Late Breaking Trials From the AHA Meeting
January 1, 2001 10 minutes read
Late Breaking Trials From the AHA Meeting
Conference Coverage
Editor’s Note: The following reports from the annual scientific session of the American Heart Association held Nov. 12-15, 2000, in New Orleans, La., were obtained by handwritten notes, discussions with investigators, and news reports. No peer reviewed publications of these trials are available.
VAL-HEFT Trial
Angiotensin receptor blockers (arb) have been available for a number of years, but their efficacy, with respect to angiotensin converting enzyme inhibitors (ACEI), remains unclear. ARBs are indicated for ACEI intolerant individuals, but direct comparisons have been few and inconclusive. VAL-HEFT, a long- awaited congestive heart failure (CHF) randomized trial was carried out in 5010 patients with class II-III CHF; 45% had coronary artery disease and 60% were NYHA class II, 55% were class III. Subjects all had increased LV dimensions; mean ejection fraction was 27%. Medications: 92% were on an ACEI, 85% diuretic, and 60% were on digoxin at baseline; 34% were on a beta-blocker. This was an international trial conducted in 300 centers in 16 countries. Patients were randomized to the ARB valsartan (VAL) or placebo (PLAC). Mean follow-up was 27 months. The primary end point was all- cause mortality and time to death, as well as a combined end point of all-cause mortality and major morbidity. The average dose of baseline ACEI was 18 mg/d for enalapril or its equivalent. The average dose of valsartan was 254 mg/d. Blood pressure decreased by 5-6 mm Hg in the VAL cohort over 30 months and by 2-3 mm Hg in the placebo (PLAC) group. The results were negative for the first end point of all-cause mortality (19.7% VAL vs 19.4% PLAC), but were positive for the combined end point of mortality and morbidity, 28.8% VAL vs. 32.1% PLAC, resulting in a relative risk reduction of 0.87 (P = 0.009). The major component of the composite end point was reduced hospitalization for CHF with VAL, which occurred in 9% of the VAL cohort patients vs. 18.5% of PLAC, a risk reduction of 37% (P = 0.00001). There was early curve separation for both end points. Mortality rate in this cohort of class II-III patients was approximately 10% per year. There were no differences in outcomes related to age, sex, ejection fractions below or above 27%, or etiology of heart failure. In patients who were on ACEI at baseline, the primary end point reduction was 12-13%, whereas there was a 45% reduction with VAL in the 7% of individuals who were not on an ACE inhibitor. All patients were stratified for beta-blocker use; at the time of randomization, 35% of patients were on a beta-blocker. In those individuals who were on beta-blockers at entry, there was no reduction in either primary end point. However, for the 65% of individuals not taking a beta-blocker, there was a 22% reduction in the composite end point, which was statistically significant. A variety of secondary end points, including NYHA class, dyspnea and fatigue, and edema, all tended to be more favorable on VAL. Major adverse events were comparable—approximately 10% in each cohort. In conclusion, combination therapy with an ACE inhibitor and VAL resulted in a decrease in mortality and morbidity by 13%; a decrease in repeat hospitalization for congestive heart failure of 27%; and a decrease in NYHA class and an increase in quality of life. Benefits of valsartan were seen across all degrees of heart failure.
Comment by Jonathan Abrams, MD
VAL-HEFT appears to answer at least one issue related to ACEI and ARB therapy: Greater angiotensin II blockade does not appear to affect survival more than therapy with ACEI alone. Hypotheses regarding breakthrough of angiotensin II and aldosterone in patients on ACEI, as well as more potent interference with the angiotensin II receptor, did not appear to make a major difference in this large, well conducted trial. Furthermore, of great interest is the observation that an ACEI and a beta-blocker eliminated the benefit of VAL on the combined end point, also suggesting that there may be a limit to the degree of neurohormonal blockade that can be beneficial. The maximum benefits seen in this trial were in patients on an ACEI and a beta-blocker or an ACEI and an ARB. Data are not available to determine which combination was more beneficial. Given that recurrent hospitalization for heart failure and need for inotrophic support represents a large economic burden in patients with chronic CHF, it is worth emphasizing that the combination of an ACE inhibitor and an ARB could be cost effective in such individuals; there was an absolute 4.6% difference in first hospitalization after randomization between the combination therapy and placebo cohort, which reflected a 37% reduction and is highly statistically significant. Such an approach needs to be balanced against the adverse responses with ACEI/ARB therapy, which appear to be equal. It is also clear that for those individuals who cannot tolerate an ACEI for any reason, an ARB provides substantial benefit, achieving 45% reduction in morbidity and mortality in the small cohort (366 patients) who were not on ACEI. Conclusion: VAL-HEFT does not provide an absolute mandate for combination ACEI and ARB therapy, but in appropriately selected patients, particularly those not taking a beta- blocker who have the characteristics of being "frequent flyers" with respect to recurrent hospitalizations, should strongly be considered for both ACE inhibition and angiotensin II receptor blockade.
