantly more than did EPA-EE. EPA+DPA-FFA also reduced triglycerides and high-sensitivity C-reactive protein without increasing low-density lipoprotein cholesterol. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04177680.

Circadian body temperature variability is an indicator of poor prognosis in cardiomyopathic hamsters.

BACKGROUND: Low body temperature is an independent predictor of poor prognosis in patients with congestive heart failure. The cardiomyopathic hamster develops progressive biventricular dysfunction, resulting in heart failure death at 9 months to 1 year of life. Our goal was to use cardiomyopathic hamsters to examine the relationship between body temperature and heart failure decompensation and death. METHODS AND RESULTS: To this end, we implanted temperature and activity transducers with telemetry into the peritoneal space of 46 male Bio-TO-2 Syrian cardiomyopathic hamsters. Multiple techniques, including computing mean temperature, frequency domain analysis, and nonlinear analysis, were used to determine the most useful method for predicting poor prognosis. Data from 44 hamsters were included in our final analysis. We detected a decline in core body temperature in 98% of the hamsters 8+/-4 days before death (P < .001). We examined the dominant frequency of temperature variation (ie, the circadian rhythm) by using cosinor analysis, which revealed a significant decrease in the amplitude of the body temperature circadian rhythm 8 weeks before death (0.28 degrees C; 95% CI, 0.26-0.31) compared to baseline (0.36 degrees C; 95% CI, 0.34-0.39; P=.005). The decline in the circadian temperature variation preceded all other evidence of decompensation. CONCLUSIONS: We conclude that a decrease in the amplitude of the body temperature circadian rhythm precedes fatal decompensation in cardiomyopathic hamsters. Continuous temperature monitoring may be useful in predicting preclinical decompensation in patients with heart failure and in identifying opportunities for therapeutic intervention.

Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) registry.

BACKGROUND: Limited data are available on the care of patients with acute severe hypertension requiring hospitalization. We characterized contemporary practice patterns and outcomes for this population. METHODS: STAT is a 25-institution, US registry of consecutive patients with acute severe hypertension (>180 mm Hg systolic and/or >110 mm Hg diastolic; >140 and/or >90 for subarachnoid hemorrhage) treated with intravenous therapy in a critical care setting. RESULTS: One thousand five hundred eighty-eight patients were enrolled (January 2007 to April 2008). Median age was 58 years (interquartile range 49-70 years), 779 (49%) were women, and 892 (56%) were African American; 27% (n = 425) had a prior admission for acute hypertension and 486 (31%) had chronic kidney disease. Median qualifying blood pressure (BP) was 200 (186, 220) systolic and 110 (93, 123) mm Hg diastolic. Initial intravenous antihypertensive therapies used to control BP varied, with 1,009 (64%) patients requiring multiple drugs. Median time to achieve a systolic BP <160 mm Hg (<140 mm Hg for subarachnoid hemorrhage) was 4.0 (0.8, 12) hours; 893 (60%) had reelevation to >180 (>140 for subarachnoid hemorrhage) after initial control; and 63 (4.0%) developed iatrogenic hypotension. Hospital mortality was 6.9% (n = 109) with an aggregate 90-day mortality rate of 11% (174/1,588); 59% (n = 943) had acute/worsening end-organ dysfunction during hospitalization. The 90-day readmission rate was 37% (523/1,415), of which one quarter (132/523) was due to recurrent acute severe hypertension. CONCLUSION: This study highlights heterogeneity in care, BP control, and outcomes of patients hospitalized with acute severe hypertension.

Re-evaluating risk factors for periprocedural complications during percutaneous coronary intervention in patients with unstable angina/non-ST-elevation myocardial infarction: who may benefit from more intensive antiplatelet therapy?

PURPOSE OF REVIEW: Controversy regarding the optimal antiplatelet/antithrombotic regimen indicates a need to re-evaluate the place of these agents in treating patients with unstable angina/non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. RECENT FINDINGS: Although clinical trial data suggest that glycoprotein IIb-IIIa inhibition benefits moderate-risk to high-risk patients, recent studies question the use of intensive antiplatelet therapy in lower risk patients. The resultant shift towards less intensive alternative regimens raises questions about identifying patients in whom an alternative strategy is preferable. The concept of risk stratification for coronary intervention has evolved from lesion-based categorization to include clinical factors, for example, elevated levels of cardiac troponin. SUMMARY: Risk factors for periprocedural complications during percutaneous coronary intervention can be divided into anatomic (unprotected left main stenting, bifurcation lesions, and diffuse disease) and clinical (older age, diabetes, renal disease, left ventricular function, recent myocardial damage, and female sex) factors. These may interact additively or synergistically, increasing the likelihood of complications in patients who might otherwise have been considered at low risk. We need to reconsider, therefore, how we identify appropriate options and, hopefully, optimize clinical outcomes. This review evaluates risk factors for periprocedural complications in an effort to determine patients who may benefit most from intensive antiplatelet regimens.

