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Biomedical subjects

Steven R Steinhubl

Publications and source records attributed to Steven R Steinhubl.

At least 19 recordsLinked to original sources
PubMed2007

Risk stratification for patients undergoing nonurgent percutaneous coronary intervention using N-terminal pro-B-type natriuretic peptide: a Clopidogrel for the Reduction of Events During Observation (CREDO) substudy.

BACKGROUND: The utility of N-terminal pro-BNP (NT-proBNP) measurement as a prognostic marker during nonurgent percutaneous coronary intervention (PCI) has been suggested in several studies. The comparative prognostic values between NT-proBNP levels and left ventricular ejection fraction (LVEF) in the nonurgent PCI setting are unclear. METHODS: CREDO was a double blind, placebo-controlled, randomized trial comparing 2 clopidogrel regimens before and after nonurgent PCI. Baseline NT-proBNP levels and LVEF were measured in 1468 subjects using the Roche Elecsys proBNP assay (Roche Diagnostics, Indianapolis, IN), and the 1-year combined end point of death/myocardial infarction (MI)/stroke was analyzed according to NT-proBNP quartiles in impaired and preserved LVEF. RESULTS: In this patient cohort (mean age 61.6 +/- 10 years, 22% with LVEF < 50%), the median NT-proBNP level was 131 pg/mL. Increasing quartiles of NT-proBNP were associated with a higher rate of death, MI, and the combined end point (but not stroke) at 1 year, including those with LVEF > or = 50% (P < .001 for trend). This prognostic power for death and MI remained robust even when adjusted for other clinical or biochemical markers including cardiac troponin, creatinine clearance, and high-sensitive C-reactive protein (hazard ratio 1.249, P = .006). Despite its robust prognostic value, baseline NT-proBNP levels did not identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy. CONCLUSIONS: In patients undergoing a nonurgent PCI, NT-proBNP levels may provide important prognostic value for death and MI, even in patients with preserved cardiac function, However, NT-proBNP levels were unable to identify patients with enhanced benefit from pre-procedural and prolonged clopidogrel therapy.

Aged↗
PubMed2006

First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity.

BACKGROUND: Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study. METHODS AND RESULTS: Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline. CONCLUSIONS: These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

Adult↗
PubMed2006

The influence of peripheral arterial disease on outcomes: a pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials.

OBJECTIVES: We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI). BACKGROUND: A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes. METHODS: We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events. RESULTS: In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013). CONCLUSIONS: The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.

Angioplasty, Balloon, Coronary↗
PubMed2006

Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention.

BACKGROUND: Despite its limitations, unfractionated heparin has been the standard anticoagulant used during percutaneous coronary intervention (PCI). Several small studies have suggested that intravenous enoxaparin may be a safe and effective alternative. Our primary aim was to assess the safety of enoxaparin as compared with that of unfractionated heparin in elective PCI. METHODS: In this prospective, open-label, multicenter, randomized trial, we randomly assigned 3528 patients with PCI to receive enoxaparin (0.5 or 0.75 mg per kilogram of body weight) or unfractionated heparin adjusted for activated clotting time, stratified according to the use or nonuse of glycoprotein IIb/IIIa inhibitors. The primary end point was the incidence of major or minor bleeding that was not related to coronary-artery bypass grafting. The main secondary end point was the percentage of patients in whom the target anticoagulation levels were reached. RESULTS: Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non-CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, -2.6; 95% confidence interval [CI], -4.7 to -0.6; P=0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, -2.0; 95% CI, -4.0 to 0.0; P=0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P<0.001). CONCLUSIONS: In elective PCI, a single intravenous bolus of 0.5 mg of enoxaparin per kilogram is associated with reduced rates of bleeding, and a dose of 0.75 mg per kilogram yields rates similar to those for unfractionated heparin, with more predictable anticoagulation levels. The trial was not large enough to provide a definitive comparison of efficacy in the prevention of ischemic events. (ClinicalTrials.gov number, NCT00077844 [ClinicalTrials.gov].).

Aged↗
PubMed2006

Early coronary revascularization diminishes the risk of ischemic stroke with acute myocardial infarction.

