CLINICAL TRIAL UPDATE
Clinical trial update
Barcelona, 4 September 2006
An update on six clinical studies was provided in a hot line session. The session was chaired byV. Fuster (New York, US) and S.C. Smith (Chapel Hill, US).
The session opened with a contribution by M. Gibson (Boston, US) on the PCI-ExTRACT-TIMI-25 (PCIEnoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment -Thrombolysis In Myocardial Infarction) study. This worldwide trial in 20,479 STEMI patients all treated by thrombolysis (of which 20.2% streptokinase) had previously compared adjunctive anticoagulation strategies to prevent reocclusion. A new strategy (A) using enoxaparin, weight-based and dose-adjusted for age and renal function continued until discharge or a maximum of eight days, was compared with the guideline-recommended strategy (B) ofunfractionated heparin (weightbased) with blinded APIIT monitoring, continued for at least 48 hours. At 30 days, the relative risk of a primary endpoint (death or nonfatal reinfarction) was 0.83 (0.77-0.90) but at the cost of more major bleeding in strategy A versus B. Pooled (net) clinical effect (death or nonfatal reinfarction or nonfatal major bleeding) remained in favour of the 8-day treatment with enoxaparin compared with 48-hour treatment with unfractionated heparin (RR 0.86 (0.80-0.93)). The speaker presented a subanalysis within the 2178 participants who were still on blinded study medication while receiving a subsequent PCI within 30 days (mean time from randomisation to PCI 122 vs. 109 hours (p=0.006) in the enoxaparin vs. UFH groups). Periprocedural antithrombotic treatment consisted of the previously allocated blinded study medication (either continued or reinstated). The enoxaparin-managed patients were at significantly lower risk for the primary endpoint (RR 0.77, p=0.001), and any stroke (RR 0.30, p=0.006). Moreover, risk of major bleeding complications was similar in both treatment arms (RR 0.75, p=0.33). Enoxaparin therefore appeared to be superior over current guideline-recommended unfractionated heparin in patients receiving thrombolysis for STEMI, and enoxaparin can be used as periprocedural antithrombotic during PCI in these patients. JJ. Reglell Department of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands E-mail: [email protected]
10
Nevertheless, in generalising these results, it was noted by discussant C. Hamm (Bad Nauheim, Germany) that concomitant treatment (e.g. use of streptokinase) was not fully contemporary, and furthermore a selection bias towards lower-risk patients had occurred in this specific PCI-treated population. Next, F. Perez Gomez (Madrid, Spain) addressed the World Congress of Cardiology's highlight topic 'cardiovascular disease and ageing', presenting a subgroup analysis of the NASPEAF (National Study for Prevention of Embolism in Atrial Fibrillation) trial. Currently, vitamin K antagonists with target INR of 2.0 to 3.0 are a class I recommendation (ESC guideline 2006) in chronic AF with defined risk factors (including age >75). The overall trial had previously demonstrated that a strategy ofmoderated target INR (1.4-2.4) with addition of the antiplatelet drug trifusal (combination therapy) resulted in a better prevention ofemboli in both intermediate-risk patients (HR0.33, p=0.02) and high-risk patients (HR 0.51, p=0.03) than the guideline-recommended strategy, without increasing major bleeding, thus a favourable benefit/risk ratio for this strategy. This analysis explored benefits and risks of this new strategy in the 75+ subgroup (n=271), who are at a higher risk of both thromboembolic stroke and bleeding. Despite the small numbers (patients and events), the results suggested fewer intracranial bleeding and - surprisingly - prevention of noncerebral, nonembolic deaths (sudden death and acute coronary syndromes) under combination therapy. The discussant J.C. Daubert (Rennes, France) pointed out that these new results on a very important clinical dilemma (benefit vs. risk of bleeding) are promising with trifusal but might not be extrapolated to aspirin, thus warranting further study.
