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(Circulation. 1996;93:843-846.)
© 1996 American Heart Association, Inc.
Articles |
Meeting Highlights
American Heart Association 68th Scientific Sessions, Anaheim, California, November 13 to 15, 1995
From St Luke's Episcopal Hospital, Texas Heart Institute, Baylor College of Medicine, University of Texas Health Science Center at Houston.
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TIMI 9B: Heparin Versus Hirudin as Adjunctive Therapy for Thrombolysis in Acute Myocardial Infarction |
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TIMI 9B: Heparin Versus...
TIMI 10A: TNK for...Dr Elliott Antman, of Harvard Medical School and Brigham and Women's Hospital in Boston, Massachusetts, presented the results of the Thrombolysis in Myocardial Infarction (TIMI) 9B study at a Satellite Symposium sponsored by George Washington University immediately prior to the American Heart Association Meetings in Anaheim, California, in November 1995. The TIMI 9 trial was a randomized, double-blind study conducted in 150 clinical centers that was designed to compare the efficacy and safety of intravenous heparin versus the direct-acting thrombin inhibitor hirudin in patients with acute myocardial infarction (<12 hours from onset) treated with a thrombolytic agent (streptokinase or tissue-type plasminogen activator [TPA], at the discretion of the treating physician). The TIMI 9A study (n=757) was suspended in April 1994 because of excessive bleeding in both the heparin and hirudin groups. The TIMI 9B trial was restarted in May 1994 with lower doses of both heparin and hirudin; enrollment (n=3002) continued through August 1995. The primary end point of the study was the 30-day incidence of death, myocardial infarction, congestive heart failure, and shock. At 30 days, there was no significant difference in the primary end point between heparin (11.8%) and hirudin (12.8%) and no difference in the incidence of death and myocardial infarction (9.3% in the heparin group, 9.6% in the hirudin group). Similarly, there was no significant difference in major bleeding events (including intracranial hemorrhage) between treatment groups.
The TIMI 9 Investigators concluded that hirudin was equally effective as but not superior to heparin with respect to either clinical outcome or bleeding risk in patients with acute myocardial infarction receiving thrombolytic therapy.
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TIMI 10A: TNK for Acute Myocardial Infarction |
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Also at the George Washington University Satellite Symposium, Dr Eugene Braunwald, of Harvard Medical School and Brigham and Women's Hospital in Boston, presented the results of the TIMI 10A phase I trial. TIMI 10A is an open-label, dose-ranging study of TNK, a modified form of TPA that has been structurally altered to (1) reduce hepatic clearance (making it suitable for bolus administration), (2) increase fibrin specificity, and (3) increase resistance to inactivation by plasminogen activator inhibitor. There were eight ascending doses from 5 to 50 mg that were studied in 113 patients with acute myocardial infarction; angiographic TIMI flow grades and frame counts were measured at 90 minutes. The measured clearance of TNK was approximately one third that of wild-type TPA. Patients receiving doses of 30 mg achieved TIMI grade 2 or 3 flow patency in 80%, with 73% achieving TIMI grade 3 flow. No reduction in fibrinogen or plasminogen consumption was observed. The overall incidence of bleeding was 6.2%, and no instances of intracerebral bleeding were noted.
Dr Braunwald concluded that TNK is a promising agent that is more fibrin-specific than wild-type TPA, and it can be given as a bolus. It has a promising patency profile and an acceptable safety profile, and further clinical trials with this new agent are currently in the planning stage.
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Bypass Angioplasty Revascularization Investigation |
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Dr Robert Frye, of the Mayo Clinic in Rochester, Minnesota, who served as the Bypass Angioplasty Revascularization Investigation (BARI) study chairman, presented the primary findings of this large-scale, multicenter study, comparing the long-term safety and efficacy of bypass surgery versus angioplasty in 1829 patients with multivessel coronary artery disease undergoing a first revascularization procedure. The study was initiated in August 1988 and concluded in September 1995. The primary end point of the study was 5-year mortality. At baseline, approximately 25% of the patients had diabetes; 63% presented with unstable angina. At 5 years, there were no significant differences in survival for percutaneous transluminal coronary angioplasty (PTCA) (86.3%) versus bypass surgery (89.3%) or myocardial infarction–free survival (78.9% versus 80.4%, respectively). There was significant survival benefit associated with bypass surgery in diabetic patients on medication (80.6% versus 65.5% with PTCA) as noted in the September 21, 1995, Clinical Alert from NHLBI.
