Assessment of the Safety and Efficacy of a New Thrombolytic Regimen in the Prehospital Setting (ASSENT III Plus)
Lars Wallentin, Paul Armstrong, Chris Granger, Frans van de Werf, for the ASSENT-III PLUS investigators From the Departments of Cardiology, University Hospitals Uppsala, Sweden, Alberta Canada, Durham, USA, and Leuven, Belgium.
Background: The purpose was to evaluate the efficacy and safety of enoxaparin (ENOX) versus unfractionated heparin (UFH) added to tenecteplase in myocardial infarction in the prehospital setting concerning 30-day outcome and the time gain and outcome compared to in-hospital treatment in the previously reported ASSENT-III trial. Methods: Patients with chest pain <6 hours after symptom onset and demonstrating ST-elevation were randomized. The pre-hospital ASSENT-III PLUS trial recruited 1639 patients at 88 sites in 11 countries and was also compared with the 4038 patients in the ASSENT III trial. The designs were open label, parallel group trials with randomization to treatment with tenecteplase in combination with either ENOX given as an IV bolus 30 mg followed by s.c. 1 mg/kg every 12 hours until hospital discharge or 7 days, or UFH IV bolus 60 IU/kg followed by infusion 12 IU/kg/h with target APTT for 50–70 seconds. The primary efficacy end point was 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischemia, and the primary efficacy and safety end point also added in-hospital intracranial hemorrhage (ICH) or in-hospital major bleeds. ⇓
The excess of ICH in the ENOX group was only seen in patients aged >75 years and also explained the numerically higher mortality in that group. Compared with in-hospital, there was a 41 minutes time gain from symptom onset to treatment by the prehospital treatment. Conclusions: Prehospital thrombolysis reduces treatment delay with 40 to 45 minutes. Prehospital use of TNK-tPA and UFH appears as safe and efficacious as when given in-hospital. The combination of TNK-tPA with ENOX reduces in-hospital ischemic events but appears associated with an elevated risk of major bleeding and ICH above 75 years of age. Therefore, further trials with TNK-tPA and reduced doses of ENOX in the elderly are eagerly awaited.
Preliminary Results of the Complement and ReDuction of INfarct Size After Angioplasty or Lytics (CARDINAL) Trials
Christopher Granger, on Behalf of the CARDINAL Investigators
Background: Complement activation may mediate myocardial damage during ischemia/reperfusion via multiple inflammatory pathways. We performed two separate phase II randomized, double-blind, placebo-controlled trials to determine the effect of the complement inhibitor pexelizumab (C5 complement mAb fragment) on infarct size in patients treated with two different reperfusion strategies–thrombolysis (COMPLY) or primary PCI (COMMA). Methods: Patients with ST elevation acute myocardial infarction within 6 hours of symptom onset (20% with isolated inferior ST elevation) were randomized to placebo, pexelizumab 2.0 mg/kg bolus over 10 minutes, or pexelizumab 2.0 mg/kg bolus over 10 minutes plus 1.0 mg/kg infusion over 20 hours. The primary analysis was on the population treated with study drug and reperfusion therapy (n=920 in COMPLY, n=814 in COMMA), comparing infarct size determined by CK-MB area-under-the-curve over 72 hours with a log rank test. Secondary analyses included evaluation of the clinical composite (death, CHF, cardiogenic shock, or stroke) and its individual components through 90 days. COMPLY Results: There was no significant difference in infarct size (bolus vs placebo P=0.85; bolus plus infusion vs placebo P=0.81) or the clinical composite through 90 days (placebo 18.6% vs bolus 18.4% vs bolus plus infusion 19.7%). COMMA Results: There was no significant difference in infarct size (bolus vs placebo P=0.89, bolus plus infusion vs placebo P=0.76) or the clinical composite through 90 days (placebo 11.1% vs bolus 10.7% vs bolus plus infusion 8.5%). However, there was a significant reduction in all-cause mortality with pexelizumab bolus plus infusion at 90 days (5.9% 16/271 placebo vs 1.8% 5/281 bolus plus infusion [nominal P=0.014]). Bolus alone had intermediate mortality (4.2% 11/262). The mortality reduction with bolus plus infusion not only appeared early (1.9% absolute, 52% relative reduction at day 6) but became larger over time (4.1% absolute, 70% relative reduction at 90 days). Shock was nonsignificantly lower with bolus plus infusion at day 90 (5.2% 14/271 placebo vs 2.8% 8/281 bolus plus infusion, P=0.20). In the pooled analysis of COMPLY and COMMA, 90 day mortality was non-significantly reduced in the pooled studies (P=0.24). However, in the prespecified subgroup of North American region (n=1248) mortality was reduced (6.3% placebo vs 2.8% bolus-plus-infusion, P=0.019). Pexelizumab appeared to be safe, with no excess in infections or myocardial rupture. Conclusions: Pexelizumab had no measurable impact on infarct size. However, the finding of a significant reduction in mortality in the COMMA trial suggests that pexelizumab may have a clinical benefit through novel mechanisms. These results provide impetus for further investigation of pexelizumab in acute myocardial infarction.
