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.

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.

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.

The impact of postrandomization crossover of therapy in acute coronary syndromes care.

BACKGROUND: In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology. METHODS AND RESULTS: Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI. CONCLUSIONS: Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784.

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.

Relationship between renal function and outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes: results from SYNERGY.

BACKGROUND: Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial. METHODS: Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI. RESULTS: Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11). CONCLUSIONS: Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.

Obesity in patients with non-ST-segment elevation acute coronary syndromes: results from the SYNERGY trial.

BACKGROUND: Obese patients are at increased risk of acute coronary syndromes (ACS). We evaluated the prevalence of obesity in a large ACS population, as well as the relationship between body mass index (BMI) and the use of cardiac medications and procedures, clinical outcomes, and treatment effects between enoxaparin and unfractionated heparin (UFH). METHODS: Using the database of the SYNERGY trial, we identified 9978 patients in 12 countries who were randomly assigned to receive enoxaparin or UFH. Patient weight at baseline and 30-day follow-up was recorded. BMI information was available on 9837 patients. BMI was analyzed in clinically meaningful categories (<20, 20-25, 30-35, > or =35 kg/m(2)) and as a continuous variable. RESULTS: Thirty-two percent of patients were obese (BMI> or =30), with a greater proportion of patients with obesity from North America (36%) compared with other regions. Enoxaparin was dosed as 1 mg/kg regardless of body weight without maximum. The first dose of enoxaparin was underdosed in 15% of patients assigned enoxaparin, and obese patients were more likely to be underdosed than non-obese patients. Obese patients were younger, less often white, had more diabetes, hypertension, hyperlipidemia, family history of coronary artery disease, and congestive heart failure but fewer strokes, less peripheral vascular disease, and less often smoked. After adjustment, increased BMI was not an independent predictor of bleeding outcomes or 30-day death/myocardial infarction (MI), but increased BMI was predictive of lower 1-year mortality in the subgroup of patients with BMI at baseline below approximately 30 kg/m(2). No statistical interaction term was observed between obesity and randomized therapy for the outcomes of death/MI at 30 days and 6 months; death at 30 days, 6 months, and 1 year; and GUSTO or TIMI bleeding. CONCLUSIONS: Nearly one third of patients in SYNERGY were obese. Despite multiple comorbidities, obese patients had better unadjusted short- and long-term outcomes. After adjustment, higher BMI was not an independent predictor of in-hospital bleeding events or 30-day death/MI, but increased BMI was an independent predictor of 1-year mortality in patients with lower BMI but not in heavier patients. No interaction between the randomized treatment and obesity for efficacy and safety outcomes was observed across the range of BMI in this dataset. Standard dosing of enoxaparin should be used in patients without extreme obesity due to limited outcome data in these patients.

Comparison of site-reported and core laboratory-reported creatine kinase-MB values in non-ST-segment elevation acute coronary syndrome (from the international trial SYNERGY).

The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (>or=2 times the ULN) by the core laboratory but normal (<2 times the ULN) by local standards in 708 instances (15%). There were 162 MI end points according to the core laboratory values versus 91 MI end points using the site-reported CK-MB data (kappa statistic 0.48). Compared with patients with no MI by the core or site laboratory values, patients with MI, as determined by both the core and the site laboratories, had significantly lower unadjusted 1-year survival rates (80.6% vs 93.5%, p <0.0001). Patients with MI, as determined by the core laboratory but not by the site laboratory, showed a trend toward a lower 1-year survival rate (89.8% vs 93.5%, p = 0.20). In conclusion, a substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial. More MI outcomes were identified by the core laboratory, and patients with MI as defined by core laboratory data had lower 1-year survival, making these events potentially clinically important.

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.

Antithrombotics in acute coronary syndromes.

Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

Safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention.

