Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

80th Scientific Sessions of the American Heart Association

Orlando, Florida / November 5, 2007

Reported by:

Jean-François Tanguay, MD, FRCPC

Associate Professor of Medicine

Division of Medicine

Université de Montréal Montreal, Quebec

Clinicians have failed to reach a consensus about the most appropriate regimen for reducing the risk of thrombotic complications of percutaneous coronary intervention (PCI). Recent studies have provided a solid base of data favouring higher doses of clopidogrel in PCI patients. The findings included evidence that:

• 900 mg is equivalent to 600 mg, which is more efficacious than 300 mg (von Beckerath et al. Circulation 2005;112(19):2946-50).

• 600 mg significantly reduces the risk of periprocedural myocardial infarction (MI) compared with 300 mg (Patti et al. Circulation 2005;111(16):2099-106).

• Elevated platelet activity after coronary stenting increases the risk of subacute thrombosis (Gurbel et al. J Am Coll Cardiol 2005;46(10):1827-32).

• Poor response to clopidogrel increases the risk of in-stent thrombosis (Buonamici et al. J Am Coll Cardiol 2007;49(24):2312-7).

Exploring Dosing Strategies

Against that background, Dr. Philippe L’Allier, Montreal Heart Institute, Quebec, and colleagues conducted a randomized clinical study to compare three dosing strategies. The study involved 148 patients with stable coronary artery disease undergoing coronary angiography and PCI (if indicated). They were randomized to one of three cohorts: group A received clopidogrel 300 mg the day before PCI followed by 75 mg the morning of PCI; group B were administered 600 mg the morning of PCI; and group C received 600 mg the day before PCI and another 600 mg the morning of PCI.

The primary end point of the study was the per cent inhibition of peak platelet aggregation (at angiography vs. baseline), defined as either 5 µmol/L adenosine diphosphate (ADP) or 20 µmol/L ADP. Secondary end points were per cent inhibition of late aggregation; per cent inhibition of peak aggregation post-PCI vs. baseline; percentage of clopidogrel nonresponders; composite end point of death, MI and target vessel revascularization at 30 days; and major and minor bleeding complications during the first 30 days.

By either definition of platelet aggregation, group C (600 mg + 600 mg) achieved significantly greater peak platelet aggregation inhibition. When defined as 5 µmol/L ADP, peak platelet aggregation was inhibited by almost 50% in group C compared with about 30% in group A (P=0.0002) and <30% in group B (P=0.0001). When aggregation was determined by 20 µmol/L ADP, group C had >40% inhibition compared with 20% and 25% for groups A and B (P<0.0001).

Similar differences favouring the group C regimen were observed in the secondary end points, including inhibition of late aggregation (P<0.0001 for all comparisons) and post-PCI aggregation (P=0.0005 to P<0.0001). Significantly fewer patients in group C were clopidogrel-resistant (P=0.002 to P=0.0003). No patient in any of the groups had major bleeding complications during the first 30 days and the incidence of minor bleeding events was similar in all three cohorts.

As Dr. L’Allier acknowledged, the study was underpowered to detect meaningful differences in clinical events. Nonetheless, the data clearly demonstrated that a 600-mg double loading dose inhibits platelet aggregation significantly better than either of the other two regimens and does so with no increase in bleeding complications and with significantly fewer nonresponders. Dr. L’Allier and colleagues concluded that the 600-mg double loading dose should become the reference standard for future clinical trials.

Refining Antiplatelet Therapy in PCI

A retrospective review of data from a large clinical trial sought to determine the optimal timing and loading dose of clopidogrel prior to PCI. Current AHA/ACC guidelines recommend 300 mg administered at least six hours before intervention. However, as Dr. Herbert Aranow, University of Michigan, Ann Arbor, noted, clopidogrel doses >300 mg are associated with higher plasma concentrations of the compound and its active metabolite, as well as greater platelet inhibition.