A Phase 2, Randomized, Multicenter, 26-Week Study to Assess the Efficacy and Safety of BIOBYPASS (AdGVVEGF121.10) Delivered Through Minimally Invasive Surgery Versus Maximum Medical Treatment in Patients With Severe Angina, Advanced Coronary Artery Disease, and No Options for Revascularization
Duncan John Stewart, on behalf of the REVASC study investigators
Background: This is the first major randomized “proof of concept” study in coronary artery disease (CAD) that uses intramyocardial gene delivery with an angiogenic growth factor to induce collateral vessel formation. This phase 2, randomized, multicenter trial assessed the activity and safety of AdVEGF121, a replication-deficient adenovirus carrying the transgene encoding for vascular endothelial growth factor 121, in patients with severely symptomatic CAD who were not candidates for conventional revascularization. Methods: Eligible patients were randomized to receive AdVEGF121 (4x1010pu) in 30 direct intramyocardial injections throughout the free wall of the left ventricle via a minithoracotomy (32 patients), or continuation of optimal medical management (35 patients). Twenty-seven AdVEGF121 and 29 control patients were eligible for the primary analysis (a prospectively defined, modified intention-to-treat analysis, excluding patients with significant protocol violations). Results: Exercise treadmill (ACIP protocol) time to additional 1-mm ST depression (primary analysis assessed by blinded reading center) was significantly improved in the AdVEGF121 group compared with control group at 26 weeks (P=0.024), but not at week 12 (P=0.356). All other exercise test parameters showed statistically significant improvement in the AdVEGF121 group compared with control group, including time to angina at week 12 (P=0.006) and week 26 (P=0.002), and total exercise duration at week 12 (P=0.011) and week 26 (P=0.014). The proportion of responders on Canadian Cardiovascular Society Angina Class (defined as an improvement of at least one class) was significantly greater in the AdVEGF121 group at Week 6 (48% vs 10%), week 12 (82% vs 14%), and week 26 (85% vs 24%). Similarly, statistically significant improvements in the AdVEGF121 group compared with control group were seen in all 5 functional domains of the Seattle Angina Questionnaire at weeks 12 and 26. There were no significant differences in adverse events between groups. Serious cardiac events were attributed to the minithoractomy/AdVEGF121 injection procedure in 4 patients. The incidence of additional serious adverse cardiac events was not significantly different between the AdVEGF121 and control group (3 vs 9 patients, respectively). Three control patients underwent surgical cardiac interventions (cardiac transplant, CABG, and PTCA). Adenoviral cultures (urine and throat swab) were negative, and no significant changes in plasma vascular endothelial growth factor levels were noted. Conclusions: AdVEGF121 significantly improves exercise capacity and symptomatology of CAD. The effect appears durable with continuous improvement from 3 to 6 months. AdVEGF121 was well tolerated. A randomized, double-blind, placebo-controlled study with an injection catheter introduced via cardiac catheterization is the next logical step.
