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These studies were presented at the American College of Cardiology 50th Annual Scientific Session held in Orlando, Fla, March 18-21, 2001. The reports are based upon hand notes taken at the conference presentations. No written reports were available.
The clopidogrel in unstable angina trial to prevent Recurrent Events (CURE) was designed as a randomized, double-blinded multicenter study to compare the safety and efficacy of the combination of aspirin and clopidogrel with aspirin alone in the treatment of acute coronary syndromes. A total of 12,562 patients were randomized to standard dose aspirin or standard dose aspirin with a loading dose of 300 mg of clopidogrel followed by 3-6 months of 75 mg daily. Inclusion criteria included patients admitted to the hospital with onset of symptoms consistent with an acute coronary syndrome within 24 hours, ECG’s consistent with new ischemia, and elevated cardiac enzymes (CPK-MB or troponin T/I). Exclusions included ST elevation, IIb/IIIa inhibitors within 3 days, contraindications to anticoagulation, patients at high-risk for bleeding complications, and PCI or CABG within 3 months. The primary end point was a composite of cardiovascular death, myocardial infarction (MI), or stroke. The secondary end point was recurrent ischemia. Concurrent medications in both groups included aspirin in 99%, beta-blockers in 78%, low molecular weight heparin in 56%, unfractionated heparin in 44%, ACE inhibitors in 50%, and calcium channel blockers in 26%.
The composite primary end point of death, MI, or stroke was reached in 11.4% of the patients receiving clopidogrel and 13.6% of patients receiving ASA alone with other standard therapy. This was an absolute risk reduction of 2% with a relative risk reduction of 18%, which was statistically significant (P = .0005). The breakdown in events was death reduced by 0.43%, MI by 1.4%, and stroke by 0.2%. The secondary end point of recurrent ischemia was reduced by 2.3% or a relative risk reduction of 14% (P = .0004). The beneficial effect was seen in all patient subgroups at 2 hours. There was an increased risk of major bleeding defined as life-threatening, associated with hypotension or requiring blood transfusion in 3.6% of the clopidogrel group vs. 2.7% of the aspirin group. This reached statistical significance. There was also a statistically significant increased risk of minor bleeding. The investigators concluded that the treatment of 1000 patients with clopridogel and aspirin for a mean of 9 months will prevent 28 major events in 23 patients at a risk of 3 major or life-threatening bleeds.
Comment by Michael H. Crawford, MD
This is compelling data in an environment where small absolute reductions in cardiac events continue to improve outcomes in acute coronary syndromes. Though the absolute change is small, the impact is great. In fact, the magnitude of improvement was more than achieved with tissue plasminogen activator versus streptokinase in acute MI. However, the issue of whether to use it in all acute coronary syndromes is not clear. Many of these patients in this trial would fit into the group of patients that have a clear indication for IIb/IIIA inhibitors, but the majority of patients in this trial were enrolled outside the United States where IIb/IIIa inhibitor use is not as prevalent as it is here. We do not know if there is an additive beneficial effect in these patients who almost certainly would receive a IIb/IIIa inhibitor in the United States. Additionally, those already on IIb/IIIa’s were excluded from the trial. We do know that it is safe to use all 3 agents and do so in many patients undergoing percutaneous revascularization with stents. Clopidogrel should not be substituted for IIbIIIa’s, as it has a different effect and the data to support this substitution are not available. Perhaps we will eventually be able to further risk stratify patients to those who would benefit most from each strategy. Also, the use of clopidogrel in acute MI treated with thrombolytics should be approached with caution. We do not have safety data and the increased risk of bleeding may prove to be prohibitive. Stent trials suggest this may be a safe strategy in acute coronary syndrome patients treated with primary angioplasty, but patients who eventually need surgical revascularization may be at increased risk for bleeding. Many surgeons are reluctant to operate on patients on combination therapy. Thus, clopidogrel should be used in unstable angina patients, especially those deemed to be at high risk. The benefit is seen at 2 hours and clopidogrel should be given early with a loading dose of 300 mg. Concommitant use with IIb/IIIa inhibitors needs to be explored further. Use in the early stages of acute MI with thrombolytics is not recommended.
