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Clin. Cardiol. 23, 56–58 (2000)
Presenters: Louis Fiore, M.D., and Michael Ezcekowitz, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta Georgia
Background: This 10-year study, the Veterans Affairs cooperative clinical trial, is one of the largest secondary prevention studies on survival rates following acute myocardial infarction (AMI).
Purpose: The study was designed to detect a 15% reduction in all-cause mortality in AMI survivors randomized to long-term treatment with aspirin and warfarin therapy compared with those treated with aspirin monotherapy.
Study population: Twenty-five percent of the 20,036 patients screened over a five-year period were entered into the study. Mean age was 62 years, and 11% were black. Comorbidities included hypertension, 54%; previous angina, 47%; current smokers, 43%; prior AMI, 35%; diabetes, 27%; prior stroke, 9%; and history of CHF, 8%.
Study design: Patients were recruited within 14 days of AMI and assigned either to aspirin 162 mg daily (n = 2,537) or to aspirin 81 mg daily plus warfarin titrated to achieve an INR of 1.5:2 (n = 2,522). The median follow-up in both arms was 2.7 years with a range of 1–5 years.
Results: No significant difference was found between the two cohorts in the primary endpoint of all-cause mortality. There were 438 deaths (17%) in the aspirin arm and 444 deaths (18%) in the combination therapy arm. The study also found no significant difference in the secondary endpoints of nonfatal MI, nonfatal strokes, and hemorrhagic complications.
Conclusion: There is no survival advantage with the addition of warfarin to aspirin in patients who have survived an AMI. Combination therapy does not reduce the rates of non- fatal MI, nonfatal stroke or vascular mortality.
Presenter: Edward L.C. Pritchett, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: In prior clinical trials, doses of azimilide ranging from 35 to 125 mg were tested for efficacy in treating symptomatic arrhythmia. Researchers found that higher doses were significantly more effective in lengthening arrhythmia-free intervals.
Purpose: This placebo-controlled follow-up study focused on the efficacy of a 125 mg dose of azimilide daily.
Study population: The trial evaluated 462 patients (mean age, 63) with atrial fibrillation, atrial flutter, and paroxsysmal supraventricular tachycardia (PSVT). They were required to be in sinus rhythm at the time the first dose was received.
Study design: Patients were assigned to an arrhythmia stratum--either fibrillation-flutter (n = 402) or PSVT (n = 60)--and then randomized to receive azimilide 125 mg or placebo. The primary outcome variable was the first electrocardiographically documented symptomatic recurrence of atrial fibrillation, atrial flutter, or PSVT.
Results: The 125 mg dose of azimilide did not significantly lengthen the tachycardia-free period as it had in the prior study, in which there was a significant dose-related response to azimilide over the entire dose range from 35 to 125 mg. In the current study, the median time to event--approximately 38 days with azimilide 125 mg compared with 27 days (placebo)--was not significant.
Conclusion: The apparent inconsistent magnitude of the treatment effect of azimilide compared with other studies is unexplained. Whether the results represent a random event, a difference in the study population, or some other technical variation remains unclear. Additional testing of azimilide in patients with supraventricular arrythmias is warranted and currently in progress.
Presenter: Eric J. Eichhorn, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: While previous studies of beta blockade in heart failure have shown a significant mortality benefit, patients included in those studies generally had less advanced disease and were not representative of typical heart failure populations in terms of race and gender.
Purpose: BEST was undertaken to test whether the addition of a beta blocker to standard therapy can reduce the incidence of all-case mortality in patients with New York Heart Association functional classes III and IV congestive heart failure.
Patient population: The global, multicenter study evaluated 2,708 patients 18 years of age or older, 22% female, and 23% black. Ninety-two percent were in class III heart failure, 8% in class IV.
Study design: Patients were randomized to receive bucindilol or placebo. Initial dosing of 3 mg twice a day was titrated over 6–8 weeks as tolerated to a target of 50 mg twice a day for patients <75 kg and to 100 mg twice a day for patients >=75 kg. The primary endpoint was all-cause mortality.
Results: Estimated risk of death was reduced by 10% among patients in the bucindilol group compared with those in the placebo group. The trend, however, was not statistically significant (p = 0.109). Bucindilol significantly reduced cardiovascular death by 12.5%. There were no significant differences for the individual components of pump failure death, sudden death, or death due to MI.
Conclusions: In classes III and IV heart failure, bucindilol does not provide a benefit in all-cause mortality. Blacks and class IV patients have no benefit from this therapy. Nonblack patients with less advanced heart failure have an apparent mortality benefit. In light of this and previous trials, treatment with beta blockade at earlier stages of disease is warranted.
Presenter: Gregg W. Stone, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: A major limitation of angioplasty is restenosis, which occurs in up to 50% of patients. While stent implantation reduces restenosis significantly, an unanticipated event in the earlier Primary Angioplasty in Myocardial Infarction (PAMI)-STENT trial was thrombus extrusion through the stent struts, which led to a reduction in TIMI-III flow and a trend toward increased early mortality.
