Long-Term Reduction of Mortality in the 4-Year Follow up of Tirofiban Therapy in Elective Percutaneous Coronary Interventions (TOPSTAR) Trial

ABSTRACT: Background. TOPSTAR was a randomized, placebo-controlled trial studying the effects of adding the glycoprotein IIb/IIIa inhibitor tirofiban to conventional treatment with aspirin and clopidogrel in patients undergoing elective percutaneous coronary interventions (PCI). TOPSTAR demonstrated a lower periprocedural troponin release and a reduced 6-month mortality risk following PCI. The present study analyzed the corresponding long-term effects. Methods. All 96 patients who were initially included were followed for a minimum of 4 years (median follow-up time, 4.3 years). The prespecified endpoints were: 1) all-cause mortality and 2) the combined endpoint of all-cause death, myocardial infarction and target vessel revascularization by intention-to-treat analysis in patients randomly assigned to elective PCI. Survival analyses were carried out using Kaplan-Meier analysis and Cox proportional hazard regression. Results. After 4 years of follow up, no differences were observed between the two groups with respect to medical therapy, NYHA classification and number of reinterventions and target vessel revascularizations. All-cause mortality was still higher in the placebo group (10.9%; 5/46) compared with the tirofiban group (0%; 0/50; Kaplan-Meier log rank = 0.017). The combined endpoint occurred in 21.7% (10/46) in the placebo group versus 8.0% (4/50) in the tirofiban group (Kaplan-Meier log rank = 0.056). Conclusions. The reduced 6-month mortality risk after elective PCI in the TOPSTAR trial persisted after 4 years of follow up. Even in this relatively small study, periprocedural effective platelet inhibition had a sustained impact on long-term mortality risk. J INVASIVE CARDIOL 2011;23:128–132 ———————————————————— Platelet glycoprotein (GP) IIb/IIIa inhibitors are widely used in the treatment of acute coronary syndromes and as an adjunctive therapeutic option in percutaneous coronary interventions (PCI). Numerous placebo-controlled trials demonstrated a significant reduction of post-procedural death or non-fatal myocardial infarction (MI) 30 days post PCI using various GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban) mainly in acute coronary syndromes (ACS).^1–7 Fewer data are available concerning the long-term benefit of GP IIb/IIIa inhibitors. Topol et al reported a significant improvement of long-term survival in patients treated with abciximab during percutaneous coronary revascularization.⁸ A mean 20% risk reduction for all-cause mortality after 6–12 months was found by analyzing three randomized, placebo-controlled trials that utilized abciximab during coronary intervention.^9–11 However, important long-term follow-up data on tirofiban use from large clinical trials such as RESTORE⁷ (Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis) and TARGET¹² (do Tirofiban [Aggrastat^®] and ReoPro^® Give similar Efficacy outcomes Trial) are not yet available. It is well known that the release of troponin during coronary interventions is associated with an adverse prognosis.^13–16 The randomized, double-blind, placebo-controlled TOPSTAR trial (The Effect of Additional Temporary Glycoprotein IIb/IIIa Receptor Inhibition on Troponin Release in Elective Percutaneous Coronary Interventions after Pre-treatment with Aspirin and Clopidogrel) was first to observe that additional competitive inhibition of platelet aggregation by tirofiban on top of aspirin and clopidogrel reduced periprocedural troponin release and the combined endpoint (death, MI and target vessel revascularization [TVR]) after 9 months.¹⁷ In TOPSTAR, all patients undergoing elective PCI were pretreated with aspirin and clopidogrel. One study arm (n = 50) received an additional peri- and post-procedural bolus of tirofiban followed by an 18-hour infusion of tirofiban. The control arm (n = 46) received boluses and infusion of placebo (0.9% sodium chloride solution). Up to now, no data are available regarding the long-term effect of periprocedural GP IIb/IIIa inhibition in elective coronary interventions. The aim of the present study was to analyze the long-term effects of periprocedural tirofiban administration in patients undergoing elective coronary interventions on: 1) mortality risk; and 2) the combined endpoint of death, MI and TVR using the TOPSTAR trial cohort.