"The CarvedilOl ProspEctive RaNdomized Cumulative Survival" Trial
This study was initially reported at the european Society of Cardiology meeting in Amsterdam in August 2000, some months after the data and safety committee recommended trial cessation due to a strongly favorable outcome in the carvedilol arm. COPERNICUS enrolled patients with class IV heart failure and an ejection fraction (EF) of less than 25% who had symptoms of heart failure (HF) at rest or with minimal exertion despite conventional therapy, including an ACE inhibitor. A total of 2289 patients were randomized to carvedilol or placebo, with initial dosage of 3.125 mg b.i.d. increasing to 25 mg b.i.d. over a 12-week period. Baseline ejection fraction was 20% in both groups; 60% of individuals had been hospitalized for HF within 1 year before enrollment. The primary end point of total mortality was decreased by the beta blocker, 35% risk reduction (P = .001), at the time of premature cessation of the study (patients followed up to 29 months). Secondary end points were also decreased, including total mortality plus all hospitalizations (decreased 24%), CV hospitalization (23%), and HF hospitalization (31%). The secondary end points were the subject of this report by Dr. Milton Packer. In addition to the decrease in HF hospitalizations, length of stay was reduced. Kaplan-Meier curve separation began by 2 months of therapy. There was a lower use of echocardiography and intravenous inotropic therapy in the beta-blocker patients. Side effects were predominately dizziness and bradycardia. The placebo cohort had more HF, atrial fibrillation, angina, and sudden death. There was no increase in worsening HF in the carvedilol patients. Three-quarters of the carvedilol patients were able to tolerate the target dose. A retrospective analysis of the highest risk patients indicated comparable or greater decreases in hazard ratios with carvedilol in the primary end point.
"The Carvedilol Post-Infarct Survival Control and Left Ventricular Dysfunction"
This international study, presented as a late- breaking trial by Dr. Henry Dargie from the University of Glasgow, asked whether routine use of carvedilol in the post-infarction patient would improve survival and need for hospitalizations. This is the first post-myocardial infarction (MI) trial to use a beta blocker in the lytic and direct angioplasty era. Carvedilol or placebo was added to an ACE inhibitor in 1959 patients who had a recent MI and a decreased ejection fraction of less than 40%. Signs and symptoms of heart failure were not mandatory for enrollment. The drug was up-titrated, as in COPERNICUS, and the trial lasted for a total of 1.3 years. The trial stopping point was predetermined by a specific number of events. Patients were randomized an average of 10 days after admission, and after at least 48 hours of ACE inhibitor. The primary end point was all-cause mortality. Secondary end points included mortality and hospitalization for heart failure, MI, and sudden death. There was a substantial reduction in mortality of 23% (15% placebo, 12% carvedilol; P = .03) but no significant reduction in the co-primary end point of all-cause mortality and cardiovascular hospitalization (37%, 35%, respectively). Nonfatal MI was decreased by 41% (P = .02); all-cause mortality plus infarction were reduced by 29%; P = .002. Baseline parameters included a mean ejection fraction of 32% and reperfusion therapy in 45%. A total of 86% of the individuals were on aspirin, and 98% were on an ACE inhibitor. Three-quarters or more of the patients reached the highest dose of carvedilol or placebo; curve separation began at 6 months and continued throughout the study. In conclusion, carvedilol in post MI patients on an ACE inhibitor decreased major coronary events of death and MI, but not hospitalization for congestive heart failure or sudden death.
Comment by Jonathan Abrams, MD
These studies augment the already robust beta blocker-heart failure data base. COPERNICUS confirms that a beta blocker, at least carvedilol, can be given to patients with severe symptomatic heart failure with surprising tolerability. This study extends the use of these drugs from class II-III CHF, as previously supported by MERIT- HF, CIBIS-II, and the multiple carvedilol trials in the literature, to very ill patients. Meta-analyses of all of the published beta blocker studies confirm an adjusted reduction in mortality of approximately 30%; the large majority of patients in these trials were class II-III. These results appear valid for a variety of beta blockers, and in dilated or ischemic cardiomyopathy. It is now accepted that the standard of practice in mild-to-moderate heart failure is to add a beta blocker in addition to ACE inhibition. Beta blockers result in reverse LV remodeling, with improvement in LVEF and reduction of LV dimensions, as well as reduced cardiovascular death and hospitalization for heart failure. CAPRICORN indicates that advanced heart failure, a beta blocker (or at least carvedilol), can be given safely, with a reduction of total mortality and need for hospitalization. One beta blocker trial (BEST) was not positive, and this trial suggested that there may be racial differences in the response to beta blockers. It remains unclear as to whether there really is a "winner" in the choice of beta blockers, as head-to-head comparisons are not yet available. The COMET trial is testing metroprolol vs. carvedilol and is ongoing.