CQI in CABG: a National Randomized Trial in Quality Improvement
T. Bruce Ferguson, Jr, Eric D. Peterson, Laura P. Coombs, Mary E. Eiken, Meghan Carey, Elizabeth R. DeLong
From the Society of Thoracic Surgeons, Chicago, Ill, and the Duke Clinical Research Institute, Durham, NC. Background: To date, rigorous evaluation of the impact of continuous quality improvement (CQI) on medical practice has not been achieved on a large, multicenter scale. Using the infrastructure of the Society of Thoracic Surgeons (STS) National Cardiac Database (NCD), we undertook to determine whether a successful CQI initiative for coronary artery bypass grafting (CABG) could be implemented on a national level. Methods: The trial objective was to test whether a low-intensity CQI intervention could be used to speed the adoption of two CABG process of care measures. The STS, the largest cardiothoracic surgical specialty society in the United States, partnered with the Duke Clinical Research Institute (DCRI) to randomize 359 sites into one of three groups: Intervention #1: increase preoperative β-blocker (β-B) use; Intervention #2: increase internal mammary artery (IMA) graft use in elderly patients (aged >75 years); and Control: no QI intervention. Both intervention arms received (1) a Call to Action to a physician leader at intervention sites; (2) educational products (CQI slides, white papers, etc); and (3) longitudinal, nationally-benchmarked site-specific feedback. We used two methods of analysis: (1) a site-level analysis of differences between pre- and postintervention measure use, and (2) a hierarchical analysis using risk-adjustment for patient characteristics and accounting for clustering due to site. Results: From January 2000 to July 2002, overall use of both process measures increased (β-B, 59% to 67%; IMA, 74% to 85%). Patient clinical characteristics were similar across the 3 intervention groups (n>88|000 pts/group). Use of β-B was more rapidly adopted in the β-B group than in the Control group (▵=7% vs ▵=4%). This more rapid adoption was significant in both the site level (P=0.04) and the hierarchical analyses (P=0.0006). Use of IMA grafts in patients >75 years also increased faster in the IMA intervention sites, but this did not reach statistical significance (▵=9% vs ▵=5%; P=0.20 and P=0.11, respectively). However, the IMA intervention had significantly more impact on lower case volume sites (P=0.02 for interaction); these IMA sites showed significant improvement over lower case volume Control sites (▵=14% vs ▵=8%). Conclusions: This trial demonstrates that a multifaceted, physician-led, low-intensity effort can have an impact on the adoption of care processes into national practice. This successful CQI in CABG trial is a potential model for large-scale QI efforts across all disciplines of medicine.
A Randomized, Double-Blind, Controlled Trial of Early and Sustained Dual Oral Antiplatelet Therapy for Percutaneous Coronary Intervention: Results of the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial
Background: After percutaneous coronary intervention (PCI), short-term clopidogrel therapy on top of a background of aspirin leads to greater protection from thrombotic complications than aspirin alone, but the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. Methods: The Clopidogrel for the Reduction of Events During Observation (CREDO) trial is a randomized, double-blind, controlled trial designed to evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI, as well as to determine the benefit of initiating clopidogrel with a preprocedural loading dose, both on a background of aspirin therapy. A total of 2116 patients from 99 centers in the United States and Canada were randomized to receive a 300-mg clopidogrel loading dose or placebo 3 to 24 hours before PCI. Thereafter, all patients received daily clopidogrel 75 mg until day 28. After 28 days and up until 12 months, patients in the loading-dose group received clopidogrel 75 mg/day, and those in the control group received placebo. Both groups received aspirin throughout the study. The primary outcomes were the incidence at 28 days of the composite of death, myocardial infarction (MI), or urgent target vessel revascularization, and incidence at 1 year of the composite of death, MI, or stroke. Results: Clopidogrel pretreatment was associated with only a trend in the reduction of the composite 28-day end point by 18.5% (95% CI -14.2–41.8, P=0.23). However, the duration of pretreatment strongly influenced the degree of benefit; thus, in patients who received clopidogrel >6 hours before PCI, there was a relative risk reduction of 38.6% (95% CI -1.6–62.9, P=0.05). At 1 year, long-term clopidogrel therapy was associated with a significant 27% reduction in the combined risk of death, MI, or stroke (95% CI 3.9–44.4, P=0.023). Conclusions: After PCI, long-term (1-year) clopidogrel plus aspirin therapy, compared with the current standard of 2 to 4 weeks, significantly reduced the risk of adverse ischemic events. For pretreatment to be beneficial durations of >6 hours appear necessary, or possibly loading doses >300 mg.