TACTICS (TIMI 18) and TARGET Trials
The results of TACTICS (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy, or TIMI 18) and TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Outcomes Trial), two major clinical trials evaluating the use of glycoprotein (GP) IIb/IIIa receptor antagonists, add to a rapidly accumulating body of information outlining the use of these agents in the management of patients undergoing percutaneous coronary intervention (PCI), and patients with acute coronary syndromes (ACS). It had become quite clear that the GP IIb/IIIa antagonists, abciximab (ReoPro®, Centocor/Lilly), tirofiban (Aggrastat®, Merck), and eptifibatide (Integrilin®, Cor/Key) are effective in preventing ischemic complications in both of these clinical scenarios, particularly in the highest risk subgroups of patients. However, much remains to be learned about the use of these drugs, including optimal patient selection, choice of specific agent, dose, duration and timing of treatment, and, importantly, how these agents fit into a contemporary, cost-effective, and rapidly evolving overall strategy of management of patients with coronary artery disease. In the context of previously published literature, the results from TACTICS and TARGET help to clarify some of these issues while further confounding others.
TACTICS was designed to evaluate the efficacy of an early invasive strategy (routine catheterization and revascularization) vs. an early conservative strategy (catheterization only for spontaneous or provokable ischemia) in the management of patients with ACS treated with the short-acting GP IIb/IIIa antagonist tirofiban (Aggrastat, Merck). While this question had previously been addressed in TIMI 3B, which showed no benefit for an early invasive approach, the present study sought to revisit the question in the context of contemporary medical and revascularization therapy, namely GP IIb/IIIa inhibition and coronary stenting. The investigators hypothesized that the early invasive approach would lead to superior outcomes and chose the composite of death, myocardial infarction (MI), and need to repeat hospitalization for ACS at six months as their primary end point. They further hypothesized that the higher risk patients with elevated serum troponin T (TnT) would derive additional benefit from an early invasive approach.
A total of 2220 patients were randomized and no significant differences in baseline characteristics between the groups were noted. The patients in this study represent a reasonably high-risk ACS population: 54% demonstrated elevated TnT, 48% had ischemic ECG changes, and 66% were prior aspirin users. All patients received aspirin and unfractionated heparin. All patients received tirofiban (0.4 mcg/kg/min for 20 minutes, followed by 0.1 mcg/kg/min); the invasive group for 4-48 hours before catheterization and for 12 hours after intervention, and the conservative group for 48 hours before noninvasive testing. Of the invasively randomized patients, 97% underwent catheterization and 60% were revascularized, and of the conservative group, 51% crossed over to receive catheterization, while 36% were revascularized during the index hospitalization.
At six months, the composite primary end point had occurred in 15.9% of invasively managed patients vs. 19.4% of conservatively managed patients (OR = 0.78; P = 0.05). This was due largely to the reduction of MI in invasively treated patients (4.8% vs 6.9%; P = 0.029), with a marginally significant reduction in the composite of death and MI (7.3% vs 9.5%; P < 0.05) and a trend toward reduction in rehospitalization (11.0% vs 13.7%; P = 0.054) for invasively treated patients. This difference was established within the first 30 days of the follow-up period. As expected, patients with elevated TnT demonstrated a more marked reduction in the primary end point when treated using an early invasive strategy (14.3% vs 24.2%, OR=0.52; P < 0.001). In addition, subgroup analysis revealed that patients with ST segment depression on ECG and those with higher TIMI Risk scores also derived more benefit when treated with an early invasive approach. There was a higher incidence of major bleeding (related to vascular access sites), and a shorter initial length-of- stay in the invasively treated patients. Economic and quality-of-life analyses were not presented at this meeting but are planned for the future. Thus, TACTICS concludes that in ACS patients treated with tirofiban in addition to standard medical therapy, an early invasive strategy of catheterization and revascularization results in a significant reduction in major adverse cardiac events (largely MI) at six months of follow-up.