Time to coronary angiography and outcomes among patients with high-risk non ST-segment elevation acute coronary syndromes: results from the SYNERGY trial.

BACKGROUND: Optimal timing for an early invasive strategy in patients with non-ST-segment-elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non-ST-segment-elevation acute coronary syndrome who underwent angiography within 48 hours of admission. METHODS AND RESULTS: Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals. CONCLUSIONS: A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non-ST-segment-elevation acute coronary syndrome management.

Patients with non-ST-elevation acute coronary syndromes undergoing coronary artery bypass grafting in the modern era of antithrombotic therapy.

BACKGROUND: Many high-risk patients with non-ST-elevation acute coronary syndromes within the SYNERGY trial required coronary artery bypass grafting (CABG) for optimal revascularization. We explored the clinical outcomes among high-risk patients undergoing CABG and the impact of modern pharmacology. METHODS: We evaluated 180-day rates of death and myocardial infarction (MI) and 30-day GUSTO severe bleeding among patients undergoing CABG, contrasting them with patients undergoing percutaneous coronary intervention (PCI) or medical management. The relationships between perioperative MI, bleeding events, and 6-month mortality were explored. The effect of random assignment to unfractionated heparin or enoxaparin and the relationships between use of clopidogrel and glycoprotein IIb/IIIa inhibitors and clinical outcomes were assessed. RESULTS: Death or MI at 6 months was more common among patients requiring CABG (CABG 31.2%, PCI 15.9%, medical 9.9%). Thirty-day GUSTO severe bleeding was also higher (CABG 6.4%, PCI 1.1%, medical 0.9%). Perioperative MI and GUSTO severe bleeding were associated with excess 6-month mortality (hazard ratio 2.1, 95% CI 1.27-3.53 and hazard ratio 7.6, CI 4.78-12.09, respectively). Randomization to enoxaparin was not associated with an increase in bleeding or a reduction in death or MI. No differences in ischemic outcomes were observed among patients given glycoprotein IIb/IIIa inhibition or clopidogrel. CONCLUSIONS: High-risk patients still commonly require CABG with greater bleeding and ischemic event rates observed. Current definitions of perioperative MI and GUSTO severe bleeding portend an increased in 6-month mortality among CABG patients. Modern pharmacotherapies do not appear to impact these higher event rates.

Coronary artery bypass surgery in patients with acute coronary syndromes is difficult to predict.

BACKGROUND: Although the use of clopidogrel in patients "unlikely" to require coronary artery bypass grafting (CABG) is recommended in current guidelines of acute coronary syndrome (ACS) management, an important minority of patients require CABG. We assessed the ability to predict need for CABG from demographics known at the time of ACS presentation, using data from SYNERGY. METHODS: Patients undergoing CABG at any time after the index angiogram were included. Early CABG was defined as surgery <72 hours after angiography. The relationship between cessation of enoxaparin and glycoprotein IIb/IIIa inhibition, CABG timing, and 30-day death or MI and bleeding events was assessed. Demographic and clinical factors and geographic location were assessed as predictors of early CABG or CABG at any time. The discriminatory utility is reported with the c-index. RESULTS: Of the 9053 patients undergoing angiography, 1793 (18.1%) received CABG. Early CABG (n = 972) was associated with more bleeding events (39.2% vs 29.4%, P < .001) but not death or MI. The risk of bleeding events diminished when surgery was delayed >18 hours after cessation of enoxaparin and glycoprotein IIb/IIIa inhibition. Clinical factors associated with early CABG included diabetes and lack of prior CABG or clopidogrel. However, overall the logistic regression model had poor discriminatory ability to predict patients likely to require CABG in the setting of an ACS presentation (c-index 0.671). CONCLUSIONS: It is difficult to predict those high-risk patients with ACS who will undergo surgical revascularization based on baseline clinical characteristics.