R.J. De Winter (Amsterdam, the Netherlands) followed with a presentation on early invasive versus selective management for acute coronary syndromes, discussing the results of the three-year follow-up of the ICTUS (Invasive vs. Conservative Treatment in Unstable Coronary Syndromes) trial. This trial randomised 1200 Dutch patients with NSTE ACS and troponin T elevation to a primarily invasive management (prompt angiography and revascularisation) versus a selectively invasive management (only in the case of refractory ischaemia). One-year risk of the primary endpoint Netherlands Heart Journal, Volume 14, Supplement 2, November 2006
qc
28th Congress of the European Society of Cardiology / World Congress of Cardiology
(death, MI or rehospitalisation for recurrent ACS) had been equal in both groups. The currently available three-year survival analysis on the composite endpoint yields an HR of 1.20 (95% CI 0.97-1.49, p=O.10) of the early-invasive versus selective arm, confirming equality of the two strategies. This, however, is in disagreement with the benefits from an early-invasive strategy found in the RITA 3 (Randomised Intervention Trial of Unstable Angina 3 and FRISC (Fast Revascularisation during Instability in Coronary Artery Disease) trials addressing similar questions. According to the speaker and K.A. Fox (Edinburgh, UK), one plausible explanation would be the different rates of revascularisation in these trials, the ICTUS cohort being revascularised at a much higher rate than RITA and FRISC. Assuming that the ICTUS cohort was indeed a higher-risk population with a high need for revascularisation, the contrast between the two strategies under comparison would become lost. Putting all this into the clinical perspective, discussant W. Wijns(Aalst, Belgium) concluded that there is no need to rush and proceed with an emergency angiogram in every patient. Five-years follow-up of the PRAGUE 2 trial was discussed by P. Widimsky(Prague, Czech Republic). The study randomised 850 patients presenting to community hospitals (with no primary PCI facility), within 12 hours of onset of an STEMI. The previous analysis at 30 days reported that direct transportation to a primary PCI centre had benefits on morbidity but not mortality over a strategy of thrombolysis by means of streptokinase. A composite endpoint of death, reinfarction and stroke had occurred in 8.4 versus 15.2% (p=0.03), but it was not known whether this benefit would translate into a lower morbidity and mortality in the long term. The five-year data (mean follow-up 58 months) now available confirmed this, showing a primary endpoint (death, reinfarction, stroke or reintervention) rate of 73.3 versus 58.5% (p
Clinical trial update
Barcelona, 4 September 2006
An update on six clinical studies was provided in a hot line session. The session was chaired byV. Fuster (New York, US) and S.C. Smith (Chapel Hill, US).
The session opened with a contribution by M. Gibson (Boston, US) on the PCI-ExTRACT-TIMI-25 (PCIEnoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment -Thrombolysis In Myocardial Infarction) study. This worldwide trial in 20,479 STEMI patients all treated by thrombolysis (of which 20.2% streptokinase) had previously compared adjunctive anticoagulation strategies to prevent reocclusion. A new strategy (A) using enoxaparin, weight-based and dose-adjusted for age and renal function continued until discharge or a maximum of eight days, was compared with the guideline-recommended strategy (B) ofunfractionated heparin (weightbased) with blinded APIIT monitoring, continued for at least 48 hours. At 30 days, the relative risk of a primary endpoint (death or nonfatal reinfarction) was 0.83 (0.77-0.90) but at the cost of more major bleeding in strategy A versus B. Pooled (net) clinical effect (death or nonfatal reinfarction or nonfatal major bleeding) remained in favour of the 8-day treatment with enoxaparin compared with 48-hour treatment with unfractionated heparin (RR 0.86 (0.80-0.93)). The speaker presented a subanalysis within the 2178 participants who were still on blinded study medication while receiving a subsequent PCI within 30 days (mean time from randomisation to PCI 122 vs. 109 hours (p=0.006) in the enoxaparin vs. UFH groups). Periprocedural antithrombotic treatment consisted of the previously allocated blinded study medication (either continued or reinstated). The enoxaparin-managed patients were at significantly lower risk for the primary endpoint (RR 0.77, p=0.001), and any stroke (RR 0.30, p=0.006). Moreover, risk of major bleeding complications was similar in both treatment arms (RR 0.75, p=0.33). Enoxaparin therefore appeared to be superior over current guideline-recommended unfractionated heparin in patients receiving thrombolysis for STEMI, and enoxaparin can be used as periprocedural antithrombotic during PCI in these patients. JJ. Reglell Department of Cardiology, University Medical Centre Utrecht, Utrecht, the Netherlands E-mail: [email protected]
