Meeting New Challenges with Antiplatelet Therapy in Primary Care

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Medical Education Library

Meeting New Challenges with Antiplatelet Therapy in Primary Care

June 2012 · Vol. 61, No. 06 Suppl: S22-S28

References

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Ticagrelor

Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).¹⁰

The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).^11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).¹¹ Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.

The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.¹⁰

Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.

TABLE 2

Ticagrelor: PLATO and subanalyses

	PLATO Cohort^9,12	PLATO Selected Subanalyses^13-16
Treatment	Ti 180 mg LD, then 90 mg BID or Cl 300-600 mg LD then 75 mg QD plus Aspirin 75-325 mg QD for 12 months
Population	ACS with/without ST elevation (N = 18,624)	ACS planned for non-invasive management (N = 5216)	ACS with ST elevation or left bundle branch block planned for PCI (N = 7544)	ACS with/without ST elevation managed with CABG (N = 1261)	ACS with/without ST elevation but with chronic kidney disease (eCrCl < 60 mL/min) (n = 3237)
Efficacy Outcomes	Primary end point (death from vascular causes, MI, or stroke): Cl 11.7% vs Ti 9.8% (P < .001) Death from any cause, MI, or stroke: Cl 12.3% vs Ti 10.2% (P < .001) Death from any cause, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event: Cl 16.7% vs Ti 14.6% (P < .001) Death from nonvascular causes: Cl 0.8% vs Ti 0.5% (P = .08)	Primary end point (death from vascular causes, MI, or stroke): Cl 14.3% vs. Ti 12.0% (P = .045) CV death: Cl 7.2% vs Ti 5.5% (P = .019)	Primary end point (death from vascular causes, MI, or stroke): Cl 10.8% vs Ti 9.4% (P = .07) CV death, MI (excluding silent): Cl 10.2% vs Ti 8.4% (P = .01) All cause death, MI (excluding silent), stroke: Cl 11.3% vs Ti 9.8% (P = .05) CV death, total MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, TIA, arterial thrombotic events: Cl 15.0% vs Ti 13.3% (P = .03) MI (excluding silent): Cl 5.8% vs Ti 4.7% (P = .03) Stroke: Cl 1.0% vs Ti 1.7% (P = .02) All-cause mortality: Cl 6.1% vs Ti 5.0% (P = .05) Definite, probable, or possible stent thrombosis: Cl 4.3% vs Ti 3.3% (P = .04)	Primary end point (death from vascular causes, MI, or stroke): Cl 13.1% vs Ti 10.6% (P = .29) All-cause death: Cl 9.7% vs Ti 4.7% (P < .01) CV death: Cl 7.9% vs Ti 4.1% (P < .01) Non-CV death: Cl 2.0% vs Ti 0.7% (P = .07) Stroke: Cl 2.1% vs Ti 2.1% (P = .70)	Primary end point (death from vascular causes, MI, or stroke): Cl 22.0% vs Ti 17.3% All-cause death: Cl 14.0% vs Ti 10.0%
Safety Outcomes	TIMI major bleeding^a: Cl 7.7% vs Ti 7.9% (P = .57) TIMI major bleeding^a unrelated to CABG: Cl 2.2% vs Ti 2.8% (P = .03) PLATO major bleeding^b: Cl 11.2% vs Ti 11.6% (P = .43) PLATO major bleeding^b unrelated to CABG: Cl 3.8% vs Ti 4.5% (P = .03) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.9% (P < .001)	PLATO major bleeding^b: Cl 10.3% vs Ti 11.9% (P = .079) Life-threatening/fatal bleeding: Cl 5.6% vs Ti 5.5% (P= . 911) Major/Minor bleeding unrelated to CABG: Cl 6.7% vs Ti 8.3% (P = .0182)	PLATO major bleeding: Cl 9.2% vs Ti 9.0% (P = .76) TIMI major bleeding: Cl 6.4% vs Ti 6.1% (P = .66) PLATO non-procedure-related major/ minor bleeding: Cl 3.7% vs Ti 5.1% (P = .02) PLATO minor bleeding: Cl 3.8% vs Ti 4.9% (P = .05) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.5% (P = .0004)	Major/Life-threatening CABG-related bleeding causing death within 7 d after CABG: Cl 3.0% vs Ti 1.3% (P = .052) Major CABG bleeding: Cl 80.1% vs Ti 81.2% (P = .669) TIMI major CABG bleeding: Cl 57.6% vs Ti 59.3% (P = .53)	PLATO major bleeding: Cl 14.3% vs Ti 15.1% PLATO fatal major bleeding: Cl 0.77% vs Ti 0.34% PLATO non-CABG major bleeding: Cl 7.3% vs Ti 8.5% Dyspnea: Cl 11.5% vs Ti 16.4%
Key Findings	Ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding; ticagrelor led to increased major bleeding unrelated to CABG. Fatal bleeding was low and did not differ between groups.	Consistent with the general PLATO population, ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding.	Consistent with the general PLATO population, compared with clopidogrel, ticagrelor reduced CV and all-cause death, MI, stent thrombosis and improved survival without increasing major bleeding. Ticagrelor resulted in a higher rate of stroke.	Ticagrelor compared with clopidogrel reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor.	In ACS with CKD, ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non-procedure- related bleeding.
ACS, acute coronary syndrome; BID, twice daily; CABG, coronary artery bypass graft; Cl, clopidogrel; CKD, chronic kidney disease; CV, cardiovascular; eCrCL, estimated creatinine clearance; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; QD, once daily; Ti, ticagrelor; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. ^aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). ^bPLATO major bleed (fatal bleeding, intrapericardial bleeding with cardiac tamponade, intracranial bleeding, severe hypotension, or hypovolemic shock due to bleeding and requiring either vasopressors or surgical intervention, a decline in hemoglobin of 5.0 g/dL or more after adjusting for red blood cell transfusions, or the need for transfusion of 4 or more units of packed red blood cells)