Randomized Trial of Telephonic Intervention in Chronic Heart Failure: DIAL Trial
D. Nul, H. Grancelli, S. Varini, S. Soifer, D. Ferrante, C. Zambrano, A. Díaz, A. Fernández, O. Gabrielli, C. Dumont, J. Curotto, H. and Doval, on behalf of GESICA Investigators.
Background: Different approaches based on comprehensive patient care and close surveillance by multidisciplinary teams showed promising results in heart failure. However, current evidence mainly arises from small studies, performed at a single academic center, with selected populations using dissimilar strategies. DIAL trial is a large, multicenter, randomized controlled study designed to test the effect of a single intervention on prognosis in chronic heart failure. Objectives: To determine the benefit of the telephonic intervention (TI) as compared with usual follow-up on the combined end point of all-cause mortality and/ or heart failure (HF) hospitalization. Secondary outcomes were total mortality, admission for worsening of HF, and all-cause hospitalizations. Methods: The intervention was based on frequent telephonic follow-up, performed by nurses trained in the management of chronic HF. The purpose of each phone call was to provide education and counseling to achieve compliance and self-control. According to the evaluation, nurses could change the frequency of calls as well as diuretic doses. We randomized 1518 patients of 51 medical centers of Argentina: 760 were assigned to TI and 758 to usual care. Statistics were performed according to the intention-to-treat analysis with log rank test. Results: We completed follow-up for 99.5% of the patients with an average of 439 days. Baseline characteristics were similar in both groups. We found a 20% of relative risk reduction of the combined primary end point of all-cause mortality and/or HF admission, 26.3% in the intervention group, and 31.0% in the control group (P=0.026). There was no difference between groups in all cause mortality (15.3% in the TI group and 16.1% in the usual care group, P=0.69). Admissions for worsening HF were significantly reduced in the TI group (16.8% to 22.3%, RRR=28%, P=0.005), as well as all-cause admissions (34.3% to 39.1%, RRR=15%, P=0.05). Conclusions: Our centralized, telephonic intervention program was effective in reducing the end point of morbidity and/or mortality in patients with chronic HF mainly due to the impact on admissions for worsening HF.
Assessment of the Value of Cooling-Off Strategy (Extended Antithrombotic Pretreatment) in Patients With Unstable Coronary Syndromes Treated Invasively: the Intracoronary Stenting With Antithrombotic Regimen Cooling-off (ISAR-COOL) Trial
F.-J. Neumann, A. Kastrati, G. Pogatsa-Murray, J. Mehilli, H. Bollwein, H.-P. Bestehorn, J. Dirschinger, C. Schmitt, A. Schömig Deutsches Herzzentrum München, 1. Medizinische Klinik, Technische Universität München, Herz-Zentrum Bad Krozingen
Background: In acute coronary syndromes without ST-elevation, percutaneous catheter intervention is frequently preceded by extensive antithrombotic treatment (cooling-off) to reduce the risk of the procedure. The clinical efficacy of cooling-off in unstable coronary syndromes has not yet been tested in a randomized trial. Our prospective, randomized multicenter study sought to test the hypothesis that cooling-off can improve the outcome of catheter intervention in patients with acute coronary syndromes as compared with early catheter intervention. Methods: The study included patients with the clinical diagnosis of acute coronary syndrome plus positive troponin T and/or ST-segment depression. Important exclusion criteria were ST-segment elevation and contraindications to one of the study drugs. After study entry, all patients were treated with aspirin, clopidogrel, tirofiban, and heparin. Tirofiban was continued for 24 hours after percutaneous catheter intervention, clopidogrel for 4 weeks, and aspirin indefinitely. The patients were randomly allocated to either an antithrombotic pretreatment for 72–120 hours (cooling-off) or antithrombotic pretreatment for <6 hours. The primary end point was the composite of death and nonfatal myocardial infarction within 30 days. The study included 410 patients, 207 who were allocated to the cooling-off strategy, 203 to the strategy with early catheter intervention. Results: The two study groups did not show any significant difference with respect to major baseline characteristics. Positive troponin T was present in 67% of the study population, 65% had a ST-segment depression. The definite treatment was not significantly different between the two treatment groups (67% catheter intervention, 8% bypass operation). The primary end point was reached in 11.6% (3 deaths, 21 nonfatal infarctions) of the cooling-off group and in 5.9% (no death, 12 myocardial infarctions) of the early intervention group (relative risk 2.0, 95%-confidence interval, 1.01–3.94, P=0.04). Between study entry and catheterization, there were 13 events in the cooling-off group and one event in the early intervention group (P=0.002). After catheterization, 10 events occurred in both groups (P=0.96). Although bleeding requiring transfusion occurred more frequently in the cooling-off group as compared with the early intervention group (3.4% vs 1.0%), there were no significant differences in noncardiac complications. Conclusion: In patients with non—ST-elevation acute coronary syndromes, deferral of intervention for extensive antithrombotic pretreatment (cooling-off) does not improve the outcome compared with immediate intervention under intense antiplatelet coverage.