Comment by Sarah M. Vernon, MD
While TACTICS was not designed to test the efficacy of tirofiban for the medical therapy of ACS, the previously published clinical trials PRISM and PRISM-PLUS have shown that tirofiban is beneficial when compared with placebo. The results are somewhat difficult to reconcile with those of GUSTO IV ACS, which was recently presented at the 2000 European Society of Cardiology Meeting. This study was also designed to test the role of GP IIb/IIIa inhibition in acute coronary syndromes, but differed from TACTICS somewhat in that PCI was discouraged by design, with only 5% of patients undergoing revascularization during the treatment period. In GUSTO IV, 7800 patients believed to have unstable angina and receiving conventional therapy were randomized to receive placebo, or abciximab bolus followed by a either a 24-hour or 48-hour abciximab infusion. GUSTO IV showed no reduction in the primary composite of death and MI at 30 days in either abciximab treated group (8.0% vs 8.2% vs 9.1%) when compared with placebo. In addition, patients receiving abciximab demonstrated a concerning trend toward harm, including a higher incidence of death during the first 48 hours of treatment. Taken together, these studies suggest tirofiban may be superior to abciximab as the initial medical therapy of patients with ACS.
In contrast to the data for their use in ACS, evidence for the beneficial effects of these GP IIb/IIIa antagonists in PCI is much more robust, with durable benefit now reported out to eight years of follow-up. In addition, for this clinical indication, the superior agent to date has appeared to be abciximab. TARGET was designed to compare the efficacy of tirofiban with abciximab in patients undergoing PCI, specifically stent implantation. This study is notable in that it is the first head-to-head clinical trial comparing two GP IIb/IIIa antagonists directly, as all previous studies had been placebo controlled. TARGET was designed to include a broad range of patients undergoing stent procedures and was powered to test the hypothesis that the two agents would be equivalent.
TARGET included a broad range of patients undergoing stent implantation for both elective (non-ACS) or urgent (ACS) clinical indications. Because tirofiban is primarily renally excreted, patients with a serum creatinine of 2.5 were not enrolled in the study. Patients were randomized to receive tirofiban (10 mcg/kg, then 0.15 mcg/kg/min for up to 24 h) or abciximab (0.25 mcg/kg bolus, then 0.125 mcg/kg/min for 12 h). This is the tirofiban dose used in the RESTORE trial and is a higher dose than was used in any of the aforementioned ACS trials. All patients received unfractionated heparin and clopidogrel (Plavix®). The primary end point of TARGET was a composite of death, MI, or urgent revascularization at 30 days and each component was also assessed individually.
The results of 4812 randomized patients were reported. Of note, 500 patients were excluded from analysis. These patients were randomized but did not receive a study drug, largely because they did not undergo intervention. No significant differences in baseline patient characteristics between the tirofiban- and abciximab- treated groups were reported, and culprit vessel distribution was balanced between the groups. There was a relative risk reduction in the primary end point of 26% for the abciximab-treated patients (6.01% vs 7.55%; P = 0.037). Thus, tirofiban appears to be inferior to abciximab for the primary end point at 30 days. This benefit for abciximab was evident by 48-72 hours suggesting that the majority of events were likely procedural in origin. While questions about adequacy of dosing and extent of platelet inhibition have been raised in previously published trials of small molecule GP IIb/IIIa antagonists, adequate platelet inhibition was confirmed in greater than 90% of the tirofiban-treated patients in this study. Minor bleeding complications were more common with abciximab as has been noted in previous clinical trials with these agents. Thrombocytopenia was more common with abciximab treatment; however, this was not associated with need for transfusion or any major bleeding complication. TARGET would, therefore, suggest that abciximab remains the gold standard GP IIb/IIIa antagonist for prevention of ischemic complications in PCI.
The results of TACTICS and TARGET support the use of tirofiban in the medical therapy of ACS with an early invasive strategy and the use of abciximab in coronary stent procedures. The difficulty now lies in knowing which agent to use in a high-risk ACS patient who will ultimately undergo coronary stenting, a scenario that is not at all uncommon in clinical practice. It is also difficult to know where eptifibatide, which is presently the only agent FDA approved for both clinical indications, fits into this overall scheme. To much fanfare, results of the ESPRIT trial were presented at the ACC meeting in March 2000, one month after randomization was stopped early due to the benefit of eptifibatide. ESPRIT compared eptifibatide to placebo in a relatively stable group of patients undergoing PCI with respect to the composite end point of death, MI, ugent target vessel revascularization, or need for "bailout" (unblinded) GP IIb/IIIa antagonist administration at 48 hours. ESPRIT showed a 37% reduction in the primary end point in the eptifibatide-treated group (6.6% vs 10.5%; P = 0.0015). Results of an analysis of the secondary 30-day composite end point have not yet been reported, and it is unclear whether follow-up at later timepoints will be performed. Therefore, unlike for abciximab, the durability of the benefit of eptifibatide is, as yet, unknown. It is also important to note that eptifibatide has not been directly compared to either abciximab or tirofiban in a randomized clinical trial.
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