SISA

In the USA, about one of every five deaths is attributable to coronary artery disease (roughly one every minute, 450 000 a year).1 Reperfusion therapy is the foundation for effective management of patients with ST-segment elevation myocardial infarction (STEMI), and primary percutaneous coronary intervention (PCI) results in greater myocardial salvage, and lower mortality, reinfarction, recurrent ischaemia, and stroke than fibrinolytic therapy.2, 3 Increased use of interventional therapies has been strongly associated with a steady decline in the yearly incidence of death, cardiogenic shock, and heart failure in STEMI.4

Appropriate use of antiplatelet drugs can optimise outcomes after PCI, particularly in acute coronary syndromes, which are characterised by increased platelet activation. Aspirin and adequate preloading with the thienopyridine clopidogrel before PCI reduces the 30-day composite rates of cardiovascular death or myocardial infarction in patients with non-STEMI and STEMI needing revascularisation.5, 6 However, clopidogrel takes several hours to act, which limits the platelet inhibition achievable during primary PCI in STEMI in view of the emphasis on short door-to-balloon times.7 Furthermore, many patients have platelet hyporesponsiveness to clopidogrel, which has been associated with major adverse cardiovascular events and stent thrombosis.8 The delayed onset and wide variability in efficacy with clopidogrel suggest the need for more rapid and profound platelet inhibition. Prasugrel, a thienopyridine currently undergoing review by the US Food and Drug Administration, has a more rapid onset of action than clopidogrel and is significantly more potent, overcoming clopidogrel-related platelet resistance in almost all patients.9, 10 However, the inherent risk of increased platelet inhibition is bleeding, which has been strongly linked to mortality after PCI, especially in patients with STEMI.11, 12

In The Lancet today, Gilles Montalescot and colleagues13 report a prespecified analysis from two somewhat heterogeneous STEMI subgroups of the TRITON-TIMI 38 trial. One group included 2438 patients with evolving myocardial infarction reperfused within 12 h of symptom onset (true primary PCI), and the other included 1094 patients in whom PCI was done within 14 days of myocardial infarction for ongoing or recurrent ischaemia or as part of a routine invasive strategy (secondary PCI). Of all STEMI patients who were randomised, prasugrel (compared with clopidogrel) resulted in significant reductions in the 30-day rates of all-cause and cardiovascular death, myocardial infarction, and stent thrombosis, without significant differences in bleeding. Between 30 days and 15 months, the rates of death, myocardial infarction, and stent thrombosis were similar in both groups. After 15 months, rates of myocardial infarction and stent thrombosis remained significantly reduced with prasugrel, although there were no significant differences in all-cause or cardiovascular death between the groups. More episodes of major and minor bleeding accumulated between 1 and 15 months in the prasugrel group, especially bleeding related to coronary-artery bypass grafting, similar to that seen in the entire TRITON study population.14

It is important to note that no significant interactions were seen between STEMI versus NSTEMI presentation and prasugrel versus clopidogrel randomisation on the major efficacy or safety endpoints. Therefore, because the STEMI subgroup was underpowered for stand-alone conclusions, the effect of prasugrel on both ischaemia suppression (efficacy) and haemorrhagic complications (safety) should be deemed similar in the patients with STEMI and NSTEMI enrolled in TRITON, unless larger studies show otherwise.

This latest TRITON-TIMI 38 report has several limitations. The protocol specified prasugrel randomisation against a 300 mg clopidogrel loading dose rather than the more rapidly acting and more potent 600 mg dose, which is now considered standard-of-care for primary PCI (but was not at the time when TRITON was designed). Similarly, most patients in the secondary PCI group probably did not achieve the benefits of adequate clopidogrel preloading before intervention. These limitations are not idle academic musings; the size of the 30-day reduction in major adverse cardiovascular events in TRITON with prasugrel compared with clopidogrel was similar to that seen with adequate clopidogrel loading compared with placebo in the PCI-CURE and PCI-CLARITY studies.5, 6

Colour-enhanced angiogram of heart showing stenosis in a coronary artery

Despite these caveats, the lessons and clinical implications from TRITON are clear, and apply equally to the patients with STEMI and NSTEMI. The accelerated and more profound inhibition of the platelet surface-membrane P2Y12 receptor with prasugrel compared with clopidogrel results in a substantial incremental reduction in ischaemic cardiovascular complications (especially myocardial infarction) and an impressive reduction in stent thrombosis after PCI.15 Offsetting these benefits is the potential for serious and occasionally fatal haemorrhagic complications, resulting in an all-cause mortality that is similar with both agents. The clear challenge ahead is to identify those patients at low-to-intermediate risk of bleeding (or at high risk of atherothrombotic events) who will benefit from prasugrel without haemorrhagic complications.

