Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS.

OBJECTIVE: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNbeta-1a) combined with methotrexate (MTX), i.v. methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNbeta-1a monotherapy. METHODS: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0-5.5, and > or = 1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNbeta-1a monotherapy. Participants continued weekly IFNbeta-1a 30 microg i.m. and were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg p.o., with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. RESULTS: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNbeta-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNbeta neutralizing antibody titers. CONCLUSIONS: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis.

Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the platelet IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial.

Background- A reactivation of ischemia after the discontinuation of intravenous heparin in acute coronary syndromes has been described. The effect of glycoprotein IIb/IIIa blockade on heparin rebound is unknown. Methods and Results- Patients with acute coronary syndromes who received heparin therapy but not initial revascularization in the Platelet IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial were analyzed. Rates of death or myocardial (re)infarction while on heparin therapy and in 12-hour periods in the 2 days after heparin discontinuation were compared between eptifibatide and placebo. There was no difference between study groups in event rates during heparin infusion. In the 12 hours after heparin discontinuation, there was a 2.5-fold increase in all events, an 8-fold increase in death, and a 2-fold increase in myocardial infarction. However, in the 12 hours after heparin discontinuation, there was a significantly lower rate of events (1.68% versus 2.53%, P=0.03) and death (0.77% versus 0.21%, P=0.002) in the eptifibatide group compared with the placebo group. When only considering patients who were on study drug at the time of heparin discontinuation, the reduction in the combined end point was marginally significant, but the difference in the rate of death remained significant (0.68% versus 0.06%, P=0.004). In logistic regression analyses, the multivariate predictors of rebound events were the duration of heparin therapy, age, North American site, and lack of eptifibatide treatment. Conclusions- An increase in death or myocardial infarction occurs in the 12 hours after heparin discontinuation in patients with acute coronary syndromes. This rebound is attenuated by glycoprotein IIb/IIIa inhibition with eptifibatide.

Predictors and prognosis of suboptimal coronary blood flow after primary coronary angioplasty in patients with acute myocardial infarction.

We hypothesized that certain clinical and angiographic characteristics on presentation predict suboptimal infarct artery flow after percutaneous intervention during acute myocardial infarction (AMI). The goal of angioplasty (percutaneous transluminal coronary angioplasty [PTCA]) during AMI is the prompt restoration of normal flow to achieve myocardial reperfusion. However, inadequate epicardial coronary flow is observed in 10% to 20% of patients. From 2 large randomized trials-Global Use of Strategies To open Occluded arteries in Acute Coronary Syndromes-IIb, and Randomized Placebo-Controlled Trial of Platelet glycoprotein IIb/IIIa Blockade With Primary Angioplasty for Acute Myocardial Infarction-patients undergoing primary PTCA during AMI were included in the analysis. A multivariate logistic model was used to identify factors associated with final Thrombolysis In Myocardial Infarction (TIMI) flow grade < or =2. The 891 patients were aged (mean +/- SD) 61 +/- 12 years, 75% were men, and 39% had an anterior wall AMI. Patients underwent PTCA within 4.8 +/- 3.2 hours from the onset of chest pain. The incidence of final TIMI 3 flow was 81%. TIMI flow grade < or =2 was independently associated with increasing age (odds ratio [OR] 1.39 for every 10 years, 95% confidence interval [CI] 1.19 to 1.62), increasing heart rate (OR 1.16 for every 10 beats, 95% CI 1.05 to 1.28), and presence of visible thrombus on baseline angiogram (OR 1.89, 95% CI 1.18 to 3.05). Conversely, baseline TIMI 2 or 3 flow grade (OR 0.46, 95% CI 0.28 to 0.75) and left circumflex intervention (OR 0.42, 95% CI 0.23 to 0.79) correlated with normal postprocedural coronary flow. Mortality was significantly higher in patients with TIMI < or =2 than TIMI 3 flow grade (10.2% vs 1.5%, p <0.001, respectively). Thus, angiographic evidence of thrombus and 2 pivotal clinical characteristics, advanced age and elevated heart rate, predict lack of adequate coronary reperfusion. Conversely, the presence of normal or near-normal coronary flow before intervention correlates with a good angiographic result. Mortality risk is increased in patients with postprocedural suboptimal angiographic coronary flow.

Prognostic value of absolute versus relative measures of the procedural result after successful coronary stenting: importance of vessel size in predicting long-term freedom from target vessel revascularization.

