New drugs steal the spotlight at the ESC Congress 2009

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The hotline sessions at the European Society of Cardiology Congress 2009 were dominated by the results of several new drug trials. PLATO (a study of platelet inhibition and patient outcomes) was presented on Sunday 30 August and compared the antiplatelet ticagrelor with clopidogrel to test the efficacy in reducing the rate of cardiovascular events. The RE-LY (Randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran) trial, also presented during the first hotline session, compared the two anticoagulant therapies for the prevention of stroke in patients with non-valvular atrial fibrillation.

The second hotline, on Monday 31 August, featured the PRAGUE-7 study, which was designed to determine whether the routine upfront administration of abciximab (a IIb/IIIa GP inhibitor) improves outcome when compared with conventional selective administration. Finally, the results of PROTECT (Placebo-controlled randomized study of the selective A1 adenosine receptor antagonist KW–3902 for patients hospitalized with acute HF and volume overload to assess treatment effect on congestion and renal function trial), were presented in the third and final hotline session on Tuesday 1 September. The study compared the effects of rolofylline on symptoms, renal function, and short-term morbidity and mortality in heart failure patients.

Ticagrelor shows reduction in death over Plavix

The presentation of the PLATO (A Study of Platelet Inhibition and Patient Outcomes) showed that ticagrelor (Brilinta) reduced the rate of cardiovascular events (cardiovascular death, myocardial infarction or stroke) from 11.7% to 9.8% compared clopidogrel (Plavix) (p<0.001, RRR=16%), without an increase in major bleeding. This efficacy endpoint was driven by a statistically significant reduction in both cardiovascular death and infarction with no difference in stroke. Ticagrelor is the first antiplatelet agent to demonstrate a reduction in cardiovascular death across all major acute coronary syndromes patient types.


For every 1,000 patients admitted to the hospital because of an acute coronary syndrome event, use of ticagrelor instead of clopidogrel, for up to one year, led to 14 fewer deaths, or 11 fewer infarctions, or eight fewer cases of stent thrombosis, without an increase in major bleeds. In the PLATO study, the reduction in risk of cardiovascular events appears early and the benefit over clopidogrel grows with time. Ticagrelor demonstrated a consistent benefit across multiple secondary efficacy endpoints including cardiovascular death and total mortality; myocardial infarction; the composite of myocardial infarction, stroke, and total mortality; and a composite of cardiovascular death, myocardial infarction, stroke, transient ischaemic attack, recurrent cardiac ischaemia, severe recurrent cardiac ischaemia, and other arterial thrombotic events.


“Ticagrelor is the first antiplatelet therapy to achieve a significant reduction in cardiovascular mortality in acute coronary syndrome patients versus clopidogrel and perhaps most importantly without an increase in major bleeding,” commented Lars Wallentin, co-chair of the PLATO Executive Committee. “PLATO has redefined what is possible in the prevention of recurrent events in patients with acute coronary syndromes.”


Across all the important patient subgroups (e.g. gender, weight, history of stroke/transient ischaemic attack) in PLATO, ticagrelor showed no difference versus clopidogrel in the incidence of major bleeding. When minor bleeding was added, ticagelor showed a small increase in PLATO defined major plus minor bleeding versus clopidogrel. At continuous ECG monitoring wile in hospital, but not at later follow-up in the outpatient setting, pauses in the heart rhythm were seen more frequent with ticagrelor. However such pauses were not associated with any symptoms or clinical consequences for the patient. Transient symptoms of dyspnoea were reported more often by patients on ticarelor but only one in 100 ticagrelor treated patients overall stopped taking study medication due to dyspnoea.


PLATO was a head-to-head outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel plus aspirin, and was designed to establish whether ticagrelor could achieve meaningful cardiovascular endpoints in ACS patients. 18,624 patients at 893 sites in 43 countries across all continents were sucessfully recruited. All patients were admitted to hospital because of acute coronary syndrome, one third with ST-elevation myocardial infarction and two thrirds without ST-elevation. Shortly after admission to hospital, the patients started their long-term anti-platelet treatment with either ticagrelor (90mg twice daily) or clopidogrel (75mg daily) in a randomized, double-blind fashion for 6–12 months. The PLATO study was led by the Executive Committee co-chairs, Wallentin, Sweden (Uppsala Clinical Research Center) and Robert Harrington, US (Duke Clinical Research Institute).


