Primary percutaneous coronary intervention (PCI) is widely recognised as the most effective treatment after myocardial infarction (MI). However, time delays are frequent with only a minority of patients reaching catheterisation labs within the 90-minute window recommended by current guidelines. Previously, it was believed that additional early pharmacological interventions to achieve good blood flow could improve outcomes.
The results of two trials recently presented at the European Society of Cardiology 2007 meeting in Vienna, Austria, suggest that primary stenting is the most effective treatment (FINESSE), although there could still be a role for facilitated angioplasty in certain situations (CARESS).
FINESSE
The FINESSE (Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events) trial was designed to investigate this theory. The aim of the trial was to evaluate a strategy of abciximab with half-dose thrombolytic (reteplase), abciximab alone, or placebo among patients undergoing PCI for ST-elevation MI (STEMI). The results were presented by Dr Stephen Ellis, Cleveland Clinic, OH, and the trial was sponsored by Centocor and Eli Lilly. FINESSE randomised 2,452 patients presenting with acute STEMI from 20 countries who had been referred for primary PCI into three groups. The first two groups received two different facilitated PCI treatments regimens, early administration of reduced-dose reteplase and abciximab combination therapy (n=828) or abciximab alone (n=818). Both treatments were followed by PCI after an interval.
The third group received primary PCI with abciximab alone administered just prior to PCI in the cath lab (n=806). An IV infusion of abciximab 0.125µg/kg/min was to be administered to all patients in the catheterisation laboratory and continued for 12 hours. The trial was designed so that approximately 50% of patients were to be entered into the trial at non- PCI hospitals, initiate randomised therapy, and be transferred urgently to the PCI hospital.
Outcomes
Time from arrival at the hospital to PCI (ie, door to balloon time) was 120 minutes in the 60% of patients who were randomised at a hospital with PCI facilities and 155 minutes among the 40% of patients who were transferred from a non-PCI hospital, an average time delay of 35 minutes. Anterior MI was present in 48% of the population. When arriving at the catheterisation lab, more patients in the combination facilitated PCI arm (reteplase+abciximab+PCI) had an open artery prior to PCI (61%) compared with either the abciximab facilitated PCI arm (26%; p< 0.001) or the primary PCI alone group (25%; p< 0.001). ST segment resolution of >70% by 60-90 minutes was also more common in the combination facilitated PCI arm (44%) compared with either the abciximab facilitated PCI arm (33%; p=0.013) or the primary PCI alone group (31%; p=0.003).
There was no difference in the primary endpoint of death, cardiogenic shock, heart failure, or resuscitated ventricular fibrillation by 90 days between the three groups (9.8% of the combination facilitated PCI arm, 10.5% of the abciximab facilitated PCI arm, and 10.7% of the primary PCI alone arm; p=NS). There was also no difference in the components of the primary endpoint, including mortality (5.2%, 5.5%, 4.5%, respectively), heart failure (1.9%, 2.9%, 2.2%, respectively), cardiogenic shock (5.3%, 4.8%, 6.8%, respectively), or ventricular fibrillation (0.6%, 0.2%, 0.4%, respectively). Thrombus in myocardial infarction (TIMI) major or minor bleeding through discharge or day seven was higher in the combination facilitated PCI arm (14.5%) compared with either the abciximab facilitated PCI arm (10.1%; p=0.008) or the primary PCI alone group (6.9%; p<0.001). Intracranial haemorrhage occurred in 0.6% of the combination facilitated PCI arm but none of the abciximab facilitated PCI arm and in 0.1% of the primary PCI alone group.
"Primary PCI with in-lab abciximab provides a better benefit-risk profile than the two facilitated strategies in patients with STEMI who can undergo PCI within four hours of first medical contact. There may still be a role in extreme cases where there are long delays, but the broad approach of offering facilitated therapy prior to PCI is now dead," commented Ellis. He added that despite the outcomes, the FINESSE study does not totally rule out the prospect of new drug combinations that might offer future benefits in facilitated PCI.
In a discussion following the results, Dr Frans Van de Werf, Gasthuisberg University Hospital, Leuven, Belgium, said that FINESSE has confirmed the outcomes of the ASSENT-4 PCI study (published in 2006), which showed patients randomised to tenecteplase followed by primary PCI had excessive in-hospital mortality compared to the control group receiving PCI alone. "The explanation of the negative effects of FINESSE and ASSENT-4 PCI could be that the trials had no upfront clopidogrel. There are also difficulties that patients could be randomised up to six hours and there is little to gain from pharmacological therapy after three to four hours."
Lytic strategy
As well as the issue surrounding antithrombotic therapy, de Werf commented that PCI may have been performed on an already-patent vessel or the study population may have been wrong. He added that a strategy of early, lytic-based pharmacological treatment preceding PCI can only be beneficial in patients who meet the following criteria:
Present early (<2-3 hours of symptom onset); Have a large amount of viable mmyocardium; Have an anticipated long delay to PCI; Are already receive adequate antithrombotic cotherapy; and In whom PCI is postponed if there is evidence of successful (TIMI 3) reperfusion after pharmacological treatment.