Smoking status and antithrombin therapy in patients with non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Smoking remains a major public health issue. We investigated the incidence of smoking and outcomes in high-risk patients with acute coronary syndromes. Differences in treatment effect of antithrombin therapies were also investigated. METHODS: Using data from SYNERGY, patients were categorized by their self-reported smoking status. They were followed at 30 days and 6 months for death, nonfatal myocardial infarction (MI), revascularization procedures, stroke, and need for rehospitalization, and at 1 year for occurrences of death. RESULTS: Overall, 9,971 patients were evaluated, of whom 2,404 (24%) were current smokers, 3,491 (35%) were former smokers, and 4076 (41%) had never smoked. Current smokers were younger (median age 61 years, interquartile range [IQR] 52-67) than former smokers (median age 69 years, IQR 63-75) and never smokers (median age 70 years, IQR 64-77) and had fewer additional coronary artery disease risk factors (hypertension, diabetes, hypercholesterolemia). The 30-day death/MI rate was similar for former versus never smokers (15% vs 13.6%, P = .079) and for current versus never smokers (14% vs 13.6%, P = .585). Adjusted odds ratios for 30-day death/MI in patients receiving enoxaparin compared with those receiving unfractionated heparin were 1.065 (95% CI 0.883-1.283, P = .51) in never smokers, 1.034 (95% CI 0.853-1.254, P = .733) in former smokers, and 0.742 (95% CI 0.582-0.948, P = .017) in current smokers. A significant interaction for treatment and smoking status was found at 30 days (P = .0215), but not at 6 months (P = .1381) or 1 year (P = .1054). One-year unadjusted mortality rates were higher for former versus never smokers (9.1% vs 6.7%, P = .0002) but were similar for current versus never smokers (6.5% vs 6.7%, P = .7226). On follow-up at 30 days, 62.3% (n =1397) of current smokers reported not smoking. CONCLUSIONS: Smokers with non-ST-segment elevation acute coronary syndrome are generally younger and have fewer cardiac risk factors. A significant interaction of smoking and enoxaparin was seen at 30 days, but not sustained at 6 months and 1 year. More than 60% of smokers quit within 30 days of their cardiac event. There was little difference in outcomes from 30 days to 1 year for these smokers who quit versus those who did not.

Prediction of one-year survival in high-risk patients with acute coronary syndromes: results from the SYNERGY trial.

BACKGROUND: Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality. OBJECTIVE: The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS. DESIGN AND PARTICIPANTS: A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial. MEASUREMENTS: Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper. RESULTS: Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82). CONCLUSIONS: Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.

Low-molecular-weight heparins : mechanisms, trials, and role in contemporary interventional medicine.

The clinical spectrum of acute coronary syndromes (ACS) encompasses unstable angina, non-ST-elevation, and ST-elevation myocardial infarction (STEMI). Within an atherosclerotic plaque, disruption of the endothelium can lead to exposure of tissue factor, with platelet adhesion, activation and aggregation, along with activation of the coagulation cascade, culminating in thrombin formation and the development of a cross-linked fibrin clot at the site of injury. Therapy aimed at blocking thrombin formation is now an integral part of the current cardiovascular guidelines in the treatment of ACS. Although unfractionated heparin (UFH) has been the mainstay of antithrombin therapy in the past, it has numerous clinical and biochemical limitations, including substantial protein binding (leading to inconsistent bioavailability), a need for frequent monitoring and adjustment, unreliable and variable degrees of anticoagulation, significant platelet activation, risk of heparin-induced thrombocytopenia, and the inability to block clot bound thrombin. With all of these limitations of UFH, low-molecular-weight heparins (LMWHs) have emerged as attractive alternatives. This review discusses the mechanism of action of LMWHs, and summarizes available literature concerning the use of LMWHs in a variety of clinical settings. Included in this review is an analysis of both current and prior data showing LMWH is as effective as UFH in the conservative and invasive management of patients with ACS. As well, very recent data are evaluated showing the safety and efficacy of LMWHs used in patients transitioning to the cardiac catheterization laboratory, and in those patients undergoing elective or urgent percutaneous coronary intervention (PCI). We also appraise the literature, along with the very recent studies investigating the use of LMWHs as adjunctive therapy to fibrinolytics in patients with STEMI. Finally, we set forth real-world conclusions concerning the use of LMWHs in contemporary interventional practice, including elective PCI and the treatment of ischemic coronary artery disease in the context of rapid invasive management of ACS.