10
Nevertheless, in generalising these results, it was noted by discussant C. Hamm (Bad Nauheim, Germany) that concomitant treatment (e.g. use of streptokinase) was not fully contemporary, and furthermore a selection bias towards lower-risk patients had occurred in this specific PCI-treated population. Next, F. Perez Gomez (Madrid, Spain) addressed the World Congress of Cardiology's highlight topic 'cardiovascular disease and ageing', presenting a subgroup analysis of the NASPEAF (National Study for Prevention of Embolism in Atrial Fibrillation) trial. Currently, vitamin K antagonists with target INR of 2.0 to 3.0 are a class I recommendation (ESC guideline 2006) in chronic AF with defined risk factors (including age >75). The overall trial had previously demonstrated that a strategy ofmoderated target INR (1.4-2.4) with addition of the antiplatelet drug trifusal (combination therapy) resulted in a better prevention ofemboli in both intermediate-risk patients (HR0.33, p=0.02) and high-risk patients (HR 0.51, p=0.03) than the guideline-recommended strategy, without increasing major bleeding, thus a favourable benefit/risk ratio for this strategy. This analysis explored benefits and risks of this new strategy in the 75+ subgroup (n=271), who are at a higher risk of both thromboembolic stroke and bleeding. Despite the small numbers (patients and events), the results suggested fewer intracranial bleeding and - surprisingly - prevention of noncerebral, nonembolic deaths (sudden death and acute coronary syndromes) under combination therapy. The discussant J.C. Daubert (Rennes, France) pointed out that these new results on a very important clinical dilemma (benefit vs. risk of bleeding) are promising with trifusal but might not be extrapolated to aspirin, thus warranting further study.
R.J. De Winter (Amsterdam, the Netherlands) followed with a presentation on early invasive versus selective management for acute coronary syndromes, discussing the results of the three-year follow-up of the ICTUS (Invasive vs. Conservative Treatment in Unstable Coronary Syndromes) trial. This trial randomised 1200 Dutch patients with NSTE ACS and troponin T elevation to a primarily invasive management (prompt angiography and revascularisation) versus a selectively invasive management (only in the case of refractory ischaemia). One-year risk of the primary endpoint Netherlands Heart Journal, Volume 14, Supplement 2, November 2006
qc
28th Congress of the European Society of Cardiology / World Congress of Cardiology
(death, MI or rehospitalisation for recurrent ACS) had been equal in both groups. The currently available three-year survival analysis on the composite endpoint yields an HR of 1.20 (95% CI 0.97-1.49, p=O.10) of the early-invasive versus selective arm, confirming equality of the two strategies. This, however, is in disagreement with the benefits from an early-invasive strategy found in the RITA 3 (Randomised Intervention Trial of Unstable Angina 3 and FRISC (Fast Revascularisation during Instability in Coronary Artery Disease) trials addressing similar questions. According to the speaker and K.A. Fox (Edinburgh, UK), one plausible explanation would be the different rates of revascularisation in these trials, the ICTUS cohort being revascularised at a much higher rate than RITA and FRISC. Assuming that the ICTUS cohort was indeed a higher-risk population with a high need for revascularisation, the contrast between the two strategies under comparison would become lost. Putting all this into the clinical perspective, discussant W. Wijns(Aalst, Belgium) concluded that there is no need to rush and proceed with an emergency angiogram in every patient. Five-years follow-up of the PRAGUE 2 trial was discussed by P. Widimsky(Prague, Czech Republic). The study randomised 850 patients presenting to community hospitals (with no primary PCI facility), within 12 hours of onset of an STEMI. The previous analysis at 30 days reported that direct transportation to a primary PCI centre had benefits on morbidity but not mortality over a strategy of thrombolysis by means of streptokinase. A composite endpoint of death, reinfarction and stroke had occurred in 8.4 versus 15.2% (p=0.03), but it was not known whether this benefit would translate into a lower morbidity and mortality in the long term. The five-year data (mean follow-up 58 months) now available confirmed this, showing a primary endpoint (death, reinfarction, stroke or reintervention) rate of 73.3 versus 58.5% (p