The PLATO study was sponsored by AstraZeneca which has developed and manufactures ticagrelor (Brilinta).


Reduced incidence of stroke in the RE-LY trial

Results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy, Warfarin, compared with Dabigatran) study were presented for the first time at the ESC Congress and published online in the New England Journal of Medicine. The primary objective of RE-LY was to assess the safety and efficacy of the investigational oral direct thrombin inhibitor, dabigatran etexilate (Boehringer Ingelheim) against warfarin (titrated to INR 2.0 to 3.0) for the prevention of stroke in patients with non-valvular atrial fibrillation.


The RE-LY study results have shown:

  • Both doses of dabigatran etexilate were non-inferior to warfarin on the primary endpoint of reducing the incidence of stroke (including haemorrhagic) and systemic embolism (p < 0.001)
  • Dabigatran etexilate 150mg BID was superior to warfarin in reducing the incidence of stroke (including haemorrhagic) and systemic embolism by 34% (RR 0.66, 95% CI, 0.53–0.82, p<0.001)
  • There was no significant difference in the rate of major bleeding for dabigatran 150mg BID compared to warfarin (3.11 percent/year, 3.36%/year, respectively p=0.31)
  • The rate of major bleeding with dabigatran etexilate 110mg BID (2.71%/year) was 20% lower compared to warfarin (p=0.003)


Also presented and published today were results in other outcomes from the RE-LY trial, including significantly lower incidence of haemorrhagic strokes with both 150mg and 110mg BID doses (RRR 74%, p < 0.001 and RRR 69%, p < 0.001, respectively), and a lower incidence of vascular mortality with the 150mg BID dose (RRR 15%, p=0.04). Abnormal liver function (ALT or AST >3xULN with concurrent bilirubin >2xULN) did not occur more frequently among patients taking dabigatran etexilate 110mg BID, 150mg BID than warfarin (0.2%, 0.2%, and 0.3% respectively).


“Up to 20% of strokes in the US each year are associated with atrial fibrillation. As clinicians, our main objective in managing patients with atrial fibrillation is to prevent stroke without increasing the risk of dangerous or life-threatening bleeds,” said Michael Ezekowitz, professor and vice president, Lankenau Institute for Medical Research and vice president for clinical research, Main Line Health System. “The study results seen with the two respective doses of dabigatran evaluated in RE-LY indicate that this compound has the potential to improve patient care.”

RE-LY was a global, phase III, randomised trial of 18,113 patients enrolled in more than 900 centres in 44 countries, investigating whether dabigatran etexilate (two blinded doses) was as effective as well-controlled warfarin – INR 2.0–3.0 – (open label) for stroke prevention.


Abciximab during primary PCI: The PRAGUE-7 Study

Registries have shown further therapeutic benefit from the administration of glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary intervention in acute myocardial infarction patients with cardiogenic shock. However, there are no randomised data to support this approach in these high risk patients. The PRAGUE-7 study was designed to determine whether the routine upfront administration of abciximab (a IIb/IIIa GP inhibitor) improves outcome when compared with conventional selective administration.


This study, which is part of a series of randomised trials in cardiology and cardiac surgery performed in the Czech Republic, enrolled 80 of these most critically ill patients but failed to show any benefit from the routine upfront administration of abciximab to all patients (before coronary angiography) over a more conventional selective use of abciximab during subsequent primary PCI.


All 80 patients in this open-label multicentre trial received standard antithrombotic and anticoagulant treatment (either during transport or directly at the catheterisation laboratory) and coronary angiography. Patients in the upfront treatment group (group A) received a bolus of abciximab immediately after randomisation followed by an infusion for 12 hours. PCI was performed immediately after coronary angiography. Group B received standard therapy with optional abciximab administration during PCI according to the interventional cardiologist.


The study’s primary endpoint was a 30-day combined outcome of death/reinfarction/stroke/new renal failure. Secondary objectives were left ventricular ejection fraction assessed by echocardiography on day 30, major bleeding complications, myocardial blush grade after PCI, and TIMI-flow (a system for measuring coronary blood flow) after PCI.


