March 27, 2007 (New Orleans, LA) - A novel oral antiplatelet agent has shown promising results in a phase 2 trial in patients undergoing elective stenting, showing a trend toward fewer ischemic events without increasing bleeding when added to standard antiplatelet therapy with aspirin and clopidogrel.
The drug, SCH 530348 (Schering Plough), is the first of a new class of agents. Because it blocks the platelet PAR-1 receptor to which thrombin binds, thus inhibiting thrombin-induced activation of platelets, it is known as a thrombin receptor antagonist (TRA).
Presenting the study results today at the American College of Cardiology 2007 Scientific Sessions, Dr David Moliterno (University of Kentucky, Lexington) said: "We're very excited about this. We appear to have stumbled across an antiplatelet drug that reduces ischemic events without increasing bleeding. If this is borne out in larger trials, that would be a tremendous achievement." Phase 3 trials are now being planned.
In the current study, known as TRA-PCI, 1031 patients scheduled for angiography and possible elective stenting were randomized to SCH 530348 or placebo in a 3:1 ratio. All patients also received aspirin, clopidogrel, and antithrombin therapy (heparin or bivalirudin). Patients randomized to SCH 530348 received one of three single-loading doses (10, 20, or 40 mg) before angiography and, in the 573 patients who actually underwent PCI, maintenance therapy with one of three chronic doses (0.5, 1.0, or 2.5 mg daily) for two months. The primary end point was bleeding at 60 days in the PCI cohort; the secondary end point was death or major cardiac event. Moliterno explained that safety was the primary end point because this new antiplatelet agent was being added on top of many other antithrombotic therapies, and bleeding was obviously a key issue.
However, results showed that there was no increase over placebo in bleeding in patients receiving SCH 530348.
PCI cohort: Bleeding results
|Bleeding category||Placebo (n=151)||All SCH 530348 doses (n=422)||SCH 530348 10 mg (n=129)||SCH 530348 20 mg (n=120)||SCH 530348 40 mg (n=173)|
|TIMI major/minor (% of patients)||3.3||2.8||1.6||2.5||4.0|
|TIMI major (% of patients)||1.3||0.7||1.6||0||0.6|
|TIMI minor (% of patients)||2.0||2.1||0||2.5||3.4|
|Non TIMI (% of patients)||32||41||36||43||43|
Moliterno said that bleeding results were also "reassuring" in patients in the non-PCI cohort who underwent cardiac surgery. "Bleeding is obviously a key focus in these patients especially, as in this trial a third antiplatelet agent was given, and although bleeding appeared slightly increased in this group with SCH 530348 vs placebo, the overall amount of blood lost in chest-tube drainage was not different," he commented to heartwire .
CABG cohort: Bleeding results
|Bleeding category||Placebo (n=24)||All SCH 530348 doses (n=51)||SCH 530348 10 mg (n=10)||SCH 530348 20 mg (n=18)||SCH 530348 40 mg (n=23)|
|TIMI major/minor (number of patients)||19||48||9||17||22|
|Transfusion >2 units (number of patients)||5||9||2||2||5|
|Chest tube drainage (mL)||996||988||1393||1015||870|
Moliterno noted that although bleeding did not increase, SCH 530348 seemed to be associated with a reduction in ischemic events. "We were surprised to see this, as generally if an anticoagulant works in reducing events it would increase bleeding. This may be explained by the fact that SCH 530348 blocks the thrombin pathway of platelet activation but does not impact the collagen pathway, which is important in the development of platelet plugs or hemostasis," he added. Although the efficacy results were not statistically significant, Moliterno noted that this study was not powered to show a reduction in clinical events, and there was a very encouraging 46% decrease in cardiovascular events in the group receiving the highest dose. It is this 40-mg loading dose that is to be taken forward into phase 3 trials (along with the 2.5-mg maintenance dose).
PCI cohort: Cardiac events
|Event||Placebo (n=151)||All SCH 530348 doses (n=422)||SCH 530348 10 mg (n=129)||SCH 530348 20 mg (n=120)||SCH 530348 40 mg (n=173)|
|Recurrent ischemia (%)||0.7||0.2||0.8||0||0|
*primary efficacy end point
MACE=MI/ischemia requiring hospitalization/coronary revascularization
Asked whether the cost of a third antiplatelet agent is feasible, given that many patients are now struggling to pay just for clopidogrel, Moliterno answered that this depended on the trade-off. "It is always feasible to add another drug if there is clinical benefit. If SCH 530348 brings about a further reduction in death/MI then, yes, the cost will be justifiable," he said.
In an interview with heartwire , Moliterno said that because SCH 530348 was a new class of agent, it had to be used on top of existing treatment at first, but there is a possibility down the line that it could replace other agents, such as clopidogrel, in certain situations. "If this drug does turn out not to increase bleeding, there would be an obvious use for it as long-term treatment following stent placement. If, as seems likely now, patients need lifelong dual antiplatelet therapy after a drug-eluting stent, then bleeding risk of the antiplatelet agents used will be of the utmost importance, and SCH 530348 may be a preferable choice to clopidogrel in this regard. But this is a step away as yet," he commented.
Heartwire from Medscape © 2007 Medscape
Cite this: Sue Hughes. Novel Antiplatelet "May Reduce Events Without Increasing Bleeding" - Medscape - Mar 26, 2007.