Clinical implications of the results of recent atherothrombotic trials on patient management
Department of Cardiology Hemodynamic Unit, Hospital Clínic Barcelona, Villarroel 170, 08036 Barcelona, Spain
* Corresponding author. Tel: +34 93 227 5751, fax: +34 93 451 4148. E-mail address: abetriu{at}clinic.ub.es
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Abstract |
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 Top Abstract IntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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Significant advances have been made over the last several years in the treatment of patients with acute coronary syndromes including the introduction and approval of new antithrombin and antiplatelet agents. Results from a number of studies have impacted treatment strategies of patients with and without percutaneous coronary intervention. The study design and results of five trials: OASIS-5 PCI, PCI-ACUITY, TRITON–TIMI-38, FINESSE, and CARESS-in-AMI will be reviewed, and implications for clinical practice presented.
Key Words: Acute coronary syndrome • Percutaneous coronary intervention • Atherothrombotic trials • Glycoprotein IIb/IIIa inhibitors • Heparin • Clopidogrel
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Introduction |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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Significant advances have been made over the last several years in the treatment of patients with acute coronary syndromes (ACS), including the introduction and approval of new antithrombin and antiplatelet agents. Clinical trials to assess these new agents can be arbitrarily divided into studies to prevent ischaemic events, studies of treatment before percutaneous coronary intervention (PCI) to prevent complications, and studies after PCI to prevent stent thrombosis and thrombotic events unrelated to the PCI. This article reviews the clinical implications of a number of recently completed and published atherothrombotic trials with relevance to practicing and interventional cardiologists.
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The OASIS-5 PCI trial |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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The Fifth Organization to Assess Strategies for Ischemic Syndromes–Percutaneous Coronary Intervention (OASIS-5 PCI) trial1 was a substudy of the main OASIS-5 trial, which had compared fondaparinux and enoxaparin in 20 018 patients. The substudy included 6177 patients undergoing PCI. The study drugs were tailored according to the time when each patient received his or her last subcutaneous dose of fondaparinux or enoxaparin and according to the concomitant use of glycoprotein (GP) IIb/IIIa inhibitors (GPIs). The results showed no differences in mortality, incidence of myocardial infarction (MI), or stroke at 9 days, but the administration of fondaparinux was associated with a 50% reduction in major bleeding. However, fondaparinux caused an increase in the rate of guiding-catheter thrombus formation.
Some of the criticisms levelled against the OASIS-5 trial have also been directed towards the PCI substudy; primarily because the two study agents were administered for different periods of time (fondaparinux for 1 week; enoxaparin for 48 h). In addition, the rate of bleeding in patients allocated to enoxaparin was higher than that seen in other contemporaneous trials. For example, in the Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein inhibitors (SYNERGY) trial,2 the bleeding rates reported in patients receiving enoxaparin were about half those reported in the OASIS-5 trial and, thus, comparable with those observed in patients who received fondaparinux. Also, the use of unfractionated heparin (UFH) in OASIS-5 was almost twice as high in the patients who received fondaparinux as in the patients who received enoxaparin. Finally, there is concern about catheter-tip thrombosis, which mandates the concomitant administration of UFH.
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The PCI-ACUITY substudy |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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Bivalirudin, in contrast to UFH and low-molecular weight heparin (LMWH), is active against clot-bound thrombin. As shown previously in patients presenting with moderate- to high-risk ACS,3 bivalirudin monotherapy is as efficacious as the combination of UFH or LMWH plus a GPI to prevent ischaemic complications while lowering the risk of bleeding.
The purpose of the PCI-ACUITY substudy4 was to assess anticoagulation with bivalirudin monotherapy in the subset of 7789 patients in the ACUITY trial who underwent PCI. The primary 30 day endpoint of the study was a composite of ischaemic events (e.g. death, MI, unplanned revascularization), major bleeding, and net clinical outcomes. The results were similar to those of the main trial; there were no significant differences found in ischaemic or net clinical benefit, whereas major bleeding was reduced when bivalirudin monotherapy was used.
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The TRITON–TIMI 38 |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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Although it is known that prasugrel inhibits adenosine diphosphate-induced platelet aggregation more rapidly, more consistently, and to a greater degree than does clopidogrel, large trials comparing prasugrel with clopidogrel have been lacking.
The TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction 38 (TRITON–TIMI 38)5 randomized a series of 13 608 patients presenting with moderate- to high-risk ACS to receive prasugrel (60 mg loading dose followed by a 10 mg/day maintenance dose) or clopidogrel (300 mg loading dose followed by a 75 mg/day maintenance dose). The trial had both an efficacy endpoint (a composite of death, MI, and stroke) and a safety endpoint (major bleeding not related to coronary artery bypass grafting). The efficacy endpoint of decreased ischaemic events was significantly favourable to prasugrel but at the expense of an increase in bleeding complications compared with clopidogrel. Interestingly, although it was not included as an endpoint, stent thrombosis was also significantly reduced in the patients treated with prasugrel.
Notably, the trial included a population of ACS patients with a scheduled PCI, one fourth of whom presented with ST-segment elevation MI (STEMI); surprisingly, however, the rate of multivessel disease was low (14%). This study is remarkable for the fact that over the course of 15 months only 0.1% of patients were lost to follow-up.
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The PRAGUE-8 study |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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The PRAGUE-8 study compared the efficacy of two different regimens of clopidogrel on the outcomes of patients undergoing elective coronary angiography (CAG) with or without ad hoc PCI.6 The rationale for the study was provided by evidence that clopidogrel administration prior to a planned PCI reduces periprocedural complications and by the fact that PCI is not planned in most patients, as it is usually performed following diagnostic angiography.