Controversies surrounding authorship of manuscripts by industry employees: academic and industry perspectives.

The medical device and pharmaceutical industries play an essential role in the development of cardiovascular devices and drugs, and industry employees are frequently listed as co-authors of clinical trials published in peer-reviewed journals. Potential conflicts of interest in biomedical research have attracted significant attention in recent years, but issues and challenges surrounding authors who are industry employees have not received nearly as much scrutiny. We present a comprehensive discussion of the concerns and challenges regarding the role of industry in the authorship of scientific manuscripts. Academic co-authors, industry employees, the editors of medical journals, and, most importantly, readers, need to consider the perception and implications that accompany industry employee authorship. Potential concerns include the effect of industry authors (and industry support) on study design, data analysis, interpretations, conclusions, and, ultimately, scientific content. Meaningful contributions from industry employees must be acknowledged and reported in scientific and clinical publications. Efforts to provide full transparency on industry support and the role of industry contributors are necessary to maintain confidence in the reports of studies with industry involvement.

Racial differences among high-risk patients presenting with non-ST-segment elevation acute coronary syndromes (results from the SYNERGY trial).

Management and outcomes of patients with acute coronary syndromes (ACSs) may vary according to patient race and ethnicity. To assess racial differences in presentation and outcome in high-risk North American patients with non-ST-segment elevation (NSTE) ACS, we analyzed baseline racial/ethnic differences and all-cause death or nonfatal myocardial infarction (MI) in 6,077 white, 586 African-American, and 344 Hispanic patients through 30-day, 6-month, and 1-year follow-up. Frequencies of hypertension were 66% for whites, 83% for African-Americans, and 78% for Hispanics (overall p <0.001). Use of angiography was similar across groups. Use of percutaneous coronary intervention (46% for whites, 41% for African-Americans, and 45% for Hispanics, overall p = 0.046) and coronary artery bypass grafting (20% for whites, 16% for African-Americans, and 22% for Hispanics, overall p = 0.044) differed. African-American patients had significantly fewer diseased vessels compared with white patients (p = 0.0001). Thirty-day death or MI was 14% for whites, 10% for African-Americans, and 14% for Hispanics (overall p = 0.034). After adjustment for baseline variables, African-American patients had lower 30-day death or MI compared with white patients (odds ratio 0.73, 95% confidence interval 0.55 to 0.98). There were no differences in 6-month death or MI across racial/ethnic groups. In conclusion, baseline clinical characteristics differed across North American racial/ethnic groups in the SYNERGY trial. African-American patients had significantly better adjusted 30-day outcomes but similar 6-month outcomes compared with white patients.

Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial.

BACKGROUND: Enoxaparin reduces ischemic events more effectively than unfractionated heparin (UFH) in patients treated conservatively for non-ST-segment elevation acute coronary syndrome. The SYNERGY trial compared these agents in high-risk patients undergoing early invasive treatment. Enoxaparin was noninferior to UFH for the 30-day primary end point of death/myocardial infarction (MI), but modestly increased bleeding. METHODS AND RESULTS: This article compares the outcomes of the 4687 SYNERGY patients (47%) undergoing percutaneous coronary intervention, who were randomized to receive enoxaparin or UFH. Antithrombotic therapy was administered prerandomization in 78%. Crossover (usually in the catheterization laboratory) to the alternative antithrombotic occurred in 14.6% of enoxaparin patients and 2.9% of UFH-treated patients (P < .0001). Stenting was performed in 86.3%. Abrupt vessel closure occurred in 1.3% of enoxaparin patients and 1.7% of UFH-treated patients (P = .318). The rates of death/MI were similar at 30 days (13.1% with enoxaparin vs 14.2% with UFH, P = .289). GUSTO severe bleeding occurred with similar frequency in both groups (1.5% vs 1.6%, P = .688). TIMI major bleeding was more common with enoxaparin (3.7% vs 2.5% with UFH, P = .028). Transfusions were more frequent with enoxaparin than with UFH (6.8% vs 5.4%, P = .047). TIMI major bleeding increased with crossover from enoxaparin to UFH (from 3.7% to 7.8%) and from UFH to enoxaparin (from 2.5% to 8.6%). Statistical adjustment to model reasons for crossover did not affect the overall safety and efficacy outcomes. CONCLUSIONS: In high-risk patients undergoing early percutaneous coronary intervention for acute coronary syndrome, enoxaparin avoids the need for monitoring and achieves similar effectiveness to UFH but is associated with more bleeding.