Methods

The TOPSTAR trial design, including definitions of complications and patient characteristics, was published in 2002.¹⁷ In brief, patients underwent diagnostic coronary angiography due to angina. If a significant coronary stenosis could be detected, patients were included in the trial and preloaded with aspirin and clopidogrel. Patients were then randomized 1:1 into the tirofiban vs. placebo arms (0.9% sodium chloride solution) by an independent study nurse. Prior to the intervention on the following day, a bolus of the study medication (either placebo or tirofiban) was administered followed by a continuous infusion for another 18 hours. Dosage of placebo or tirofiban boluses (10 µg/kg body weight) and infusion (0.15 µg/kg body weight/min) was selected in accordance with the RESTORE trial.⁷ Unfractionated heparin was administered in a dosage of 5,000–10,000 Units in both groups, with a target activated clotting time (ACT) of 250 seconds. Ninety-six patients were suitable for inclusion in the study. The trial demonstrated for the first time that peri- and post-procedural administration of tirofiban on top of platelet inhibition with aspirin and clopidogrel in elective PCI resulted in a reduction of post-procedural troponin release and the combined endpoint of death, MI and TVR after 9 months.¹⁷Data analysis. Only intention-to-treat analyses are presented. Proportions were compared using Fisher´s exact test or the chi-square test, as appropriate. Kaplan-Meier plots were constructed and the log-rank test was used to compare groups. Cox proportional hazards regression analysis was used to compute hazard ratios (HR) with respective 95% confidence intervals (CI). The proportional hazard assumption was inspected using graphical methods and no violation was detected. Statistical significance was set at alpha = 0.05. All tests were performed two-sided. SPSS Version 18.1 (SPSS, Inc., Chicago, Illinois) was used for all statistical analyses.

Results

Follow up was performed after 50–53 months (median, 52 months) and was completed in 96/96 patients (100%). There were no significant differences between the tirofiban or placebo-treated patients with respect to all baseline characteristics including history of hypertension, diabetes mellitus, smoking, lipid status or pharmacotherapy (Table 1). Clinical status. Four years after randomization, no differences were found with respect to New York Heart Association (NYHA) functional class between patients treated with tirofiban (NYHA I–IV: 32/53/15/0%) or placebo (NYHA I–IV: 38/50/10/3%; p = n.s., Figure 1). If clinical status was classified according to Canadian Cardiovascular Society (CCS), also no differences emerged. Cardiac rehospitalization and reinterventions. A total of 34.7% of the tirofiban and 31.0% of the placebo patients were rehospitalized during follow up due to cardiac reasons (p = n.s.). Recurrent angina and re-angiography were the most frequent causes of rehospitalization (tirofiban vs. placebo: 58.8% vs. 61.5%; p = n.s.). Angina without re-angiography occurred in 11.8% of the tirofiban-treated patients and in 15.4% of the placebo-treated patients (p = n.s.). Rehospitalization rates due to pacemaker implantation (23.5% vs. 15.4%) or due to other cardiac reasons (5.9% vs. 15.4%) were also not different between groups. Additional PCI was performed in 20% of patients in both groups. PCI was performed in 70% of patients in the target vessel (tirofiban group) vs. 77% in the placebo group (Figure 2). All-cause mortality and combined endpoint of death, MI or myocardial revascularization. Four years after participation in the TOPSTAR trial, all-cause mortality was still higher in the placebo group (10.9%; 5/46) compared with the tirofiban group (0%; 0/50; Kaplan-Meier log rank = 0.017; Figure 3, left panel). The combined endpoint of death, MI and myocardial revascularization occurred in 8.0% of the tirofiban-treated patients and in 21.7% of the placebo patients (Kaplan-Meier log rank = 0.056; HR 2.93; 95% CI 0.92–9.34; p = 0.069; Figure 3, right panel). Further adjustment for baseline age did not materially alter this association (HR 2.82, 95% CI 0.89–9.01). Whereas the combined endpoint occurred exclusively as a consequence of myocardial revascularization in the tirofiban group (no death, no revascularization), in the placebo group 8.7% of the patients underwent myocardial revascularization, 6.5% experienced MI and 10.9% of the patients died during follow up (Figure 4). Correlation between post-interventional troponin release and follow up. In those patients experiencing events of the combined endpoint during follow up, elevated post-interventional troponin T levels were present at baseline in 66.7%. In 63% of the patients with post-interventional elevated troponin T, no combined endpoint occurred (n.s.). However, in 4 out of 5 patients (80%) who died in follow up, elevated troponin during 48 hours after intervention was present. Post-hoc power analysis. On the basis of already published data on GP IIb/IIIa trials, we had calculated a 4-year risk of death by any cause of 5–10% in the control group. Given the pronounced effect demonstrated in the present trial (HR for all-cause death about 4) and assuming alpha = 5%, a study with 2 x 137 subjects would have a power of 90% to confirm the effects on reduction of all-cause death using tirofiban. Even less optimistic scenarios based on comparable studies would result in feasible sample sizes: given a HR of 2 (1.5) for a control versus an experimental group, a follow-up period of 4 years, alpha = 5%, power = 90%, 2 x 338 (835) subjects would be needed. With respect to the combined endpoint, a study of 2 x 338 subjects with the aforementioned assumptions and a HR as found in our trial (i.e., 2.9) would yield a 99% power. With a less optimistic scenario (HR 2.0), the power would still be 90%.