An alternative strategy might be to use full-dose prasugrel in the periprocedural period for 30 days, when the rate of ischaemic complications is highest and when the greatest absolute and relative benefits of prasugrel have been seen. This step could be followed by chronic use of reduced-dose prasugrel or standard-dose clopidogrel, when most of the haemorrhagic complications with full-dose prasugrel occurred. However, these switch regimens cannot currently be recommended until formally investigated. Point-of-care platelet-function testing to tailor thienopyridine selection or dosing is also appealing but untested.

TRITON-TIMI 38 shows that additional freedom from major adverse ischaemic events is possible in patients with acute coronary syndromes undergoing PCI through more profound platelet inhibition, and also provides a tantalising glimpse that balancing ischaemic and haemorrhagic risk through careful selection of patients and personalised pharmacotherapy should result in improved outcomes for patients with cardiovascular disease. The art of clinical decision making has never been more essential.

GWS has received research support from The Medicines Company, Boston Scientific, and Abbott Vascular; and honoraria from Eli Lilly.

References

1 American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics' 2008 update. Circulation 2008; 117: e25-e146.

2 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13-20.

3 Stone GW. Angioplasty strategies in ST-segment-elevation myocardial infarction: part I: primary percutaneous coronary intervention. Circulation 2008; 118: 538-551.

4 Fox KAA, Steg PG, Eagle KA, et alfor the GRACE Investigators. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA 2007; 297: 1892-1900.

5 Mehta SR, Yusuf S, Peters RJ, et alfor the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.

6 Sabatine MS, Cannon CP, Gibson CM, et alfor the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294: 1224-1232.

7 Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564.

8 Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000.

9 Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30.

10 Wiviott SD, Trenk D, Frelinger AL, et alfor the PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932.

11 Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.

12 Stone GW, Witzenbichler B, Guagliumi G, et al HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.

13 Montalescot G, Wiviott SD, Braunwald E, et alfor the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.

14 Wiviott SD, Braunwald E, McCabe CH, et alfor the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.

15 Wiviott SD, Braunwald E, McCabe CH, et alfor the TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 371: 1353-1363.