Dr. Aranow also pointed out that several small randomized clinical trials have shown that a 600-mg pre-PCI loading dose of clopidogrel is associated with fewer post-PCI ischemic events compared with a 300-mg dose. Unfortunately, little real-world data are available to evaluate the relationship between the loading dose and short-term clinical outcomes.

Dr. Aranow presented findings from a data analysis on patients enrolled in a US National Heart, Lung and Blood Institute PCI registry in 2004 and 2006. All patients received either 300 mg or 600 mg clopidogrel no more than 24 hours before PCI. The analysis included 187 patients who received 300 mg and 202 who received 600 mg. The primary end points were all-cause mortality, MI, repeat revascularization and recurrent coronary ischemia.

Data on in-hospital outcomes showed that the 600-mg dose significantly reduced the incidence of MI (P=0.003) and recurrent ischemia (P=0.023) compared with the 300-mg dose. The rate of bleeding complications did not differ between the two groups. The 30-day outcomes revealed a significant advantage for the 600-mg dose with respect to MI (P=0.002) and the composite of death and MI (P=0.007).

Patients treated with the higher dose also trended toward a low rate of the composite end point of death and revascularization (P=0.087). Dr. Aranow concluded that the findings support the use of the 600-mg loading dose prior to PCI.

Antiplatelet Therapy in Elective Stenting

The optimal antiplatelet and anticoagulant strategy for elective coronary stenting remains controversial, as noted by Dr. Paul Gurbel, Sinai Hospital, Baltimore, Maryland. Many patients often receive only ASA and an anticoagulant.

Dr. Gurbel previously demonstrated that the addition of a GP IIb/IIIa inhibitor loading dose of clopidogrel/ASA at the time of stenting resulted in better platelet inhibition and less myocardial necrosis as compared with clopidogrel/ASA (Gurbel et al. Circulation 2005;111(9):1153-9).

At the AHA meeting, Dr. Gurbel reported findings from a study of elective stenting wherein patients received a GP IIb/IIIa inhibitor plus bivalirudin in addition to antiplatelet therapy with clopidogrel/ASA. The principal objective of the 200-patient study was to determine the impact on periprocedural MI. Those with no prior exposure to clopidogrel received a loading dose of 600 mg, whereas patients already on 75 mg/day maintenance therapy received no loading dose. All patients received ASA 325 mg and bivalirudin 1 mg/kg bolus followed by 2.5 mg/kg/hr. They were randomized to eptifibatide or no further antiplatelet therapy.

The results showed that the addition of a GP IIb/IIIa inhibitor to bivalirudin resulted in more efficacious platelet inhibition and reduced platelet/fibrin clot strength. The study also supported a previously recognized association between platelet reactivity and post-stent infarction. Dr. Gurbel concluded that use of a GP IIb/IIIa inhibitor should be targeted to patients who have high platelet reactivity despite clopidogrel therapy.

Antiplatelet Plus Anticoagulant Therapy

The safety of antiplatelet therapy with ASA and clopidogrel in patients on chronic oral anticoagulation had not been evaluated extensively. Dr. Alaide Chieffo, San Raffaele Hospital, Milan, Italy, and colleagues examined the issue in 127 patients with 224 coronary lesions treated by PCI and stent implantation. Atrial fibrillation was the principal indication for chronic warfarin therapy, accounting for 59% of the patients.

The mean duration of triple therapy was 5.6 months and mean follow-up was 21 months. During triple therapy, 7.1% of patients had bleeding events, including major bleeding complications in 4.7% of patients. Two-thirds of major bleeding events occurred within the first month of starting therapy and half of the major bleeds were fatal. The incidence of major and minor bleeding incidents did not differ by stent type (drug-eluting or bare-metal), nor did mortality. Patients with drug-eluting stents did require significantly fewer target vessel revascularization procedures (14.1% vs. 28.3%, P=0.041).