The multicenter in-sync randomized clinical Evaluation (MIRACLE) study examined the functional capacity and quality of life in 266 patients treated with the Medronic In-Sync system. The patients were in stable New York Heart Association (NYHA) class III or IV and had ECG QRS greater than 130 m/sec, ejection fraction less than 35%, and left ventricular diastolic diameter greater than 55 mm. All patients had right and left (coronary sinus) ventricular pacing systems implanted with a 93% success rate, but half were randomly assigned to no pacing for 6 months, at which time synchronized pacing was initiated. The heart failure specialist caring for the patient was blinded to the pacing mode. The 6-month results showed that complications of the pacing system were within the 20% criteria set. The 6-minute walk test and quality of life were significantly greater with pacing (P < .02) despite a large placebo effect. NYHA class increased almost 1 grade and 65% of the paced patients were in class I or II vs. 30% of the nonpaced patients. Treadmill exercise duration increased about 100 seconds in the paced group but remained unchanged in the nonpaced group. Left ventricular end-diastolic dimension decreased about 0.5 cm and ejection fraction increased 0.06 units (P < .001) but were unchanged in the nonpaced. A composite clinical end point improved in 63% of the paced vs. 38% of the nonpaced patients (P < .001). The investigators concluded that in NYHA class III-IV heart failure patients with low ejection fraction and dilated left ventricles, synchronized pacing resulted in improvements in quality of life, exercise capacity, NYHA class, and cardiac structure and function. Also, the In-Sync system was safe and well tolerated.
Comment by Michael H. Crawford, MD
The results of this study are consistent with a French study published in March.1 However, the French study reported on 67 patients with QRS duration greater than 150 m/sec. The present study seems to lower the QRS duration range to 130 m/sec, but it would be interesting to know how many patients benefited with QRS 130 to 150 m/sec. Also, the French groups success rate with implanting the left heart lead was only 88%, lower than the In-Sync study. Thus, despite the technical complexity of biventricular pacing, it appears beneficial in severe heart failure patients with intraventricular conduction delays. However, both studies were short-term (3-6 months), so long-term studies are necessary before jumping on this bandwagon.
1. Cazean S, et al. N Engl J Med. 2001;344:873-880.
Beta-Cath System Trial
Beta-radiation has been shown to be effective for the treatment of in-stent restenosis. This study was designed to evaluate beta-radiation to de novo coronary lesions undergoing primary angioplasty or stenting. A 30 mm Sr90 beta radiation system was used. Between July 1997 and September 1999, 1100 patients undergoing PTCA were enrolled. Patients were divided into optimal and suboptimal results of original angioplasty. Each group was then randomized to Sr90 vs. placebo. The suboptimal group underwent provisional stenting. The optimal group underwent stenting as needed. Primary end points were death, myocardial infarction (MI), and target vessel revascularization. Secondary end points were restenosis, minimal lumen diameter, and late lumen loss. In November 1998, the data safety monitoring board determined that there was an increased rate of late stent thrombosis, and the board recommended 60 days of clopidogrel therapy. This created a third branch of 452 patients on 60 day antiplatelet therapy. All patients had single vessel disease and 2.7-4.0 mm vessels. Patients with vessel diameter 2.6-3.2 mm had 16.1 Gy inflations, and those with vessel diameters of 3.3-4.0 mm had 27.7 Gy.