"This approach should no longer be called 'facilitated PCI' but a 'pharmacoinvasive' strategy," he concluded.
CARESS
The latest results from the CARESS in AMI (Combined Abciximab REteplase Stent Study in acute myocardial infarction) study has showed that patients who have an acute myocardial infarction (AMI) and are admitted to a hospital benefit after having received thrombolytics prior to referral for PCI. The results were presented by Dr Carlo Di Mario, Brompton Hospital, London, UK.
The aim of the study conducted in patients with high risk STEMI admitted to hospitals with no PCI facilities was to compare the effects on clinical outcome and cost-effectiveness of two reperfusion strategies: Fibrinolytic therapy with abciximab and half-dose Reteplase (with rescue PCI in case of lack of reperfusion), and elective referral for 'facilitated' PCI after early administration of abciximab and half dose of Reteplase. Primary outcome measure was to compare 30 days incidence of the composite endpoint of: mortality, reinfarction and refractory ischaemia in the two arms of the study. Secondary outcome measures compare one-year composite endpoint of: mortality, re-infarction, refractory ischaemia, hospital readmission because of heart failure in the two arms. As well as compare the resource use at 30-days and one-year, including days in hospital, cost of catheterisation and PCI, drugs, ambulance service during index hospitalisation and subsequent hospital admissions for re-AMI, and the incidence of in-hospital stroke and bleeding complications in the two arms.
Outcomes
The trial enrolled 600 STEMI patients under 75 years old within 12 hours of symptom onset who had been admitted to hospitals without PCI facilities. They all received halfdose lytic therapy (reteplase), aspirin, heparin, and abciximab bolus plus infusion and were then randomised to two groups: immediate transfer for PCI (group 1); or transfer for PCI only if they had persistent ST elevation at 90 minutes (rescue PCI). The median time from reteplase to angiography was 136 minutes in the immediate-transfer group and 212 minutes in those patients sent for rescue PCI (36% of group 2).
Patients who are transferred and receive angioplasty immediately after thrombolytics are much more likely (4.1% vs. 11.1% at 30 days, p<0.001) to be free from adverse events such as death, MI, a new acute episode of chest pain and electrocardiogram changes requiring urgent angioplasty (refractory ischaemia). This advantage was present despite the fact that all the patients (36% of the entire conservative group) randomised to the group of more conservative treatment (no immediate transfer) were also promptly referred during the first hours post treatment if there was no evidence in their ECG/clinical status that the lytic drugs had open the occluded artery.
Results at 30 days showed that 4.1% of patients in the group who had immediate transfer for PCI experienced the combined endpoint of death and MI complications, compared to 11.1% in the group who only had thrombolytic therapy (P<0.001). Additional findings showed that the average length of hospital stay was seven days in the facilitated PCI group and nine days in the thrombolysis-alone group. Current practice in most European hospitals is to administer thrombolytics and only to refer patients for PCI if they show no evidence of reperfusion. "The study suggests PCI guidelines need to be changed so that all patients are referred for PCI," said di Mario.
Discussion
In a discussion following the presentation of the trial, Dr Freek Verheugt, Nijmegen University, The Netherlands, argued that the CARESS AMI should not be thought of as a facilitated-PCI study as there was no direct-PCI comparison arm. He stressed that the trial merely suggested that patients who receive lysis immediate transfer for PCI of benefit, adding that the adoption of stents and the results from recent studies (CAPITAL and SIAM-3) have shown better results of immediate PCI (with stenting) after lysis.
Another criticism of CARESS was when the patient received clopidogrel, not at the time of lysis, rather at the time of PCI. In addition, he added that he would welcome the results in patients who had reperfused on the lytic therapy. He concluded that CARESS confirms early PCI should now routinely follow thrombolytic therapy. "But randomised trials are needed to determine whether PCI works best within 2.5 hours (CARESS) or if patients can wait 17 hours after thrombolytic therapy (GRACIA)."
Dr Christian Hamm, University Hospital Eppendorf, Hamburg, Germany, commented that this was a relatively small trial, so the results should be interpreted with caution. He also pointed out that the half-dose reteplase and abciximab regimen had not been shown to be the best treatment for STEMI in other studies evaluating lytic treatment and that CARESS cannot be compared with the larger FINESSE facilitated-PCI trial, as CARESS did not have a primary- PCI arm. "This trial is suggesting that in patients who cannot get to PCI within 120 minutes, when a lysis strategy is chosen, immediate transfer to PCI may be warranted. But it did not investigate whether transfer to PCI without lytic would have been preferable, which the FINESSE results actually suggest." CARESS was supported by grants from Lilly and Biotronik.
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