The REPLACE-2 Trial: Bivalirudin and Provisional GP IIb/IIIa Blockade Compared With Heparin and Planned GP IIb/IIIa Blockade During Percutaneous Coronary Intervention
A. Michael Lincoff, for the REPLACE-2 Investigators, from the Cleveland Clinic Foundation, Cleveland, Ohio.
Background: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during balloon angioplasty, but has not been widely tested during contemporary percutaneous coronary intervention (PCI) with stents, thienopyridines, or GP IIb/IIIa antagonists. Methods: In a Phase IIIb/IV randomized, double-blind, triple-dummy, active-controlled trial, 6010 patients over 21 years of age undergoing elective or urgent PCI were enrolled at 233 hospitals in 9 countries. Patients were randomized to receive bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg-hr during duration of PCI) with provisional GP IIb/IIIa inhibitor vs the reference standard of heparin (65 U/kg bolus) and planned GP IIb/IIIa inhibitor; the choice of abciximab or eptifibatide for GP IIb/IIIa blockade was made by the operator before randomization. Bivalirudin or heparin doses were adjusted to maintain procedural activated clotting times >225 secs, and pretreatment with clopidogrel was encouraged. The primary quadruple composite end point was death, myocardial (Q-wave or CK-MB >3 times control), urgent repeat revascularization, or major bleeding by 30 days. The primary hypothesis was that bivalirudin would be superior to heparin alone (imputed from a metaanalysis of GP IIb/IIIa placebo-controlled trials) and noninferior to heparin plus planned GP IIb/IIIa blockade with respect to the quadruple end point. Results: Provisional GP IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin arm. The quadruple composite end point occurred among 9.2% of patients in the bivalirudin arm vs 10.0% of patients in the heparin plus GP IIb/IIIa arm. Statistical criteria for superiority to (imputed) heparin and noninferiority to heparin plus GP IIb/IIIa were both satisfied. The secondary triple composite end point of death, myocardial infarction, or urgent revascularization occurred in 7.6% vs 7.1% of patients in the bivalirudin vs heparin plus GP IIb/IIIa arms, respectively; this triple end point also satisfied the statistical criterion for noninferiority to heparin plus GP IIb/IIIa. Major bleeding rates were 2.4% vs 4.1% in the bivalirudin vs heparin plus GP IIb/IIIa arms (P<0.001). Conclusions: Bivalirudin plus provisional GP IIb/IIIa blockade is superior to heparin alone and not inferior to heparin plus planned GP IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points, and is associated with less bleeding.
Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy: The SAPPHIRE Study
Jay S. Yadav, for the SAPPHIRE Investigators, from the Cleveland Clinic Foundation, Cleveland, Ohio.