Results showed that PCI was technically successful in 90% of group A and 87.5% of group B patients. Abciximab was used in 100% of group A and 35% of group B. The primary endpoint was reached in 17 group A patients (42.5%) and 11 group B patients (27.5%) (p=0.24). Fifteen patients (37.5%) died during hospitalisation in group A and 13 patients in group B (32.5%) (p=0,82). Ejection fraction among survivors after 30 days was 44 ±11% (A) vs. 41 ±12% (B) (p=0.205). Major bleeding occurred in 17.5% (A) vs. 7.5% (B) (p=0.310) and stroke in 2.5% (A) vs. 5% (B). No differences were found in TIMI-flow and MBG after PCI.


PROTECT: Effects of rollofylline in acute heart failure

Despite the promising findings of the PROTECT (Placebo-controlled randomized study of the selective A1 adenosine receptor antagonist KW–3902 for patients hospitalized with acute HF and volume overload to assess treatment effect on congestion and renal function trial) pilot study, the larger PROTECT trial found no difference with rolofylline versus placebo with respect to the primary and main secondary endpoints of the study in acute heart failure patients. Although more rolofylline patients than placebo patients experienced moderate or marked dyspnea improvement at 24 and 48 hours from randomisation, this was counterbalanced by a lack of effect on persistent renal impairment. Lastly, the risk of important neurological events was increased in patients on rolofylline.


PROTECT was aimed at the assessment of the effects of rolofylline on symptoms, renal function, and short-term morbidity and mortality in 2,033 patients hospitalised for HF within 24 hours with signs of fluid overload, impaired renal function (estimated GFR 20–80ml/min) and high BNP or NT-proBNP plasma levels (>500 pg/mL or >2000 pg/ml, respectively). Patients were randomised 2:1 to rolofylline 30 mg/day, or placebo. Dyspnea was assessed daily for the first seven days (or until discharge, if earlier) and then at 14 days.


The primary endpoint was a three-category ordered outcome of treatment success, patient unchanged, or treatment failure. Secondary endpoints were: time to death or rehospitalisation for cardiovascular or renal causes through day 60, and the proportion of subjects with persistent renal impairment. Enrolment was concluded in January 2009 and the main results became available in June 2009. Of the total sample, 677 patients received placebo and 1,356 patients received rolofylline. Follow-up was complete in all but one patient at 60 days and four patients (0.2%) at 180 days.


No significant difference was found between rolofylline and placebo with respect to the primary endpoint. Treatment success was achieved by 40.6% patients on rolofylline, compared with 36.0% of patients on placebo, 21.8% of the patients were classified as treatment failure with rolofylline versus 19.8% with placebo, the remainder being unchanged. There were no significant differences between the treatment groups in either secondary endpoint. Death or rehospitalisation for cardiovascular or renal causes at day 60 occurred in 30.7% and 31.9% of rolofylline and placebo patients. Persistent renal impairment occurred in 13.7% of placebo patients and 15% of rolofylline patients, respectively. Moderate or marked better dyspnea at both 24 and 48 hours was observed in 52% of patients in the rolofylline treated group versus 45.4% of patients in the placebo group. However, this was partially counterbalanced by the higher rate of persistent renal impairment in the rolofylline group.


Serious adverse events (SAE) occurred in 13.8% of rolofylline patients and 14.7% placebo patients and cardiac SAEs occurred in 7.2% and 9.0%, respectively. The rate of central nervous system SAEs was 1.5% in the rolofylline group versus 0.6% in placebo, including more patients experiencing seizures, a known adverse effect of A1 receptor antagonists, and 16 (1.2%) vs 3 (0.5%) patients with strokes, respectively.


In conclusion, the PROTECT trial found no difference with rolofylline versus placebo with respect to the primary and main secondary endpoints of the study. Although more rolofylline than placebo patients experienced dyspnea improvement at 24 and 48 hours from randomisation, this was counterbalanced by a lack of effect on persistent renal impairment. Lastly, the risk of important neurological events was increased in patients on rolofylline.