Author	Gregg W Stone
Title	Ischaemia versus bleeding: the art of clinical decision-making
Full source	Lancet 2009;373:695 - 696
Text	In the USA, about one of every five deaths is attributable to coronary artery disease (roughly one every minute, 450 000 a year).1 Reperfusion therapy is the foundation for effective management of patients with ST-segment elevation myocardial infarction (STEMI), and primary percutaneous coronary intervention (PCI) results in greater myocardial salvage, and lower mortality, reinfarction, recurrent ischaemia, and stroke than fibrinolytic therapy.2, 3 Increased use of interventional therapies has been strongly associated with a steady decline in the yearly incidence of death, cardiogenic shock, and heart failure in STEMI.4 Appropriate use of antiplatelet drugs can optimise outcomes after PCI, particularly in acute coronary syndromes, which are characterised by increased platelet activation. Aspirin and adequate preloading with the thienopyridine clopidogrel before PCI reduces the 30-day composite rates of cardiovascular death or myocardial infarction in patients with non-STEMI and STEMI needing revascularisation.5, 6 However, clopidogrel takes several hours to act, which limits the platelet inhibition achievable during primary PCI in STEMI in view of the emphasis on short door-to-balloon times.7 Furthermore, many patients have platelet hyporesponsiveness to clopidogrel, which has been associated with major adverse cardiovascular events and stent thrombosis.8 The delayed onset and wide variability in efficacy with clopidogrel suggest the need for more rapid and profound platelet inhibition. Prasugrel, a thienopyridine currently undergoing review by the US Food and Drug Administration, has a more rapid onset of action than clopidogrel and is significantly more potent, overcoming clopidogrel-related platelet resistance in almost all patients.9, 10 However, the inherent risk of increased platelet inhibition is bleeding, which has been strongly linked to mortality after PCI, especially in patients with STEMI.11, 12 In The Lancet today, Gilles Montalescot and colleagues13 report a prespecified analysis from two somewhat heterogeneous STEMI subgroups of the TRITON-TIMI 38 trial. One group included 2438 patients with evolving myocardial infarction reperfused within 12 h of symptom onset (true primary PCI), and the other included 1094 patients in whom PCI was done within 14 days of myocardial infarction for ongoing or recurrent ischaemia or as part of a routine invasive strategy (secondary PCI). Of all STEMI patients who were randomised, prasugrel (compared with clopidogrel) resulted in significant reductions in the 30-day rates of all-cause and cardiovascular death, myocardial infarction, and stent thrombosis, without significant differences in bleeding. Between 30 days and 15 months, the rates of death, myocardial infarction, and stent thrombosis were similar in both groups. After 15 months, rates of myocardial infarction and stent thrombosis remained significantly reduced with prasugrel, although there were no significant differences in all-cause or cardiovascular death between the groups. More episodes of major and minor bleeding accumulated between 1 and 15 months in the prasugrel group, especially bleeding related to coronary-artery bypass grafting, similar to that seen in the entire TRITON study population.14 It is important to note that no significant interactions were seen between STEMI versus NSTEMI presentation and prasugrel versus clopidogrel randomisation on the major efficacy or safety endpoints. Therefore, because the STEMI subgroup was underpowered for stand-alone conclusions, the effect of prasugrel on both ischaemia suppression (efficacy) and haemorrhagic complications (safety) should be deemed similar in the patients with STEMI and NSTEMI enrolled in TRITON, unless larger studies show otherwise. This latest TRITON-TIMI 38 report has several limitations. The protocol specified prasugrel randomisation against a 300 mg clopidogrel loading dose rather than the more rapidly acting and more potent 600 mg dose, which is now considered standard-of-care for primary PCI (but was not at the time when TRITON was designed). Similarly, most patients in the secondary PCI group probably did not achieve the benefits of adequate clopidogrel preloading before intervention. These limitations are not idle academic musings; the size of the 30-day reduction in major adverse cardiovascular events in TRITON with prasugrel compared with clopidogrel was similar to that seen with adequate clopidogrel loading compared with placebo in the PCI-CURE and PCI-CLARITY studies.5, 6 Colour-enhanced angiogram of heart showing stenosis in a coronary artery Despite these caveats, the lessons and clinical implications from TRITON are clear, and apply equally to the patients with STEMI and NSTEMI. The accelerated and more profound inhibition of the platelet surface-membrane P2Y12 receptor with prasugrel compared with clopidogrel results in a substantial incremental reduction in ischaemic cardiovascular complications (especially myocardial infarction) and an impressive reduction in stent thrombosis after PCI.15 Offsetting these benefits is the potential for serious and occasionally fatal haemorrhagic complications, resulting in an all-cause mortality that is similar with both agents. The clear challenge ahead is to identify those patients at low-to-intermediate risk of bleeding (or at high risk of atherothrombotic events) who will benefit from prasugrel without haemorrhagic complications. An alternative strategy might be to use full-dose prasugrel in the periprocedural period for 30 days, when the rate of ischaemic complications is highest and when the greatest absolute and relative benefits of prasugrel have been seen. This step could be followed by chronic use of reduced-dose prasugrel or standard-dose clopidogrel, when most of the haemorrhagic complications with full-dose prasugrel occurred. However, these switch regimens cannot currently be recommended until formally investigated. Point-of-care platelet-function testing to tailor thienopyridine selection or dosing is also appealing but untested. TRITON-TIMI 38 shows that additional freedom from major adverse ischaemic events is possible in patients with acute coronary syndromes undergoing PCI through more profound platelet inhibition, and also provides a tantalising glimpse that balancing ischaemic and haemorrhagic risk through careful selection of patients and personalised pharmacotherapy should result in improved outcomes for patients with cardiovascular disease. The art of clinical decision making has never been more essential. GWS has received research support from The Medicines Company, Boston Scientific, and Abbott Vascular; and honoraria from Eli Lilly. References 1 American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics' 2008 update. Circulation 2008; 117: e25-e146. 2 Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361: 13-20. 3 Stone GW. Angioplasty strategies in ST-segment-elevation myocardial infarction: part I: primary percutaneous coronary intervention. Circulation 2008; 118: 538-551. 4 Fox KAA, Steg PG, Eagle KA, et alfor the GRACE Investigators. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA 2007; 297: 1892-1900. 5 Mehta SR, Yusuf S, Peters RJ, et alfor the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533. 6 Sabatine MS, Cannon CP, Gibson CM, et alfor the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294: 1224-1232. 7 Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005; 111: 2560-2564. 8 Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29: 992-1000. 9 Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008; 29: 21-30. 10 Wiviott SD, Trenk D, Frelinger AL, et alfor the PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation 2007; 116: 2923-2932. 11 Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782. 12 Stone GW, Witzenbichler B, Guagliumi G, et al HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230. 13 Montalescot G, Wiviott SD, Braunwald E, et alfor the TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731. 14 Wiviott SD, Braunwald E, McCabe CH, et alfor the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015. 15 Wiviott SD, Braunwald E, McCabe CH, et alfor the TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008; 371: 1353-1363.