Angiographic follow-up was obtained in 80% of patients and 90% had clinical follow-up. There was no significant difference for the primary end points. There was a 7% incidence of late thrombosis in the stent cohort vs. less than 1% in the angioplasty groups, all of whom were treated with the standard of 2-4 weeks of clopidogrel. In the cohort treated with 60 days of clopidogrel, the incidence of late stent thrombosis was approximately 1% (equal to placebo). For all patients in the stent cohort, there was a 39% increase in target lesion revascularization (TLR), a 54% increase in target vessel revascularization (TVR), and 60% increase in the primary end points at 8 months follow-up. (P = .001). In the angioplasty group, there was an overall 35% decrease in TLR, 20% in TVR, and 30% decrease in the primary end points in the angioplasty group. The definition of lesion segment vs. analysis segment was presented; the analysis segment is the entire area undergoing radiation with the addition of 5 mm at each end of the lesion segment. Angiographic follow-up in the stent group demonstrated a 36% reduction in restenosis in the lesion segment; however, when the analysis segment was looked at, there was a 21% increase in restenosis. In the angioplasty group, there was 38% reduction in restenosis in the lesion segment (P = .003) and a 14% reduction in the analysis segment (NS). When only a lesion segment was used, there was a reduction in target vessel revascularization failure and the primary end points in the stent group.
Comment by Michael H. Crawford, MD
The overall results in the stent group were disappointing, but the investigators thought that there may be technical reasons for this lack of success. Apparently, the ribbon of radioactive beads is difficult to place exactly where it needs to be—so called geographic miss. Also, if the stent does not fully cover the lesion, radiation may be less effective at preventing restenosis—the so called edge effect. However, there was significant benefit in the angioplasty group, which was surprising. It is difficult to know what to do with the latter findings, since not many interventionalists wish to return to angioplasty only.
The "STENT or SURGERY" Trial (SoS)
This study was designed to compare coronary artery bypass graft (CABG) surgery vs. percutaneous coronary intervention (PCI) with stents in patients with multivessel coronary artery disease (CAD). In 56 centers in Europe and Canada, 988 patients who were candidates for either CABG or PCI by consensus judgment were randomized to either therapy; 488 patients in the PCI arm and 500 patients in CABG arm. In the PCI group, 1 patient died and 7 patients underwent CABG, leaving 480 patients. In the CABG group, 2 patients elected not to undergo treatment, and 11 patients had PCI, leaving 487 patients. Analysis was conducted on an intention-to-treat basis. The follow-up was 1-4 years, with a median of 2 years. There was 100% clinical follow-up at 1 year. The mean age was 61 years old and 24% of patients were hospitalized with acute coronary syndromes. Also, most had multivessel disease. In patients undergoing PCI, 85% had a single-stage procedure. The mean number of vessels was 2.2, and the mean number of lesions was 2.9. Success rate was 94%. Mean number of stents used was 2.5, (range, 0-8). A total of 54% of patients were left with at least 1 stenosis after treatment. In the CABG group, the mean number of grafts was 2.8, 93% of patients had a left internal thoracic artery graft, and 14% of patients had at least 1 vessel with disease after treatment.
All-cause mortality was 4.1% in the PCI group vs. 1.2% in the CABG group, which was statistically significant. Cardiac death was 1.6% in the PCI group vs. 0.6% in the CABG group. There were 8 cancer deaths in the PCI group and 1 cancer death in CABG group resulting in a hazard ratio of 3.5 (P = .007) for all-cause mortality. There was no significant difference in the rate of nonfatal Q-wave MI between groups. There was a 20% revascularization rate in the PCI group vs. 5.8% in CABG group (hazard ratio 3.1; P = .001).
Comment by Michael H. Crawford, MD
Although there was a significant decrease in mortality and revascularization rate in patients undergoing CABG vs. PCI, there were several problems with this study. First, there was the relatively low mortality rate for CABG in this study (1.2%). In addition , the 8 deaths in the PCI arm due to cancer vs. 1 in the CABG arm may have skewed the total mortality results. However, cardiac mortality was still significantly different between groups, but the absolute difference was small (1%). Also, the completeness of revascularization was markedly different (86% with CABG vs 46% with PCI), which may have biased the results toward CABG in this multi-vessel disease patient population. Finally, 36% of the patients had diabetes, which may predict better results with CABG based upon other previous studies. This study, although flawed, was provocative and suggests that CABG may be preferred therapy for many patients.