Objectives: Are endarterectomy and stenting with emboli protection equivalent for the treatment of patients with severe carotid stenosis who have comorbidities which increase their risk for adverse events with endarterectomy? What is the risk of endarterectomy in patients who are routinely being treated in clinical practice but have comorbidities that would have excluded them from NASCET or ACAS? Methods: Asymptomatic patients with >80% stenosis by ultrasound and symptomatic patients with >50% stenosis and a high-risk criteria (CHF, severe COPD, previous CEA, severe CAD, radical neck surgery, radiation therapy) were enrolled at 29 US centers. All patients were seen by a team composed of a neurologist, surgeon, and interventionalist. Randomization to either CEA or stenting required a team consensus; if the surgeon felt that surgery carried a prohibitive risk, the patient was entered into the stent registry; if the interventionalist felt that stenting carried a prohibitive risk, the patient was entered into the surgical registry. Results: Randomization was performed for 307 patients. The cumulative 30-day adjudicated major adverse event rate defined as death, any stroke, or myocardial infarction (Q wave or non-Q wave) was 5.8% (9/156) for patients randomized to stenting with emboli protection compared with 12.6% (19/151) for patients randomized to treatment with CEA, P<0.05. A total of 409 were turned down for surgery and enrolled in the stent registry with 30-day MACE of 7.8% (32/409). Seven patients were turned down for intervention and enrolled in the surgical registry with 30-day MACE of 14.3% (1/7). Conclusions: In the first prospective, multicenter, randomized controlled trial of carotid stenting with emboli protection versus carotid endarterectomy, carotid stenting with emboli protection was associated with a significantly lower risk of stroke, MI, or death than carotid endarterectomy in patients with comorbid conditions. One-year follow-up is pending.
A Randomized, Double-Blind, Placebo-Controlled Study of Intravenous Tecadenoson in Patients With PSVT Undergoing an Electrophysiologic Study: Trial to Evaluate the Management of PSVT during Electrophysiologic Study with Tecadenoson (TEMPEST)
Kenneth Ellenbogen, MD, and the TEMPEST Study Group From the Medical College of Virginia, Richmond.
Objective: Tecadenoson, a novel adenosine derivative, prolongs AV nodal conduction by selective activation of the A1-adenosine receptors without causing A2 -adenosine receptor-mediated reductions in blood pressure or A2B-, A3-adenosine receptor-mediated bronchospasm. Tecadenoson is under clinical investigation for treatment of supraventricular tachyarrhythmias. The primary study objective was to assess the frequency of therapeutic conversion of PSVT (ie, to normal sinus rhythm without 2° or 3° AV block) during treatment with 5 different tecadenoson dose regimens versus placebo. Methods: This multicenter, randomized, double-blind, placebo-controlled study included patients with ≥1 documented episode of spontaneous, symptomatic tachyarrhythmia consistent with PSVT, and the need for an electrophysiological study to evaluate/treat PSVT. After PSVT was induced and sustained for ≥2 minutes, tecadenoson or placebo was administered as a rapid IV bolus. If PSVT persisted 1 minute after administration of study drug, a second dose was administered. Five active tecadenoson regimens were evaluated (first dose/second dose: 75 μg/150 μg [A], 150 μg/300 μg [B], 300 μg/600 μg [C], 450 μg/900 μg [D], 900 μg/900 μg [E]) versus placebo. Results: Each tecadenoson regimen resulted in significantly higher therapeutic conversion rates compared with placebo (intent-to-treat; n=181; P<0.0005). Therapeutic conversion rates were: Placebo, 2 of 30 (7%); A, 16 of 32 (50%); B, 17 of 29 (59%); C, 28 of 31 (90%); D, 24 of 29 (83%); and E, 26 of 30 (87%). Median times to tecadenoson-related conversion for regimens C, D, and E were ≤1 minute. PSVT recurred in 0, 0, 6, 7, 12, and 7% on Placebo, A, B, C, D, and E, respectively. Conversion arrhythmias were transient and required no treatment in regimens A through D. Ten patients with a history of asthma or COPD tolerated tecadenoson without bronchospasm. As expected, transient post-conversion AV block increased with dose (P<0.0001) (placebo, A, and B [n=0]; C [n=2]; D [n=4]; E [n=7]). There was no apparent dose-dependent increase in AE frequency after tecadenoson. Blood pressure was not decreased by tecadenoson and post-conversion heart rate increased significantly less on tecadenoson than on placebo. Discussion: Each tecadenoson regimen rapidly converted PSVT to normal sinus rhythm in a dose-dependent manner. In TEMPEST, tecadenoson regimens were identified that rapidly converted up to 90% of patients without significant adverse symptoms or hemodynamic effects.