Dr Robert Jones, of Duke University in Durham, North Carolina, reported clinical outcome end points of recurrent angina/ischemia, medication usage, hospitalization requirements, left ventricular function, and quality of life. At 1 year, patients randomized to bypass surgery required significantly fewer medications, underwent fewer repeat procedures, had fewer repeat hospitalizations for angina, and had less ischemia on exercise testing. By 5 years, these differences diminished, but a significant benefit in favor of surgery remained for angina status and medication usage. By 5 years, 85% of the patients in the bypass surgery group were free of angina compared with 79% of the patients in the PTCA group. At the 5-year time point, 54% of the PTCA patients required an additional revascularization procedure (compared with 7% of the bypass surgery patients). Thirty-one percent of the PTCA patients required bypass surgery over the next 5 years. Subjective and objective measures of quality of life were similar between groups.
Dr Mark Hlatky, of Stanford University in Palo Alto, California, presented the results of SEQOL (Study of Economics and Quality of Life), a substudy of BARI focusing on cost-effectiveness outcome data in 934 patients. Among SEQOL patients, the average total medical costs over 5 years were $57 073 for bypass surgery and $54 898 for angioplasty. In SEQOL, at 3 years, physical function and angina were better with bypass surgery; by 5 years the outcome benefits of surgery were not significantly different from angioplasty. Angioplasty patients went back to work sooner than bypass surgery patients (6 versus 11 weeks after randomization), but long-term employment patterns were not significantly different.
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Carvedilol Reduces Mortality in Patients With Congestive Heart Failure |
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On behalf of the US Carvedilol Multicenter Congestive Heart Failure Trial Program, Dr Milton Packer, of Columbia-Presbyterian Medical Center in New York City, presented the combined results of four clinical protocols using carvedilol (a third-generation ß-blocker/vasodilator with
1-adrenergic
antagonist and antioxidant properties) in patients with
congestive heart failure. The large-scale clinical testing program
was conducted in 65 US medical centers and included 1094 patients who
were randomized to either placebo or carvedilol. All four protocols
used a 6-minute walk test to assess symptomatic outcome and
had all-cause mortality as an end point. Patients were followed for
an average of 6.5 months after randomization. The investigative program
was terminated prematurely in February 1995 when the Data Safety
Monitoring Board informed the sponsor—SmithKline Beecham—of a
marked reduction in mortality in patients treated with carvedilol
(3.0% versus 7.8% with placebo; P<.0001; odds ratio,
0.33; 95% confidence interval, 0.19 to 0.59). There was significant
improvement in both pump failure–associated mortality and sudden
death. Dr Packer noted that the improvement in mortality was
present in patients with both ischemic heart disease (3.6%
versus 9.0%; odds ratio, 0.32) and dilated
cardiomyopathy (2.5% versus 6.7%; odds ratio,
0.35). There was also lower mortality with carvedilol across the
spectrum of disease severity both in patients with NYHA class II
symptoms (2.4% versus 5.8%; odds ratio, 0.35) and class III-IV
symptoms (3.7% versus 10.0%; odds ratio, 0.31). Similar findings were
noted when patients were stratified by an initial 6-minute walk test
performance. Dr Packer concluded that in patients with
congestive heart failure of both ischemic and
nonischemic origin, carvedilol treatment is associated with
a 67% reduction in all-cause mortality, including improvement in
both pump failure mortality and sudden death. Dr Packer also presented the results of PRECISE (Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise Tolerance in Congestive Heart Failure), one of the studies that made up the overall program. PRECISE involved 278 patients with moderate-to-severe congestive heart failure. Carvedilol therapy was associated with decreased mortality, an improvement in ejection fraction and NYHA class, and a 46% decrease in need for hospitalization for cardiovascular disease. There was no significant effect of carvedilol on exercise test results, but there was an improvement in the assessment of symptoms by both the patients and their physicians.
Dr Michael Bristow, of the University of Colorado Health Science Center in Denver, presented the results of MOCHA (Multicenter Oral Carvedilol Heart Failure Assessment), a second study in the program. MOCHA was a placebo-controlled, dose-response evaluation of three different doses of carvedilol in 345 patients with NYHA class II-IV heart failure. The study found no significant difference in 6-minute walk test distance but did find a dose-related decrease in the need for hospitalization and an increase in the left ventricular ejection fraction, along with a dramatic dose-related decrease in mortality (15.5% with placebo, 6% with carvedilol 6.25 mg BID, 5.5% with carvedilol 12.5 mg, and 1.1% with carvedilol 25 mg BID).