The role of oral antiplatelet agents in atherothrombotic disease.

Atherothrombosis involves the mutually interactive dual mechanistic processes of atherosclerotic plaque progression and thrombus formation. In the setting of acute plaque rupture, resultant thrombus formation precipitates acute ischemic events such as acute coronary syndromes (ACS), stroke, and transient ischemic attack. Peripheral arterial disease is also a manifestation of atherothrombotic disease, and occurs both acutely and as a result of underlying disease progression. Atherothrombotic disease is highly prevalent and imposes a substantial burden on the community. For example, coronary artery disease was the single greatest cause of mortality among men and women in the US and accounted for an estimated US dollars 142.1 billion in health costs in 2005. Activated platelets are the prime mediators of arterial thrombus formation. This review discusses the evidence supporting the use of oral antiplatelet agents with other risk prevention strategies in the long-term secondary prevention of atherothrombotic disease. The most widely used oral antiplatelet agent is aspirin (acetylsalicylic acid), and both aspirin and clopidogrel have proven roles in the management of atherothrombotic disease. Clopidogrel should also be used in combination with aspirin in patients with non-ST-segment elevation ACS and those undergoing percutaneous coronary intervention. Recent data suggest that clopidogrel may have a significant role, with or without fibrinolytic therapy, in the immediate management of ST-segment elevation ACS.

Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial.

BACKGROUND: Restenosis after percutaneous coronary intervention (PCI) is a major problem affecting 15% to 30% of patients after stent placement. No oral agent has shown a beneficial effect on restenosis or on associated major adverse cardiovascular events. In limited trials, the oral agent tranilast has been shown to decrease the frequency of angiographic restenosis after PCI. METHODS AND RESULTS: In this double-blind, randomized, placebo-controlled trial of tranilast (300 and 450 mg BID for 1 or 3 months), 11 484 patients were enrolled. Enrollment and drug were initiated within 4 hours after successful PCI of at least 1 vessel. The primary end point was the first occurrence of death, myocardial infarction, or ischemia-driven target vessel revascularization within 9 months and was 15.8% in the placebo group and 15.5% to 16.1% in the tranilast groups (P=0.77 to 0.81). Myocardial infarction was the only component of major adverse cardiovascular events to show some evidence of a reduction with tranilast (450 mg BID for 3 months): 1.1% versus 1.8% with placebo (P=0.061 for intent-to-treat population). The primary reason for not completing treatment was > or =1 hepatic laboratory test abnormality (11.4% versus 0.2% with placebo, P<0.01). In the angiographic substudy composed of 2018 patients, minimal lumen diameter (MLD) was measured by quantitative coronary angiography. At follow-up, MLD was 1.76+/-0.77 mm in the placebo group, which was not different from MLD in the tranilast groups (1.72 to 1.78+/-0.76 to 80 mm, P=0.49 to 0.89). In a subset of these patients (n=1107), intravascular ultrasound was performed at follow-up. Plaque volume was not different between the placebo and tranilast groups (39.3 versus 37.5 to 46.1 mm(3), respectively; P=0.16 to 0.72). CONCLUSIONS: Tranilast does not improve the quantitative measures of restenosis (angiographic and intravascular ultrasound) or its clinical sequelae.

Contemporary utilization and outcomes of intra-aortic balloon counterpulsation in acute myocardial infarction: the benchmark registry.

OBJECTIVES: We sought to examine contemporary utilization patterns and clinical outcomes in patients with acute myocardial infarction (AMI) requiring intra-aortic balloon pump (IABP) counterpulsation. BACKGROUND: Despite increasing experience with and broadened indications for intra-aortic counterpulsation, the current indications, associated complications, and clinical outcomes of IABP use in AMI are unknown. METHODS: Between June 1996 and August 2001, data were prospectively collected from 22,663 consecutive patients treated with aortic counterpulsation at 250 medical centers worldwide; 5,495 of these patients had AMI. RESULTS: Placement of an IABP in AMI patients was most frequently indicated for cardiogenic shock (27.3%), hemodynamic support during catheterization and/or angioplasty (27.2%) or prior to high-risk surgery (11.2%), mechanical complications of AMI (11.7%), and refractory post-myocardial infarction unstable angina (10.0%). Balloon insertions were successful in 97.7% of patients. Diagnostic catheterization was performed in 96% of patients, and 83% underwent coronary revascularization before hospital discharge. The in-hospital mortality rate was 20.0% (38.7% in patients with shock) and varied markedly by indication and use of revascularization procedures. Major IABP complications occurred in only 2.7% of patients, despite median use for three days, and early IABP discontinuation was required in only 2.1% of patients. CONCLUSIONS: With contemporary advances in device technology, insertion technique, and operator experience, IABP counterpulsation may be successfully employed for a wide variety of conditions in the AMI setting, providing significant hemodynamic support with rare major complications in a high-risk patient population.

