Percutaneous coronary intervention was first accepted as a valuable treatment for coronary-artery disease in the 1980s, and became widely used after the introduction of stents reduced the rate of restenosis. However, acute ischaemic complications triggered by abrupt vessel closure have always been an associated risk.
In previous years, anticoagulants were deemed essential for weeks after percutaneous coronary intervention; heparin doses would be cautiously tapered a few hours after the procedure to allow sheath removal and then treatment with warfarin would be started. However, platelet inhibition, rather than coagulation, was shown to be the key to prevention of acute and subacute thrombosis after percutaneous coronary intervention,1 and the use of double-antiplatelet therapy, as a simpler, safer, and more effective way to avoid stent-related ischaemic events, became routine.
Treatment with aspirin and ticlopidine for a month after stenting has long been an effective and safe mainstay. Most patients who undergo elective percutaneous coronary intervention are now discharged after 24—48 h, and hardly any have acute ischaemic complications. Clopidogrel—another thienopyridine—has progressively replaced ticlopidine, mainly because it acts rapidly when given as an oral bolus. This quality means it can be given in a catheterisation laboratory after coronary angiography, when the decision is made to do percutaneous coronary intervention.2
However, haemorrhagic complications still affect, in particular, older and female patients, patients with renal impairment or diabetes, and those receiving double-antiplatelet therapy for many months after the placement of a drug-eluting stent. Even minor bleeding affects prognosis after percutaneous coronary intervention,3—6 and recent data suggest that more deaths after an acute-coronary syndrome are caused by bleeding than by reinfarction or stent thrombosis.7 Any new antithrombotic approach capable of reducing bleeding complications while retaining an equivalent anti-ischaemic profile would therefore be welcome.
Thrombin is the main mediator of blood coagulation, first in the initial activation of platelets and zymogens (factors VII, V, VIII, IX, and X), and then in the amplification and cleavage of fibrinogen to fibrin. Thrombin-activated platelets are essential for assembling activated coagulation factors into complexes, which then begin to cleave inactive zymogens and lead to the explosive phase of the cascade. Thrombin is the most potent platelet activator and is not influenced by thienopyridine or aspirin. Selective blocking of the thrombin receptor effectively inhibits thrombin-dependent platelet activation (the pathway involved in thrombosis) without affecting collagen-dependent activation (the pathway involved in haemostasis). Furthermore, this blockade does not affect thrombin's proteolytic action or its effect on coagulation factors.8
In The Lancet today, Richard Becker and colleagues9 report on a thrombin-receptor-1 antagonist in a phase II, placebo-controlled study of SCH 530348. The drug was given orally at least 1 h before percutaneous coronary intervention in three randomised loading doses, and then continued in three further randomised dose-groups for 2 months. All patients received aspirin and a loading dose of clopidogrel before percutaneous coronary intervention, and took both drugs for 4 weeks.
The findings suggest that SCH 530348 is safe, a conclusion strengthened by it being used with two other antiplatelet agents. Major and minor TIMI bleeding event rates were similar to those in PCI-CURE10 and CREDO11 (table). Patients given the highest loading dose had a more than 80% reduction in thrombin-receptor-agonist peptide-mediated aggregation 90 min after bolus administration, and all of the drug regimens were highly effective in blocking the thrombin-mediated aggregation pathway during follow-up.

Comparative bleeding incidence in percutaneous coronary interevention

This clinical report of a new antithrombotic drug developed on the basis of new knowledge about the coagulation cascade suggests that the drug works. Is the dream of an effective antithrombotic drug with a low bleeding risk becoming reality? Will this approach be effective in the acute setting (eg, primary percutaneous coronary intervention) and even in secondary prevention? Phase III trials will determine whether we are entering a new antithrombotic era.
AC declares that he has no conflict of interest. PM is national lead investigator for the TRA-2P study in Italy, and collaborates with the TIMI group.

References

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