Reports

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PRIORITY PRESS - 31st Annual Congress of the European Society of Cardiology

Barcelona, Spain / August 29-September 2, 2009

Two years ago, the European Society of Cardiology (ESC) recommended triple therapy in intermediate or high-risk non-ST-segment elevation myocardial infarction (NSTEMI), particularly in patients with elevated troponins, ST-depression or diabetes. Not all glycoprotein (GP) IIb/IIIa antagonists are considered equivalent for this indication in the ESC guidelines, which only recommend tirofiban and eptifibatide in early treatment on the basis of clinical studies.

“In high-risk patients, we need triple antiplatelet therapy to improve outcomes, particularly in troponin-positive patients and in high-risk groups. It is important to follow the guidelines,” emphasized Dr. Christian W. Hamm, Kerckhoff Heart Center, Bad Nauheim, Germany. Although Dr. Hamm, who has led several major studies in antiplatelet therapy for cardiovascular disease, cautioned that strategies for optimal antiplatelet effect are in almost constant evolution, he confirmed that the evidence provides a clear direction for current therapy.

The ESC guidelines on NSTEMI acute coronary syndrome (ACS), published in 2007, recommend the addition GP IIb/IIIa antagonists such as tirofiban or eptifibatide to dual antiplatelet therapy as early as possible, including before hospital admission when feasible, particularly in intermediate and high-risk patients. Once started, the same drug should be maintained in patients who undergo percutaneous coronary intervention (PCI) but therapy is not dependent on a planned PCI. Rather, early use of triple therapy is recommended in all patients.

The evidence cited for this recommendation includes the 38% risk reduction (P=0.01) in the primary end point of death, MI, repeat revascularization or recurrent ischemia, achieved with tirofiban relative to unfractionated heparin (UFH) on top of dual antiplatelet therapy at 30 days in the RESTORE trial. In the PRISM-Plus study, there was a 47% risk reduction (P=0.004) for a similar composite end point for the GP IIb/IIIa antagonist plus UFH over UFH alone on top of oral antiplatelets without evidence of a significant increase in major bleeds. In the PURSUIT study, the higher dose of eptifibatide on top of ASA and UFH reduced death and MI by 10% (P=0.04) with a higher risk of major bleeds relative to placebo, but the triple antiplatelet strategy produced a net clinical benefit. In all cases, the opportunity to reduce hard end points, including death, relative to a small or no increase in potentially reversible bleeding provides the justification for more aggressive antiplatelet treatment. Also based on current data, several experts now believe that there are clear indications for an immediate role for triple therapy in STEMI.

ST-segment Resolution in Diabetic Patients and in the Elderly

In STEMI patients, the 2008 ESC guidelines currently recommend peri-procedural abciximab, a GP IIb/IIIa antagonist, in a triple antiplatelet strategy for preventing or treating occlusion based on a systematic review of several randomized trials associating this agent with 32% reduction in mortality at 30 days without increasing the risk of hemorrhagic stroke or major bleeding. The evidence for triple therapy in STEMI continues to evolve.

The completed ON-TIME 2 study demonstrated that tirofiban on top of ASA, a 600-mg loading dose of clopidogrel and UFH delivered in an ambulance or pre-hospital setting provided a significant improvement in the primary end point of ST-segment resolution (3.6 mm vs. 4.8 mm; P=0.003) one hour after PCI. At 30 days, there was a significant reduction in the composite end point of death, recurrent MI, urgent target vessel revascularization or thrombotic bailout (HR 0.69; 95% CI, 0.49-0.95; P=0.02).

New data from two pre-specified secondary ON-TIME 2 analyses conducted in diabetic and elderly populations, respectively show that the greatest risk reductions were achieved in patients at highest risk. The relative benefit was substantially greater than that observed in the unselected study population.