Purpose: This global, multicenter trial was designed to test whether the outcomes of primary percutaneous transluminal coronary angioplasty (PTCA) or primary stenting could be improved by glycoprotein IIb/IIIa blockers.
Study population: A total 2,081 patients met the study's clinical criteria, including no prior stenting of the infarct vessel, vessels amenable to successful stent delivery, and infarct size coverable by 1–2 stents.
Study design: Patients were randomized to one of four intervention strategies: (1) primary PTCA, (2) PCTA + abciximab, (3) primary stenting, (4) primary stenting + abciximab. The interim analysis was based on preliminary data from 1,961 patients.
Results: The study found no significant difference in early mortality among the four arms (range: 1–1.6%). Disabling strokes were rare, and their occurrence was not affected by the strategies used. Reinfarction was also infrequent, but tended to be higher in the two arms that did not receive abciximab (PTCA, 0.6% vs. PTCA with abciximab, 0%; stent, 0.8% vs. stent with abciximab, 0.2%). Target vessel revascularization (TVR) was required in 2.3% of patients receiving PTCA alone vs. 0.2% of patients in the PTCA + abciximab arm. There was also less TVR in the stent + abciximab arm vs. stent alone. A significant reduction in recurrent ischemia was noted in the two abciximab arms: 4.5 versus 1.4% in the PTCA groups; 3.9 versus 1.2% in the stent groups.
Conclusion: Results achieved with adjunctive abciximab use in this trial were promising, but definitive recommendations on optimal reperfusion strategy in acute myocardial infarction await final analysis of safety and efficacy data at the six-month primary endpoint and one-year follow-up.
Presenters: Betram Pitt, M.D., and Philip A. Poole-Wilson, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: ELITE-I had suggested a mortality benefit for the angiotensin II blocker losartan in heart failure compared with the angiotensin-converting enzyme (ACE)-inhibitor captopril. But with a patient populaton of only approximately 1,000, the trial was underpowered to show statistical significance for the benefit.
Purpose: ELITE-II was powered to test whether losartan could significantly lower mortality in patients with heart failure compared with captopril .
Study population: The global, multicenter study evaluated 3,150 patients, 30% female, whose mean age was 71.4. Forty-nine percent were in New York Heart Association functional class II and the remainder were in classes III and IV.
Study design: Patients were randomized to receive losartan 50 mg once daily or captopril 50 mg three times a day. The primary endpoint was all-cause mortality, with secondary endpoints of sudden death/rescuscitated cardiac arrest, hospitalization, and tolerability for the two treatments.
Results: There was no significant difference in mortality between the two groups. The primary endpoint of all-cause mortality occurred in 15.9% of patients (n = 250) in the captopril group vs. 17.7% (n = 280) in the losartan arm (p = 0.16). No significant differences were found in sudden death/rescuscitated cardiac arrest, or hospitalization. Losartan was significantly better tolerated than captopril, with fewer discontinuations due to adverse events.
Conclusions: ELITE II results do not confirm the mortality benefit seen with losartan in the earlier study. In patients with heart failure, ACE inhibitors remain the therapy of choice. When ACE inhibitors are contraindicated, an angiotensin II blocker can be considered as an alternative. Caution should be taken in looking at data from small trials over short periods of observation in a complex illness such as congestive heart failure.
Comment: (Professor Jay Cohn, M.D., University of Minnesota, Minneapolis): "The ELITE II results were not surprising because the very low dose of losartan used does not supply persistent blockade of the AT1 receptor. In Val-HeFT [Valsartan-Heart Failure Trial] we are using an angiotensin II blocker [valsartan] at a much higher daily dose of 320 mg on top of an ACE inhibitor. When results come in mid 2000 I think we will be able to answer the question as to whether angiotensin receptor blockers have a place in heart failure therapy."
Presenter: James Udelson, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: Of the approximately 7 million people who visit emergency rooms each year for chest pain or other symptoms suggestive of acute cardiac ischemia (ACI), 70% are ultimately found not to have ACI. The result is 3 million unnecessary hospitalizations per year.
Conversely, 2 to 3% of patients who are sent home from the emergency department (ED) after initial evaluation are found on follow-up to have acute myocardial infarction (AMI). A total of 10,000 to 20,000 patients with AMI are mistakenly discharged from EDs every year.
Purpose: The multicenter ERASE trial sought to determine whether incorporating perfusion imaging into the ED evaluation process could improve diagnoses in patients presenting with chest pain and reduce unnecessary hospitalizations.
Study population: Eligible patients were those presenting to the ED with symptoms of ACI and normal or nondiagnostic electrocardiogram (ECG).