BACKGROUND: The procedural result is a major determinant of the incidence of 6-month target vessel revascularization (TVR) after successful coronary stenting. However, the prognostic implications of the different measures of the procedural result or procedural end points have not been directly compared. In this study, we sought to assess and compare the impact of achieving different procedural end points on the long-term (2-year) incidence of TVR. METHODS AND RESULTS: We studied 234 patients in whom 1 or 2 stents were successfully deployed and ultrasound imaging performed after angiographic optimization. End points included a visually estimated angiographic residual stenosis <10% and ultrasound stent-to-mean reference lumen area > or = 80%. After 2 years, TVR was required in 48 (20.5%) patients. Qualitative predictors of TVR were vein graft lesions, 3-vessel disease, and baseline TIMI flow grade < 3. Quantitatively, reference diameter by quantitative coronary angiography (QCA), final minimum lumen diameter (MLD) by QCA, and in-stent minimum lumen area (MLA) by ultrasound were predictive of TVR. Stent-to-reference ratios were not significantly predictive of TVR. By multivariable analysis, vein graft location and MLA by ultrasound were the only significant predictors of TVR (relative risk, 2.9 [1.5, 5.4] and 0.72 [0.6, 0.9], respectively). Receiver operator curves for MLD by QCA and MLA by ultrasound were similar in predicting TVR. Neither was significantly superior to reference vessel diameter. CONCLUSIONS: Commonly used angiographic and ultrasound stent-to-reference ratios do not predict the incidence of TVR. Absolute measures of the lumen size (MLA by ultrasound and MLD by QCA) were the most important quantitative predictors of TVR within 2 years. This emphasizes the role of the vessel size as the limiting factor in determining the long-term outcome of coronary stenting.

Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study.

BACKGROUND: Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors. However, the effect of lipid-lowering therapy on short-term mortality immediately after an acute coronary syndrome has not been determined. We did an observational study using data from two randomised trials to investigate this issue. METHODS: We used data from the GUSTO IIb and PURSUIT trials to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n=3653) with those who were not (n=17,156). A propensity analysis was done to adjust for presumed selection biases in the prescription of lipid-lowering agents. FINDINGS: Lipid-lowering therapy was associated with a smaller proportion of deaths at 30 days (17 [0.5%] vs 179 [1.0%], hazard ratio 0.44 [95% CI 0.27-0.73], p=0.001) and at 6 months (63 [1.7%] vs 605 [3.5%], 0.48 [0.37-0.63], p<0.0001). After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (0.67 [0.48-0.95], p=0.023). INTERPRETATION: Prescription of a lipid-lowering drug at hospital discharge was independently associated with reduced short-term mortality among patients after an acute coronary syndrome.

Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting. PURSUIT Investigators.

BACKGROUND: Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown. METHODS AND RESULTS: The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7). CONCLUSIONS: Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

Two internal thoracic artery grafts are better than one.

OBJECTIVE: Does the use of bilateral internal thoracic artery (ITA) grafts provide incremental benefit relative to the use of a single ITA graft? METHODS: We conducted a retrospective, nonrandomized, long-term (mean follow-up interval of 10 postoperative years) study of patients undergoing elective primary isolated coronary bypass surgery who received either single (8123 patients) or bilateral ITA grafts (2001 patients), with or without additional vein grafts. Multiple statistical methods including propensity score matching, and multivariable parsimonious and nonparsimonious risk factor analyses were used to address the issues of patient selection and heterogeneity. RESULTS: In-hospital mortality was 0.7% for both the bilateral and single ITA groups. Survival for the bilateral ITA group was 94%, 84%, and 67%, and for the single ITA group 92%, 79%, and 64% at 5, 10, and 15 postoperative years, respectively (P <.001). Death, reoperation, and percutaneous transluminal coronary angioplasty were more frequent for patients undergoing single rather than bilateral ITA grafting, and this observation remained true despite multiple adjustments for patient selection, sampling, and length of follow-up. The differences between the bilateral and single ITA groups were greatest in regard to reoperation. The extent of benefit of bilateral ITA grafting varied according to patient-related variables, but no patient subsets were identified for whom single ITA grafting could be predicted to provide an advantage. CONCLUSIONS: Patients who received 2 ITA grafts had decreased risks of death, reoperation, and angioplasty.