Treatment With Enoxaparin and Tirofiban in Acute Myocardial Infarction: the TETAMI Study
Marc Cohen, Gian Franco Gensini, Enrique P. Gurfinkel, Frans Maritz, Kurt Huber, Maria Krzeminzka Pakula, Ari Timerman, Nicolas Danchin, Harvey White, Keith A.A. Fox, Luc Vittori, Carole Hecquet
Background: Patients with ST-segment elevation myocardial infarction (STEMI) considered ineligible for reperfusion therapy (lytics or percutaneous coronary intervention) have a poor prognosis. Methods: This study was designed to investigate efficacy and safety of enoxaparin versus unfractionated heparin (UFH), and tirofiban versus placebo, in patients ineligible for reperfusion, presenting <24 hours. TETAMI was a parallel group 2 x 2 factorial, double-blind, double-dummy, international multicenter study excluding shock or planned revascularization within 48 hours. Patients were randomized to receive antithrombotic treatment for 2–8 days. All patients received either enoxaparin (30-mg IV plus 1mg/kg sc bid) or UFH (70 U/kg IV plus a PTT adjusted 15-U/kg/hr infusion); and tirofiban (10 μg/kg IV plus 0.1-μg/kg/min infusion) or placebo. The primary end point was the combined incidence of death, reinfarction, or recurrent angina at 30 days. All end points were independently adjudicated. χ2 tests were used for all comparisons. Primary efficacy and safety analyses were performed for enoxaparin versus UFH, and tirofiban versus placebo. End points were also analyzed by treatment group: enoxaparin alone, enoxaparin plus tirofiban, UFH alone, and UFH plus tirofiban. Results: 1224 patients were randomized. There were no significant differences in baseline characteristics between treatment groups. No interaction was observed between enoxaparin or UFH versus tirofiban or placebo. The incidence of the primary efficacy composite end point was 15.7% for all patients taking enoxaparin versus 17.3% for all UFH patients (OR=0.89 95% CI=[0.66–1.21], P=0.471), and 16.6% for all tirofiban patients versus 16.4% for all placebo patients (OR=1.02 95% CI=[0.75–1.38], P=0.896). There were no significant differences in the rate of TIMI major hemorrhage (enoxaparin 1.5% versus UFH 1.3% and tirofiban 1.8% versus placebo 1.0%). Conclusions: The primary objective of demonstrating a 30% relative risk reduction was not realized in this challenging high-risk patient population. However, enoxaparin may be an alternative to UFH, in nonreperfused STEMI patients. Whether combined with enoxaparin or UFH, tirofiban showed a similar safety profile. ⇓
Effects of Hormone Replacement Therapy and Antioxidant Vitamin Supplements on Coronary Atherosclerosis in Postmenopausal Women: the Women’s Angiographic Vitamin and Estrogen (WAVE) Trial
David D. Waters, Edwin L. Alderman, Judith Hsia, Barbara V. Howard, Frederick R. Cobb, William J. Rogers, Pamela Ouyang, Paul Thompson, Jean Claude Tardif, Lyall Higginson, Vera Bittner, Michael Steffes, David J. Gordon, Michael Proschan, Naji Younes, Joel I. Verter
Context: Despite an absence of clinical trial evidence showing benefit, hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease. Objective: To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography. Design and Setting: A randomized, double-blind trial conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada. Patients: A total of 423 postmenopausal women with at least one 15–75% coronary stenosis at baseline coronary angiography. Interventions: Patients were randomly assigned in a 2x2 factorial design to receive either conjugated equine estrogen 0.625 mg/day, (plus medroxyprogesterone acetate 2.5 mg/day for women with intact uteri), or matching placebo, and vitamin E 400 IU twice/day plus vitamin C 500 mg twice/day, or placebo. Main Outcome Measures: The predefined, primary outcome was annualized mean change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying lesions averaged for each patient; patients with intercurrent death or myocardial infarction were imputed the worst rank of angiographic outcome. Results: The interval between angiograms was 2.8±0.9 years. The primary outcome showed an increased risk for women in the active HRT group (P=0.045), and suggested an increased risk in the active vitamin group (P=0.093). The rates of coronary progression (mean change in mm/year) for HRT and HRT placebo were –0.047±0.15 and –0.024±0.15, respectively (P=0.17), and for antioxidant vitamins and corresponding placebo –0.044±0.15 and –0.028±0.15, respectively (P=0.32). Mortality for HRT and HRT placebo was 14 and 8 (hazard ratio 1.8, 95% CI 0.75 to 4.3), and for vitamins and vitamin placebo 16 and 6 (hazard ratio 2.8, 95% CI 1.1 to 7.2). Death, nonfatal myocardial infarction or stroke occurred in 26 HRT patients versus 15 HRT controls (hazard ratio 1.9, 95% CI 0.97 to 3.6) and in 25 vitamin patients and 16 vitamin controls (hazard ratio 1.5, 95% CI 0.80 to 2.9). There was no interaction between the two treatments. Conclusion: In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit; in fact, a potential for harm was suggested with each treatment.