Study design: Over 20 months, patients with possible ACI were randomized either to the usual care strategy (n = 1,246) or to one incorporating sestamibi perfusion scanning (n = 1,210).
Results: Final diagnoses confirmed by ECG, enzyme analysis, and stress testing with imaging showed that 13 to 14% of patients in each study arm had ACI (2% AMI and 11 to 12% unstable angina). Of the patients without ACI, 52% in the usual care group were hospitalized, compared with 42% in the group whose usual treatment was augmented by a sestamibi scan. There was a 14% reduction in total hospitalization at an estimated cost savings of $60 to $72 per patient with sestimibi perfusion scanning.
Conclusion: The use of imaging significantly and safely reduced unnecessary admissions among patients with ACI. The use of imaging was associated with improved overall emergency triaging effectiveness at lower cost. Projected nationally, the study data suggest the possibility of safely avoiding at least 240,000 unnecessary hospital admissions per year.
Presenter: Salim Yusuf, M.D., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: HOPE assessed whether patients at high risk for cardiovascular events, but who did not have left ventricular dysfunction or heart failure, would have improved outcomes with either the angiotensin-converting enzyme (ACE) inhibitor ramipril or vitamin E supplementation. Positive overall results for ramipril only were reported in a previous issue of Clinical Cardiology (Clin Cardiol 1999;23:755).
Purpose: This clinical report focuses on the large subgroup of patients with diabetes, a primary risk factor for cardiovascular disease. It examines diabetes complications and prevention of new diabetes.
Study population: Of the 9,541 patients who were evaluated in this trial, 3,578 had diabetes, making HOPE one of the largest trials of vascular disease prevention in patients with diabetes. Among included diabetic patients, 1,321 were female, the mean age was 65.4, and mean duration of disease was 11.4 years.
Study design: Patients in 267 hospitals and 19 countries were randomized in a double-blind, two-by-two factorial design, to ramipril 10 mg daily orally or placebo for a mean of 5 years. Patients were separately randomized to receive either vitamin E (400 intramuscularly) or placebo.
Results: Overall, ramipril significantly reduced the rate at which patients reached the primary endpoint of a combination of myocardial infarction (MI), stroke, or death from cardiovascular causes (653, or 14.1%, in the ramipril group vs. 824, or 17.7%, in the placebo group). In addition, in the overall population, fewer had a new diagnosis of diabetes (289 vs. 344; relative risk, 0.84; p = 0.03), and fewer in the ramipril group had diabetic complications (289 vs. 344; relative risk, 0.84; p = 0.03). In the subgroup of patients with diabetes, the analysis revealed a significant 24% reduction in the primary endpoint for treatment with ramipril versus placebo.
Conclusion: The use of ramipril significantly lowers the rates of death, MI, stroke, revascularization, cardiac arrest, and heart failure. It also reduces complications related to diabetes, and reduces new cases of diabetes in patients at high risk for cardiovascular events.
Presenter: Martha N. Hill, Ph.D., R.N., at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Georgia
Background: Social, psychological, behavioral, and genetic factors are all associated with uncontrolled high blood pressure. Young black men have the lowest rates of hypertension care and control. As a result, they suffer earliest from the severe cardiovascular complications associated with untreated high blood pressure.
Purpose: This study sought to enroll at least 300 inner-city hypertensive black men with and without controlled blood pressures and follow them for 24 months to determine the effect of both intensive and less intensive interventions on blood pressure and other cardiovascular health outcomes.
Study population: The 309 subjects recruited in Baltimore inner-city areas were black men ages 18 to 54 who had been diagnosed with hypertension (systolic >=140, diastolic >=90) on at least two occasions.
Study design: Patients were randomized to less intensive (n = 152) or more intensive (n = 157) intervention stategies. Both groups received educational information about the importance of hypertension control. Patients in the less-intensive cohort were referred to sources of care in the community. Those in the more-intensive group were referred to a multidisciplinary team (physician, nurse practitioner, and community health worker) for individualized care. Antihypertensive medications provided free during the trial were losartan, losartan plus hydrochlorothiazide, or other blood pressure medications if those were not tolerated.
Results: At 24 months, 84% of the men originally randomized were evaluated. Thirty-nine percent had controlled blood pressure, compared with the baseline of 19%, a significant 105% improvement. The improvement in blood pressure control was significant in both groups at both 12 months and 24 months. Mean systolic and diastolic blood pressures for the more intensively treated group were 149.5/101.1 at baseline, 138.3/90.8 at 12 months, and 142.3/86.8 at 24 months. For the less intensively treated group, these values were 151.2/103.4, 141.9/94.9, and 143.2/90.0.
Conclusion: A multidisciplinary program that includes community members and staff can build rapport, maintain follow-up at regular intervals, and facilitate blood pressure lowering in a very high-risk group. Further lowering of blood pressure to new national guideline standards will require stronger life-style and pharmacologic intervention.