On the basis of these findings, investigators concluded that the optimal antiplatelet strategy remains unclear for patients undergoing PCI with stent implantation and requiring chronic oral anticoagulation.

Is More Better?

South Korean investigators reported findings from a study comparing standard clopidogrel (300 mg) plus ASA therapy and triple therapy with the addition of cilostazol after implantation of a drug-eluting stent in diabetic patients with coronary artery disease. Cilostazol is a type 3 phosphodiesterase inhibitor that has been shown to reduce smooth muscle proliferation and intimal hyperplasia after stent implantation. The agent also has reduced platelet aggregation and stent thrombosis after bare-metal stent implantation, according to Dr. Young-Hak Kim, Asan Medical Center, Seoul.

The study involved 400 patients with diabetes who were randomized to ASA 100 mg/day plus clopidogrel 75 mg/day at least six months after stent implantation or to same dual therapy plus cilostazol administered as a 200-mg dose immediately after stent placement, followed by maintenance cilostazol therapy at a dose of 100 mg b.i.d. for six months. All patients received a 300-mg loading dose of clopidogrel at least 24 hours before stent implantation.

The primary end point was late loss of in-stent diameter. In that respect, the data showed that the triple therapy was more effective than dual therapy (P=0.025). In-segment restenosis also occurred significantly less often with triple therapy (P=0.033) but not in-stent restenosis. Nine-month outcomes differed only with respect to target lesion revascularization, which was lower in the triple-therapy arm (P=0.034). Dr. Kim interpreted the findings as suggesting that the benefits of adding cilostazol to clopidogrel and ASA might reflect an inhibitor effect on neointimal hyperplasia.

Is Longer Better?

A recent analysis of data from a PCI registry suggested that continuation of thienopyridine antiplatelet therapy beyond one year may reduce the risk of death and MI in patients receiving drug-eluting coronary stents (Eisenstein et al. JAMA 2007;297(2):159-68). Dr. Gregg Stone, Cardiovascular Research Foundation, New York, and colleagues performed a similar analysis of data from the TAXUS II-SR, IV and V trials of paclitaxel-eluting stents.

The analysis involved a total of 2523 patients who were free of death, MI and stent thrombosis through year 1. Patients were grouped according to the type of stent they received (paclitaxel-eluting or bare-metal) and thienopyridine use at one year. The patients were then followed for three additional years.

Patients who were taking ASA plus clopidogrel at one year had no stent thrombosis events at four years compared with six events among patients who were not on thienopyridine therapy (P=0.045). The rate of death and MI did not differ at two or four years between patients with and without thienopyridine therapy. A trend toward a reduced risk of MI was observed at two years in patients who received paclitaxel-eluting stents and were on clopidogrel (P=0.08). However, the trend had disappeared by year 4.

The authors concluded that thienopyridine therapy use at one year was associated with fewer late stent-thrombosis events and the benefit was greater in patients who received paclitaxel-eluting stents. No sustained impact on death or MI was observed at four years, suggesting that routine continuation of thienopyridine therapy beyond one year in event-free patients is not currently supported.

Summary

The search continues for an optimal antiplatelet regimen for patients undergoing PCI. Studies reported here make it clear that combination clopidogrel/ASA will figure prominently in the search for the optimal strategy to prevent thrombotic complications of PCI. Data reported at the meeting also made a persuasive argument that a 600-mg double loading dose of clopidogrel offers improved platelet inhibition and prevention of associated clinical events as compared with the standard 300 mg + 75 mg regimen. The role of GP IIb/IIIa inhibitors in PCI continues to evolve but these agents also have a role, at least in selected patients. The role of emerging therapies, such as cilostazol, remains to be determined. Clinicians can find reassurance in the current agents and strategies and optimism for emerging approaches to preventing thrombotic complications in patients undergoing PCI.

Based on the oral session:

“Antiplatelet Therapy in PCI” Monday, November 5, 14:00-17:00, Room W415d (Valencia).