Discussion

The present study investigated the long-term impact of additional platelet inhibition using the reversible GP IIb/IIIa inhibitor tirofiban on top of aspirin and clopidogrel in elective coronary interventions. The beneficial effect on reduced mortality risk observed after 9 months in the tirofiban group was sustained up to 4 years after initial intervention. These results demonstrate for the first time a long-term benefit of potent peri- and post-procedural platelet inhibition beyond routine administration of aspirin and clopidogrel, which is still the current routine clinical practice. The success of platelet GP IIb/IIIa inhibitors in the treatment of acute MI and as an adjunctive therapy in PCI and intracoronary stenting has led to their consideration as potential agents to enhance the efficiency of antithrombotic therapy. The current results provide new insights into the long-term effects of tirofiban therapy in patients undergoing PCI. We have previously shown that there is a significant reduction of both troponin release and the combined endpoint of death/MI/TVR after 9 months in the TOPSTAR trial when tirofiban was used peri- and post-interventionally.¹⁷ Importantly, 67% of the patients experiencing the secondary endpoint, and 80% of the patients who died in the subsequent 4 years had had elevated troponin levels 48 hours after intervention. Atherosclerotic plaque rupture seems to be a key event during coronary interventions, leading to embolization of atherothrombotic debris and platelet microaggregates in the coronary microcirculation.^19,20 Measurements of more sensitive markers of myocardial necrosis like troponin T point to a higher-than-expected incidence of thrombotic embolization.^17,19 Within this pathophysiological context, platelets play an important role. Apart from mechanical thrombotic obstruction, platelets in embolized vessel segments induce temporary vasospasms through the release of serotonin, thromboxan A2 and free radicals. Thus, platelets are involved both in microvascular obstruction by thrombotic emboli and temporary vasospasms, resulting in inadequate perfusion and prolonged tissue ischemia of the affected myocardial regions despite successful revascularization and normal epicardial blood flow.²⁰ Additionally, downstream activated platelets may form microaggregates and induce inflammatory reactions by releasing proinflammatory compounds after adhering to endothelial cells and leukocytes. The reduction of downstream embolization leads to decreased ischemic and inflammatory myocardial cell damage. Our current findings extend the previous findings by demonstrating a long-term benefit of peri- and post-procedural tirofiban administration in terms of both survival and the combined endpoint. Proposing several underlying mechanisms that lead to the improved long-term benefit reduction of microembolization is most likely. However, it is unknown to what extent microembolization influenced long-term myocardial function in this study population. In the TOPSTAR echocardiography substudy the tirofiban-treated patients had a benefit by exhibiting a significant increase in early diastolic velocity up to normalization of diastolic heart function after 6 months. In the placebo group, these effects remained absent (unpublished data). The advantage of improving diastolic myocardial function in the tirofiban group may be another positive additive mechanism. Interestingly, more effective platelet inhibition, e.g., with prasugrel²¹ or ticagrelor²² appears to also reduce early mortality risk after percutaneous interventions in ACS and elective PCI.²³ This suggests that peri- and post-procedural myocardial damage is related to the amount of platelet inhibition. Currently, there is a shift towards more effective oral platelet inhibition shortly before, during or after intervention. Accordingly, the administration of GP IIb/IIIa inhibitors in the future will probably only become necessary in bail-out situations. In summary, the current trial demonstrated that inhibition of platelet aggregation with tirofiban in the setting of elective PCI has beneficial effects in terms of survival and reduction of the combined endpoint of death, MI and TVR, which is sustained during long-term follow up. However, the study cohort was rather small and therefore larger studies are warranted to evaluate the benefits of more effective oral or intravenous platelet inhibition in terms of long-term mortality, MI, rehospitalization, myocardial salvage and economic aspects in this “low-risk” patient population, representing the vast majority of patients undergoing PCI.

Conclusion

The TOPSTAR trial could demonstrate for the first time a short- and long-term improvement in patient outcomes with planned elective PCI using the reversible GP IIb/IIIa inhibitor tirofiban in addition to aspirin and clopidogrel. The results underline the importance and benefits of effective peri- and post-interventional platelet inhibition on post-interventional outcomes, even in elective planned coronary interventions.

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———————————————————— From the University Hospital Würzburg, Würzburg, Germany, and the ^*Center for Cardiology, Lüneburg, Germany. The authors report no conflicts of interest regarding the content herein. Manuscript submitted July 6, 2010, provisional acceptance given August 9, 2010, final version accepted January 12, 2011. Address for correspondence: PD Dr. Andreas W. Bonz, Center for Cardiology, Feldstrasse 2a, 21335 Lüneburg, Germany. E-mail: bonz@praxis-feldstrasse.de