Exploring the role of enoxaparin in the management of high-risk patients with non-ST-elevation acute coronary syndromes: the SYNERGY trial.

BACKGROUND: In patients with non-ST-elevation acute coronary syndromes (NSTE ACS), enoxaparin has been shown to be superior to unfractionated heparin (UFH) and is associated with a reduction in ischemic end points with nonsignificant increases in bleeding. However, the critical trials comparing enoxaparin with UFH were conducted before the widespread use of early invasive management and the availability of clopidogrel and glycoprotein IIb/IIIa receptor antagonists. METHODS: SYNERGY was an international, multicenter, randomized, open-label trial that compared enoxaparin with UFH in high-risk NSTE ACS patients managed with an early invasive strategy. For enrollment, 2 out of 3 high-risk features were required: age > or =60 years, elevated cardiac biomarkers, or ST-segment changes. The primary efficacy end point was death/myocardial infarction (MI) at 30 days. The primary safety end point was inhospital major bleeding or stroke through 30 days. RESULTS: The incidence of death/MI at 30 days was 14.0% in the enoxaparin group and 14.5% in the UFH group (hazard ratio 0.96, 95% CI 0.86-1.06), demonstrating noninferiority of enoxaparin relative to UFH. Enoxaparin was associated with a small but significant excess of Thrombolysis In Myocardial Infarction (TIMI) major bleeding, but there was no statistically significant increase in Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding or the rate of transfusion. There was no difference in complications of percutaneous coronary intervention. Interpretation of trial results was complicated by widespread use of enoxaparin or UFH before randomization, and by postrandomization crossover to the nonrandomized agent. CONCLUSIONS: In patients with NSTE ACS, including high-risk patients proceeding rapidly to catheterization, enoxaparin is an effective and safe alternative to UFH.

A perspective on trials comparing enoxaparin and unfractionated heparin in the treatment of non-ST-elevation acute coronary syndromes.

BACKGROUND: Non-ST-elevation (NSTE) acute coronary syndrome (ACS) is a serious, acute illness characterized by a high rate of death and morbid events, and antithrombin therapy is integral to its management. Contemporary guidelines from the American College of Cardiology/American Heart Association call for use of low-molecular-weight heparin or unfractionated heparin (UFH). METHODS: A systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS was performed using a random-effects empirical Bayes model. Efficacy end points included the incidence of death or the composite of death and myocardial infarction (MI) at 30 days. Safety end points included major bleeding and transfusion at 7 days. RESULTS: For the aggregate of 21,946 patients, the incidence of the composite of death and MI at 30 days was lower in enoxaparin-treated patients (10.1% vs 11.0% for UFH, OR 0.91, 95% CI 0.83-0.99, number need to treat 107). For the 9,835 patients in these trials who received no prerandomization antithrombin therapy, the composite of death and MI at 30 days occurred in 8.0% and 9.4% of enoxaparin- and UFH-treated patients, respectively (OR 0.81, 95% CI 0.70-0.94, number need to treat 94). There was no significant difference in the incidence of death at 30 days in either population. A nonsignificant trend toward higher rates of major bleeding was seen at 7 days for enoxaparin-treated patients, in both the overall safety population and the population of patients who did not receive antithrombin treatment before randomization, but there was no difference in blood transfusions. CONCLUSION: In a systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS in approximately 22,000 patients, the use of enoxaparin rather than UFH was associated with a modest reduction in the incidence of the composite of death and MI at 30 days without a significant increase in the rate of major bleeding or transfusion at 7 days.

High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial.

CONTEXT: The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days. OBJECTIVE: To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. DESIGN, SETTING, AND PATIENTS: Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. MAIN OUTCOME MEASURES: Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death. RESULTS: Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55). CONCLUSIONS: In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.ClinicalTrials.gov Identifier: NCT00043784.