BACKGROUND AND PURPOSE: Ischemic stroke is an uncommon but devastating complication of myocardial infarction (MI). It is possible that delay in the acute revascularization of these patients influences the risk of peri-MI ischemic stroke independent of size of infarction or residual ventricular function. The influence of the timing and type of revascularization on risk of ischemic stroke in the patient with MI has not previously been assessed. METHODS: We used the National Registry of Myocardial Infarction 3 and 4 databases to identify 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for MI. In-hospital ischemic stroke occurred in 248 (0.54%) and 150 (0.31%) patients in the two groups, respectively. Patients were stratified based on time from presentation to initial therapy. RESULTS: A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes was associated with a lower risk of ischemic stroke (odds ratio, 0.58; 95% CI, 0.36-0.94). Primary angioplasty within 90 minutes of arrival was associated with a nonsignificant trend toward lower stroke risk (odds ratio, 0.68; 95% CI, 0.41-1.12). Interestingly, his benefit of early reperfusion therapy did not appear to be related to improvements in left ventricular function. CONCLUSIONS: Risk of in-hospital ischemic stroke with MI is closely tied to the time to revascularization with both thrombolytic and percutaneous transluminal coronary angioplasty therapies. Early revascularization is independently predictive of a lower risk of ischemic stroke, but the mechanism of this does not appear to be related to improved cardiac function. The records of 45,997 subjects who received thrombolytic therapy and 47,876 patients who were treated with primary percutaneous transluminal coronary angioplasty for myocardial infarction were analyzed to determine the relationship between time to revascularization and the occurrence of ischemic stroke. A statistically significant linear relationship between time to revascularization therapy and risk of in-hospital ischemic stroke was seen on univariate analysis. A multivariate model incorporating 26 other variables showed thrombolytic therapy within 15 minutes of presentation was associated with a lower risk of ischemic stroke, and angioplasty within 90 minutes was similarly associated with a nonsignificant trend toward lower stroke risk.

Aged↗
PubMed2006

Incidence and prevention of ischemic stroke following myocardial infarction: review of current literature.

Myocardial infarction is the leading cause of death today. With the fast progress in pharmacotherapy and revascularization technology, outcomes following a myocardial infarction have become very favorable. While most of the complications from a myocardial infarction can be adequately managed, thus leading to reduced mortality, stroke following a myocardial infarction remains a challenge even today, and can lead to potentially devastating complications. We discuss the incidence, pathophysiology, and management options of non-hemorrhagic stroke following a myocardial infarction.

Angioplasty, Balloon, Coronary↗
PubMed2006

Onset and offset of platelet inhibition after high-dose clopidogrel loading and standard daily therapy measured by a point-of-care assay in healthy volunteers.

An increased loading dose of clopidogrel has been shown to provide more intense and rapid platelet inhibition (PI) than the standard 300-mg dose. However, patient variability in PI and in the timing of platelet recovery may affect efficacy during percutaneous coronary intervention and the bleeding risk of surgery. This study examined the degree of PI after a high-dose load of clopidogrel compared with standard dosing and the time course of functional recovery after the discontinuation of daily therapy. Healthy volunteers (n = 45) were randomized to 3 loading doses of clopidogrel (300, 600, and 900 mg) and continued at 75 mg/day for 6 to 18 days. PI was calculated using a P2Y12-specific point-of-care assay at baseline, hourly for 7 hours after loading, and daily for 5 days after the discontinuation of daily therapy. The groups receiving 600- and 900-mg doses had significantly greater PI than the group receiving the 300-mg dose 2 to 3 hours after loading, but there were no differences between the 600- and 900-mg doses at any time point. Median PI decreased each day after clopidogrel cessation (p < 0.01). On day 5 after discontinuation, the median PI was 12% (interquartile range 0% to 17.4%), but 2 subjects (5%) had persistent PI > 40%. Before day 5, 57% of subjects had recovered platelet function to a PI of < 20%. In conclusion, a 900-mg dose of clopidogrel provides no benefit in terms of magnitude or time to maximal PI compared with a 600-mg dose, but both are superior to a 300-mg dose. A point-of-care assay can identify subjects who may recover platelet function before 5 days after discontinuation or, in contrast, have persistent PI despite discontinuation.

Clopidogrel↗
PubMed2006

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.

BACKGROUND: Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events. METHODS: We randomly assigned 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes. RESULTS: The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidence interval, 0.83 to 1.05; P=0.22). The respective rate of the principal secondary efficacy end point, which included hospitalizations for ischemic events, was 16.7 percent and 17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P=0.04), and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95 percent confidence interval, 0.97 to 1.61 percent; P=0.09). The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to 1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with clopidogrel (3.9 percent vs. 2.2 percent, P=0.01). In the subgroup with clinically evident atherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P=0.046). CONCLUSIONS: In this trial, there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors. Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. (ClinicalTrials.gov number, NCT00050817.).