According to Dr. Jorik R. Timmer, Department of Cardiology, Isala Klinieken, Zwolle, The Netherlands, diabetic patients randomized to active treatment had a greater likelihood of ST resolution and reduction in the infarct size than those who received placebo. Consistent with a large body of data that diabetic patients are at far greater risk of recurrent thrombotic events, the RR of a residual ST elevation of >3 mm was reduced by almost 50% (RR 0.51; P=0.017) in the 220 diabetic patients (representing 16% of the total population) vs. 17% (RR 0.83; P=0.14) in the non-diabetic patients. There was also a trend for a greater initial TIMI 3 flow in the diabetic group (RR 0.57; P=0.12).

Very similar relative benefits were achieved among the elderly in the ON-TIME 2 trial. In a second substudy that evaluated the 538 elderly patients (representing 38.5% of the study population), there was a highly significant 24% reduction (RR 0.76; 95% CI, 0.63-0.93; P=0.006) in the primary end point of residual ST elevation >3 mm. Major bleeding rates were higher but not significantly increased in those over the age of 65, who had a much higher baseline risk and a much longer time to diagnosis when compared to those younger.

“Pre-hospital initiation of triple antiplatelet therapy, including high-dose tirofiban and clopidogrel, is very effective in elderly patients,” confirmed Dr. K. Gert Van Houwelingen, Department of Cardiology, Medisch Spectrum Twente, Enschede, The Netherlands. Although he acknowledged that there was a signal for increased bleeding risk in the elderly, “net clinical outcome is still in favour of triple antiplatelet therapy.”

Improving Platelet Inhibition

A third substudy from ON-TIME 2 appears to explain these results. In more than half of participants, platelet inhibition data were available for analysis 60 minutes after the initiation of study medication using three different methodologies. In all three, inhibition was significantly improved (P<0.001) for those who received tirofiban relative to those who received placebo. Moreover, there was a significant relationship (P=0.028) between lower platelet inhibition and increased risk of mortality, target vessel revascularization and MI at 30 days as well as for subacute thrombosis (P=0.009).

“The take-home message of this study is that the antiplatelet therapy in the placebo group did not provide an adequate effect,” Dr. Jaap Jan Smit, Isala Klinieken, told delegates. However, “tirofiban was needed to boost platelet inhibition into the range most closely associated with improvements in outcome.”

The same point was made by Dr. Hamm, who emphasized that oral antiplatelet agents are not adequate in the acute setting whether STEMI or NSTEMI/ACS. There are multiple factors that limit the efficacy of ASA and thienopyridines such as clopidogrel. The most important may be the slow onset of action, particularly for thienopyridines, which ranges from about 30 minutes with prasugrel to 120 minutes for clopidogrel. Resistance to clopidogrel can be reduced from about 28% to <10% by using the 600-mg loading dose instead of 300 mg, but Dr. Hamm cautioned that this would still leave a substantial proportion of patients at increased risk of thrombotic complications.

In the TRITON-TIMI 38 trial, prasugrel provided greater protection against thrombotic events than clopidogrel at the cost of increased bleeding, but according to Dr. Hamm, physicians need to tolerate some degree of increased bleeding when the net result is better clinical outcomes. He noted that about 55% of participants in the TRITON-TIMI 38 study were also receiving GP IIb/IIIa antagonists. In these patients, bleeding rates were increased but the overall outcomes were better even when including the risk of major bleeds. Although he does not believe that GP IIb/IIIa antagonists are needed in all patients, Dr. Hamm suggested that high-risk groups could achieve better outcomes with greater antiplatelet effects.

“We do already have very effective treatment options for our patients. In high-risk patients, we need full treatment before early invasive management. We do need triple antiplatelet treatment, particularly in troponin-positive patients,” Dr. Hamm reported.

Summary

The definition of adequate antiplatelet therapy is continuing to evolve, but the benefit of aggressive use of triple antiplatelet therapy with GP IIb/IIIa antagonists is established in guidelines for the treatment of NSTEMI patients, and there are controlled data supporting this level of therapy for high-risk STEMI patients, such as the elderly and those with diabetes. There is a correlation between greater antiplatelet effect and an increased risk of bleeding, but this is counterbalanced by the correlation between inadequate antiplatelet effect and increased risk of thrombotic events. Clinical trials continue to define the optimal balance with the understanding that some cost in bleeding is acceptable for the opportunity to reduce life-threatening thrombotic events.