The X-TRACT Trial: a Prospective, Randomized Comparison of Stent Implantation in Thrombotic Native Coronary Arteries and Saphenous Vein Grafts With Versus Without Thromboatherectomy
Gregg W. Stone, David A. Cox, Joseph Babb, Dean Nukta, Luc Bilodeau, Louis Cannon, Thomas Stuckey, James Hermiller, Eric Cohen, Reginald Low, Alexandra J. Lansky, Steven R. Bailey, Richard E. Kuntz From the Cardiovascular Research Foundation and Lenox Hill Heart and Vascular Institute, New York City, NY.
Background: Percutaneous coronary intervention (PCI) of SVGs and native coronary arteries containing thrombus results in a high rate of periprocedural complications. Whether outcomes can be improved by thrombectomy before intervention is unknown. Methods: At 75 US sites, 797 consecutive patients undergoing stent implantation of 1 or more lesions in diseased SVGs (72%) or native coronary arteries containing thrombus (28%) were prospectively randomized to standard PCI versus thromboatherectomy with the X-SIZER (ev3) followed by PCI. Results: Baseline clinical and angiographic features were evenly distributed between the 2 groups, except X-SIZER patients were more likely to have thrombus present (70% vs 58%, P<0.001), and had a slightly greater initial diameter stenosis (70% vs 67%, P<0.05). GP IIb/IIIa inhibitors were administered in 78% of each group. Among patients not receiving upfront IIb/IIIa inhibitors, bail-out IIb/IIIa use was required in fewer patients treated with the X-SIZER (2.1% vs 10.3%, P=0.02). Outcomes appear in the Table. After accounting for the difference in baseline thrombus and lesion severity by multivariate analysis, use of the X-SIZER was an independent predictor of freedom from large MI (odds ratio=0.35, P=0.002) and death or large MI (OR=0.43, P=0.006). Conclusions: Thromboatherectomy with the X-SIZER before stent implantation in diseased SVGs or thrombotic native coronary lesions reduces procedural complications as evidenced by less need for bail-out GP IIb/IIIa inhibitors, and enhances 30-day survival free from large MI. The overall 30-day rate of MI and MACE were similar with and without the X-SIZER, however, consistent with the hypothesis that thrombectomy with the X-SIZER reduces the extent of periprocedural myonecrosis.
The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)
GJ Blauw, MB Murphy, J Shepherd, on behalf of the PROSPER Study Group.
Background: Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals, their efficacy and safety in elderly people is not fully established. Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with, or at high risk of developing, cardiovascular disease and stroke. Methods: We randomized 5804 men (n=2804) and women (n=3000) aged 70–82 years with a history of, or risk factors for, vascular disease to pravastatin (40 mg per day; n=2891) or placebo (n=2913). Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary end point was a composite of coronary death, nonfatal myocardial infarction, and fatal or nonfatal stroke. Results: Pravastatin lowered LDL cholesterol concentrations by 34% and reduced the incidence of the primary end point to 408 events compared with 437 on placebo (hazard ratio 0.85, 95% CI 0.74–0.97, P=0.014). Coronary heart disease death and nonfatal myocardial infarction risk was also reduced (0.81, 0.69–0.94, P=0.006). Stroke risk was unaffected (1.03, 0.81–1.31, P=0.81), but the hazard ratio for transient ischaemic attack was 0.75 (0.55–1.00, P=0.051). New cancer diagnoses were more frequent on pravastatin than on placebo (1.25, 1.04–1.51, P=0.020). However, incorporation of this finding in a metaanalysis of all pravastatin and all statin trials showed no overall increase in risk. Mortality from coronary disease fell 24% (P=0.043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. Conclusions: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals. Prosper therefore extends to the elderly the treatment strategy currently used in middle-aged subjects.