Adult↗
PubMed2006

Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention.

OBJECTIVES: This study sought to determine the optimal timing of a 300-mg clopidogrel loading dose before percutaneous coronary intervention (PCI) in patients enrolled in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. BACKGROUND: A loading dose of clopidogrel before a PCI has become relatively commonplace, although the data supporting this practice are limited and sometimes conflicting. METHODS: Patients were randomized to receive either 300 mg clopidogrel or a matching placebo administered a minimum of 3 h and a maximum of 24 h before PCI. The primary 28-day combined end point was death, myocardial infarction, or urgent target vessel revascularization. Linear splines were used to summarize the effect of the time of pre-treatment as a continuous variable. RESULTS: A total of 1,762 patients were evaluated. For patients randomized to placebo, there was no relationship between the duration of pre-treatment and the occurrence of the primary end point, whereas longer durations of pre-treatment in patients randomized to clopidogrel were associated with improved outcomes. The event rates diverged maximally at 24 h. The difference in outcomes between placebo and clopidogrel pre-treated patients was not significant until > or =15 h pre-treatment, with a 58.8% (p = 0.028) reduction in the primary end point in patients pre-treated with clopidogrel > or =15 h compared with placebo. CONCLUSIONS: When a 300-mg loading dose of clopidogrel is used, little benefit is obtained compared with just 75 mg at the time of the PCI when the treatment duration is <12 h. In patients pre-treated for longer durations, the optimal duration seems to approach 24 h.

Angioplasty, Balloon, Coronary↗
PubMed2006

Impact of drug-eluting stents on outcomes of patients with end-stage renal disease undergoing percutaneous coronary revascularization.

BACKGROUND AND OBJECTIVE: End-stage renal disease (ESRD) patients on chronic dialysis are at heightened risk for target vessel revascularization (TVR) after coronary stenting. However, ESRD patients were excluded from the trials that demonstrated the superiority of drug-eluting stents (DES) over bare metal stents (BMS) in reducing TVR. We sought to identify the impact of stent type (DES versus BMS) on TVR and other cardiac adverse events in ESRD patients. METHODS: The study included 89 consecutive ESRD patients who underwent coronary stenting and were followed for greater than or equal to 9 months. TVR was the primary endpoint, and the secondary endpoint was a composite of death, myocardial infarction (MI) and TVR. Multivariate logistic regression models were used to adjust for differences in clinical and procedural characteristics. RESULTS: DES were used in 24 and BMS in 65 patients. The stent diameter was smaller (p = 0.008), but the stent length was longer (p = 0.006) in the DES group. TVR was required in 1 (4%) of DES and 17 (26%) BMS patients, while 8 (33%) DES and 39 (60%) BMS patients met the secondary endpoint. By multivariate logistic regression, DES use was associated with a significant reduction in TVR (OR 0.07, 95% CI 0.006-0.844; p = 0.036) and a significant reduction in death, MI and TVR (OR 0.11, 95% CI 0.022-0.513; p = 0.005). CONCLUSION: A high rate of ischemic events was noted for ESRD patients, regardless of stent type. However, in ESRD patients undergoing coronary revascularization, DES use is effective in reducing 9-month TVR and the composite of death, MI and TVR.

Aged↗
PubMed2006

Optimizing antiplatelet therapy for the ACS patient: reacting to clinical trial data from the ISAR-REACT-2 studies.

Antiplatelet therapy is the cornerstone of treatment for patients with an acute coronary syndrome (ACS). However, patients presenting with possible ACS are a heterogeneous population, and there is a choice of many potential combination antiplatelet therapies, with aspirin, thienopyridines (eg, clopidogrel), and glycoprotein (GP) IIb/IIIa antagonists. The ISAR-REACT-2 trial investigated the optimal application of triple (aspirin 1 thienopyridine 1 GP IIb/IIIa inhibitor) versus dual (aspirin 1 thienopyridine) antiplatelet therapy for patients with ACS undergoing percutaneous coronary intervention. Abciximab was associated with a significant 25% relative reduction in risk for the 30-day combined endpoint of death, myocardial infarction, or urgent target vessel revascularization. All of this benefit was confined to the patients with elevated troponin levels. The data indicate that troponin can be used as a biomarker to identify patients most likely to benefit from the addition of a GP IIb/IIIa antagonist.

Acute Coronary Syndrome↗