We sought to determine the safety and efficacy of enoxaparin versus unfractionated heparin during percutaneous coronary intervention (PCI). Four hundred ninety-three consecutive patients undergoing elective or emergency PCI received unfractionated heparin (70 U/kg, intravenously) or enoxaparin (1 mg/kg, intravenously). Patients who had received subcutaneous enoxaparin in the emergency department were given a supplementary 0.3-mg/kg intravenous dose. There was no crossover of therapies. All patients received oral antiplatelet therapy and eptifibatide. Primary safety outcomes were bleeding and a postprocedural hemoglobin decrease of >or=3 g/dL. Troponin I levels were considered a marker for myocardial injury.Two hundred twenty-two patients received enoxaparin, and 271 received unfractionated heparin. There were no thrombotic events or in-hospital deaths. Multivariate logistic regression analysis showed that, compared with unfractionated heparin, enoxaparin yielded a lower risk of bleeding (odds ratio [OR]=0.47; 95% confidence interval [CI], 0.21-1.05) and significantly fewer >3-g/dL decreases in hemoglobin (OR=0.45; 95% CI, 0.22-0.94). Enoxaparin also produced less of a decrease in mean platelet count (41 +/- 34 vs 55 +/- 63 x10(9)/L; P = 0.02) and in platelets >30% from baseline (OR=0.56; 95% CI, 0.31-0.99). After elective PCI, fewer enoxaparin patients had troponin I levels >or=3 times the upper limit of normal (OR=0.40; 95% CI, 0.028-0.66).Compared with unfractionated heparin, enoxaparin entailed less bleeding during both elective and emergent PCI and less cardiac enzyme elevation in patients undergoing elective PCI. Therefore, we believe that intravenous enoxaparin is a safe alternative to unfractionated heparin in both settings.

Antiplatelet 'resistance' and 'non-responders': what do these terms really mean?

The term 'resistance' should be restricted to very specialized physiologic circumstances, if not abandoned altogether. The term 'non-responder' needs to be placed in the context of the question: 'Non-responder to what?' Even if we would somehow magically know what an optimal response to antiplatelet therapy was, it will still be challenging to demonstrate an 'inadequate' response to antiplatelet therapy. At present there are two alternatives--give more drug or give additional drugs. Both strategies may work in further inhibiting platelet function, but both strategies can also be associated with an increased risk of bleeding. The trick, for the future, much as with our antihypertensive and lipid-lowering armamentaria, will be to know in whom to do what with which drug, and why. Single isolated measurements are not useful--if you don't know where you started, how we would know that antiplatelet drug is producing an 'adequate' clinical effect? There is no evidence of any sort of absolute 'threshold' that must be exceeded for treatment to be effective, and in the absence of this, if we are to evaluate the effect of a given drug, we have to have baseline values (off drug), therapeutic values (on drug), and some sort of assessment of both resting (unstimulated) and agonist-provoked (stimulated) platelet function. Moreover, given all of the different things that platelets do, the ideal assessment of platelet function and drug responsiveness will need to incorporate more than one agonist and some sort of assessment of both platelet activation and platelet aggregation. No one man (or test) tells us everything; it is the totality of the information that gives us the most complete picture. And, ultimately, we need to more firmly establish how the variability in platelet function and drug-associated changes in that function correlates with long-term, hard-endpoint clinical events.

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.

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.

Bleeding risks of combination vs. single antiplatelet therapy: a meta-analysis of 18 randomized trials comprising 129,314 patients.

A number of antiplatelet drugs, principally aspirin alone or in combination, have been evaluated in randomized trials of survivors of prior occlusive vascular disease events or of individuals at high risk because of multiple cardiovascular risk factors. In this meta-analysis we compare single and dual antiplatelet regimens to quantitate the risks of bleeding. Data from randomized trials published in English in 1988-2006 were retrieved from MEDLINE, OVID, and CARDIOSOURCE. Inclusion criteria were clinical follow-up for at least 1 month and the presence of data on bleeding complications. Information was compiled on sample size, antiplatelet agents tested, patient characteristics as well as major, minor, fatal and intracranial bleeding. Using these criteria, we identified 18 randomized trials, which included 129,314 patients. For each endpoint, relative risk (RR) and 95% confidence intervals (CI) were calculated. Dual antiplatelet therapy is associated with a significantly increased risk of major (RR 1.47, CI = 1.36-1.60) and minor bleeding events (RR 1.56, CI = 1.47-1.66) compared to single agent therapy. Although based on small numbers, there were no significant differences in fatal (RR 1.10, CI = 0.87-1.40) or intracranial (RR 1.07, CI = 0.85-1.35) bleedings although the CIs are wide to make definite assessments. Patients treated with dual antiplatelet therapy have an approximately 40-50% increase in risks of major and minor bleeding compared to those receiving single agent therapy during the duration of the scrutinized trials. The magnitude of this excess risk is not so remote from the approximately 60% increase observed in trials comparing single antiplatelet agents to placebo. This excess risk should be considered when choosing the optimal antiplatelet strategy for long-term treatment of patients with prior occlusive vascular events or those at high risk of developing occlusive vascular disease.

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.

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.

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.