A third trial in the program was presented by Dr Wilson
Colucci, of Boston University School of Medicine and Boston University
Medical Center. This study examined the progression of congestive heart
failure in 284 patients with mild disease (able to walk 
450 m in 6
minutes). Carvedilol treatment significantly reduced the number of
patients whose heart failure progressed (as determined by a composite
end point of hospitalization, mortality, or an increase in congestive
heart failure medication) over 6 months (13% versus 26% with placebo;
P=.003).
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V-HeFT III: Felodipine in Heart Failure |
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Dr Jay N. Cohn, of the University of Minnesota in Minneapolis, presented the results of the Third Vasodilator Heart Failure Trial (V-HeFT III). V-HeFT III was a placebo-controlled study of the safety and efficacy of felodipine (a vascular-selective calcium antagonist) when added to the standard regimen of care (angiotensin-converting enzyme inhibitors and diuretic) in 450 patients with NYHA class II-III heart failure. In a separate substudy, digitalis was administered to subgroups of felodipine and placebo patients. The mean period of follow-up for study patients was 18 months. Approximately half of the patients were classified as having significant coronary artery disease. The average pretreatment left ventricular ejection fraction was approximately 30%.
The addition of felodipine to angiotensin-converting enzyme inhibition and diuretics was associated with improvement in ejection fraction, although there was no significant improvement in exercise time or in mortality: the study was not powered to detect a difference in mortality. In the first 3 months, felodipine appeared to be associated with a trend toward more hospitalizations and worsening heart failure. This trend was not sustained over time, and long-term morbidity was not affected. An initial fall in atrial natriuretic peptide levels was noted with felodipine; this effect was not sustained beyond 3 months. There were no significant differences in outcome or treatment effect when patients were stratified as dilated cardiomyopathy versus coronary artery disease. In the digitalis substudy, a large number of patients (124 of 144) who entered the trial already on digoxin had their digoxin withdrawn. They subsequently received either placebo or digoxin. After 1 to 2 months, placebo-treated patients were noted to have lower ejection fractions and higher atrial natriuretic peptide levels but no significant difference in long-term survival.
Dr Cohn concluded that a long-acting selective calcium antagonist was well tolerated in this heart failure population and did not appear to further impair cardiac function. He emphasized the importance of looking at long-term outcome (ie, longer than 90 days) in assessing agents to be used in the long-term management of heart failure patients.
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Balloon Angioplasty Versus Optimal Atherectomy |
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Dr Donald Baim, of Harvard Medical School and Beth Israel Hospital in Boston, presented the acute results of the randomized phase of the Balloon versus Optimal Atherectomy Trial (BOAT). In this trial, begun in June 1994, patients with de novo lesions in native coronary arteries were randomized to undergo either balloon angioplasty or "optimal" atherectomy (atherectomy plus adjunctive balloon angioplasty, if necessary, to achieve a final angiographic diameter stenosis of <20% by quantitative coronary angiography). By the end of November 1995, all 1000 patients had been enrolled at 39 clinical centers (36 in the United States, 1 in Canada, 2 in Europe). Of patients randomized to directional atherectomy, 95% were treated with a 7F device; about three fourths of the direct coronary atherectomy (DCA)-treated patients received adjunctive balloon postdilation. The postprocedural minimal lumen diameter was significantly greater in the DCA group (a mean of 2.82 mm versus 2.33 mm in the PTCA group), and the percent diameter stenosis was significantly lower (a mean of 15% versus 28% in the PTCA group). A total of 68% of patients in the DCA group met the goal of <20% residual diameter stenosis compared with 25% of patients in the PTCA group. The lesion success rate was significantly higher at 99% in the DCA group versus 95.7% in the PTCA group. The DCA group tended to have more Q-wave myocardial infarctions (2.2% versus 1.3%) and more large (CK>8xnormal) non–Q-wave myocardial infarctions (3.1% versus 1.1%). They also had significantly more small (CK>3xnormal) non–Q-wave myocardial infarctions (15% versus 5%). Dr Baim concluded that "optimal" directional atherectomy results in higher procedural success and lower residual stenosis, with no significant increase in major complications. The expected increase in non–Q-wave myocardial infarctions (mostly low-order elevations) was observed. Long-term outcome data regarding restenosis and late clinical outcome will be available in the near future.
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Prognostic Value of Troponin T and Troponin I |
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Three studies on the prognostic value of the cardiac contractile proteins troponin T and troponin I in patients with acute coronary syndromes were presented. The overall troponin complex, which regulates the calcium-mediated interaction of actin and myosin, comprises three regulatory proteins: troponin I, troponin C, and troponin T. The cardiac form of troponin C also appears in skeletal muscle, whereas cardiac troponin I and cardiac troponin T are the product of unique genes distinct from their skeletal muscle counterparts.