A total of 1028 patients with stable angina were randomized to receive non-selective clopidogrel 600 mg >6 h prior to CAG or selective clopidogrel 600 mg in the catheterization laboratory after CAG if they were undergoing PCI. The primary endpoint of the study was the combination of death, MI, stroke, or reintervention within 7 days, but it was not reached. There was a trend towards a decrease in bleeding when the clopidogrel dose was administered after the CAG, which became statistically significant (P = 0.027) in patients actually undergoing PCI.
The main limitation of this trial was the size of the study population, which underpowered it to prove the primary endpoint. Also, the standard 300 mg loading dose of clopidogrel was not tested.
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The FINESSE trial |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial,7 the largest trial to date on facilitated PCI, was designed to compare the efficacy and safety of the early administration of reduced-dose reteplase and abciximab in combination or abciximab alone followed by PCI with abciximab alone administered just before PCI. Patients presenting within 6 h of STEMI in primary and peripheral centres were eligible for participation. Unfortunately, the trial was stopped prematurely when only 2452 of the targeted 3000 patients had been enrolled.
Patients were randomized to one of three treatment arms. Patients in two of the arms underwent PCI facilitated by either a combination of abciximab and reteplase or abciximab alone, whereas patients in the third arm, the control group, underwent primary angioplasty. The primary efficacy endpoint was death, ventricular fibrillation, cardiogenic shock, or congestive heart failure within 90 days of randomization.
Approximately 60% of the study population received treatment within 3 h following symptom onset. Mean delays for treatment were 120 and 155 min for patients from the primary or peripheral centres, respectively. There were no intergroup differences in the primary endpoint (
10%) in the rate of major or minor bleeding (the primary safety assessment).
Overall, the results of this trial are in keeping with previous data showing a lack of benefit with this treatment strategy. Weaknesses of the study included the failure to recruit the planned patient population and a miscalculation in the predicted risk to achieve the primary endpoint (15% vs. the actual 10%).
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The CARESS-in-AMI trial |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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The Combined Abciximab REteplase Stent Study in Acute Myocardial Infarction (CARESS-in-AMI) trial compared early routine and selective (rescue, as per ST-segment resolution) transfer for PCI in patients with STEMI undergoing pharmacologic reperfusion (abciximab plus a half dose of reteplase) in non-PCI centres.8 Candidates were patients 75 years of age or younger presenting with one or more high-risk features (STEMI, left bundle branch block, prior MI, Killip class >2, or left ventricular ejection fraction
35%). Patients were treated with half-dose reteplase, abciximab, heparin, and aspirin and randomized to either transfer to the nearest interventional centre for PCI or to management in the local hospital with transfer in the case of persistent ST-segment elevation or clinical deterioration. The primary endpoint was death, MI, or refractory ischaemia at 30 days. Only 600 of the 2000 patients originally planned were recruited. Transfer times were 136 and 212 min for immediate and rescue PCI, respectively. The primary outcome occurred in 13 patients (4.4%) in the immediate PCI group and 32 patients (10.7%) in the standard care/rescue PCI group with the difference ascribed to a significant reduction in the rate of refractory ischaemia. This lytic-oriented trial did not prove the advantages of treating high-risk patients with routine pharmacologic reperfusion and immediate transfer over transfer for primary PCI within the same timeframe. Weaknesses of the trial included the small study population and the exclusion of patients over 75 years of age, thus making it difficult to assess safety.
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Conclusions |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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The message of the OASIS-5 PCI trial does not differ from that of the main OASIS-5 study. The efficacy and safety profiles of fondaparinux have resulted in the drug being recommended (class IB) in the guidelines for the diagnosis and treatment of patients with non-STEMI ACS.3 However, concern about catheter thrombus formation with the use of fondaparinux monotherapy remains, so that the concomitant administration of UFH at the time of PCI appears mandatory, although a larger data set of patients is needed to confirm the safety of this association.
As with the OASIS-5 trial, the results of the PCI-ACUITY substudy confirm those of the main trial. Thus, it seems unlikely that the substudy would influence clinical practice to a greater extent than did ACUITY. The restrictive use of bivalirudin monotherapy in Europe, which remains much lower than in North America, needs to be interpreted in the context of the large local differences in GPI administration to patients with ACS.
The greater efficacy of prasugrel compared with clopidogrel and, in particular, its superior net clinical benefit seen in the TRITON–TIMI 38 trial, allows us to predict the impact of this new agent. However, the increased risk of bleeding calls for more data on safety.
According to the results of the PRAGUE-8 study, administration of a routine 600 mg clopidogrel loading dose prior to unplanned PCI does not appear to be justified. Since such a policy has not consistently been incorporated into clinical practice, this trial is not expected to be influential.
In keeping with the experience of previous trials and meta-analyses, the results of the FINESSE study are expected to exert a negative impact on the concept of facilitated PCI, a strategy that should no longer be recommended.
Finally, since the CARESS-in-AMI study did not prove the advantages of routine pharmacologic reperfusion and immediate transfer for PCI over transfer for primary PCI, the impact of this trial is likely to be only modest.
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Funding |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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Financial support provided by Daiichi Sankyo, Inc. and Eli Lilly and Company.
Conflict of interest: none declared.
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References |
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TopAbstractIntroductionThe OASIS-5 PCI trialThe PCI-ACUITY substudyThe TRITON-TIMI 38The PRAGUE-8 studyThe FINESSE trialThe CARESS-in-AMI trialConclusionsFundingReferences |
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