Dr Berdil Lindahl, of University Hospital in Uppsala, Sweden, presented data from 976 patients in the FRISC study, a placebo-controlled trial of low-molecular-weight heparin in coronary artery disease. All of their study patients had chest pain with ECG changes within 72 hours of enrollment. Troponin T levels were measured at enrollment and after 12 and 24 hours of therapy; subsequent 6-month clinical follow-up was obtained. There was a strong association (P<.001) between troponin T levels and the 6-month incidence of both cardiac death and the combined incidence of cardiac death and myocardial infarction. Troponin T levels also were identified as an independent prognostic factor for outcome in a stepwise logistic multivariate analysis. Dr Lindahl concluded that troponin T is an inexpensive, readily and rapidly available indicator that provides independent prognostic information in patients with unstable coronary syndromes.
Dr Robert Christenson, of Duke University in Durham, North Carolina, reported on a subset of 734 patients enrolled in the GUSTO IIa study of patients with acute coronary syndromes. Troponin T samples were collected at baseline and at 8 and 16 hours following admission; all samples were analyzed at a core laboratory. Admission troponin T levels were positive (>0.1 ng/mL) in 260 patients; this was associated with a significantly higher incidence of subsequent death (9% versus 3%; P=.001). Of the remaining 474 patients, 323 (68%) developed positive troponin T levels 8 to 16 hours later; they also had a significantly higher incidence of subsequent death than patients in whom troponin T levels remained negative (4% versus 0%; P=.012). Dr Christenson concluded that an initial troponin T sample provides important risk stratification information; later samples are useful for evaluating the risk of subsequent mortality. Patients with negative troponin T levels are at low risk for subsequent events.
Dr Elliott Antman, of Harvard Medical School and Brigham and Women's
Hospital in Boston, presented a substudy of patients in TIMI
IIIB, a factorial study of TPA versus placebo and early invasive versus
conservative strategy in patients with unstable angina/non–Q-wave
myocardial infarction. Blood specimens for troponin I were obtained at
enrollment (within 24 hours of most recent angina); normal versus
abnormal (0.4 ng/mL) levels were correlated with outcome (mortality
at 42 days) in all patients and the subset of patients presenting
>6 hours out from their angina. For all patients (n=1402), the
incidence of death was 1% in patients with normal troponin I levels
(n=831) and 3.7% in patients with levels 0.4 ng/mL
(P<.001). For patients presenting >6 hours out from
their angina (n=845), the incidence of death was 0.4% in patients with
normal troponin I levels (n=473) and 4% in patients with levels 0.4
ng/mL (P<.004). After adjusting for other factors
influencing mortality, the relative risk of death at 42 days increased
by 10% for every ng/mL elevation of troponin I. There was a
significant improvement in survival in patients with elevated troponin
I levels who were treated with an early invasive strategy. Dr Antman
concluded that admission troponin I levels are useful for the early
triage and management of patients with unstable angina/non–Q-wave
myocardial infarction.
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Invasive Versus Medical Treatment of Postinfarction Ischemia |
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Dr Peer Grande, of Copenhagen, Denmark, presented the results of the DANAMI study, a multicenter randomized trial of invasive versus conservative treatment of patients with inducible post–myocardial infarction ischemia. Between September 1990 and March 1994, 1008 patients with confirmed myocardial infarction treated with thrombolytic therapy and free of unstable postinfarction angina with angina and/or ECG changes during exercise test were randomized to either an invasive strategy (revascularization of treatable vessels with >50% diameter stenosis performed in 85% of patients randomized to this arm) or a conservative strategy (angioplasty only for recurrent symptoms, performed in 3% of patients randomized to this arm). The mean time to revascularization was 18 days in patients treated with PTCA and 38 days for patients treated with bypass surgery. Follow-up visits took place at 3 and 6 months, with 6-month visits thereafter for up to 5 years. The mean follow-up on all patients is 2.4 years. Patients were stratified by age, sex, and type of ischemia (angina alone, ST-segment changes alone, or both). During follow-up, patients treated with an invasive strategy required fewer antianginal medications and had less angina, fewer admissions with unstable angina (18% versus 30%), and fewer intervening myocardial infarctions (5.6% versus 10.5%). There was no significant difference in mortality (3.6% with invasive, 4.6% with conservative). Dr Grande concluded that in patients with inducible ischemia, revascularization therapy appears superior to conservative management.
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Footnotes |
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Reprint requests to James J. Ferguson, MD, Cardiology Research, MC 1-191, Texas Heart Institute, PO Box 20345, Houston, TX 77225.
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