Benefit from long-term P2Y12 inhibitor for patients with a high-risk for stroke

M.P. Bonaca, S. Goto, D.L. Bhatt, et al.
Circulation. 2016 Aug 30. pii: CIRCULATIONAHA.116.024637. [Epub ahead of print]

Background

The majority of strokes are first events. Patients that experienced a stroke are at high risk for recurrence [1]. Strokes are often fatal or result in disability. It is therefore important to identify susceptible patients and to offer them preventative treatment. Vulnerable patients include, among others, patients with atrial fibrillation, uncontrolled hypertension or patients with symptomatic atherosclerosis including prior myocardial infarction (MI) [2].

The PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) tested the outcome on cardiovascular risk in patients with prior MI after giving ticagrelor in addition to aspirin. This revealed that 60 mg ticagrelor twice daily was well-tolerable and reduced the composite of cardiovascular death, MI or stroke by ~15% over long-term follow-up. Therefore, 60 mg ticagrelor became approved for long-term secondary prevention [3].

In this analysis, the incidence, predictors and subsequent outcomes of stroke were evaluated as well as the effect on the risk of stroke of adding long-term 60 mg ticagrelor and whether this was consistent with the results from trials in which intensive antiplatelet therapy had also been used for secondary prevention of coronary disease.
The PEGASUS-TIMI 54 trial included 21,162 patients comprising 14,112 patients with spontaneous MI 1 to 3 years before enrolment plus at least one additional high-risk factor, and that were now allocated to either placebo or 60 mg ticagrelor. Early in the course of the trial, observations of bleeding risks in other trials of different antiplatelet therapies in patients with known prior stroke resulted in an amendment to the protocol excluding these patients from PEGASUS-TIMI 54.

Main results

• After a median of 33-month follow-up, 213 patients experienced a stroke: 85% were ischemic, 8% haemorrhagic and 8% unknown.
• At baseline, patients that experienced a stroke during study follow-up were in general older, had a higher systolic blood pressure, had more frequently comorbidities and were more likely to have more extensive cardiovascular disease.
• Of the 85% patients that experienced a stroke, 87% of patients had residual disability at or beyond 24 hours, whereas 13% was asymptomatic but showed brain-imaging data of stroke.
• 85% of patients were hospitalized of which 14% did not survive and 12% of the living discharged patients were unable to return home, due to the high level of care they were depended on. Six months after discharge, 9% of patients that initially survived, died.
• Stroke of any kind was significantly reduced with the addition of ticagrelor compared to placebo (HR: 0.75, 95% CI: 0.57–0.98, P=0.034). This was driven by the reduction of ischemic stroke. Haemorrhagic stroke was infrequent and not significantly different between treatment groups.
• The reduction by ticagrelor addition of stroke that resulted in at least moderate disability or death corresponded to an HR of 0.57 (95% CI: 0.33-0.99, P=0.045) whereas less severe strokes with no or minimal disability corresponded to an HR of 0.81 (95% CI: 0.56-1.17, P=0.26).
• Ticagrelor increased TIMI major bleeding (HR 2.32, 95% CI: 1.68-3.21, P<0.001) but this was not statistically significant for intracranial haemorrhage (HR 1.33, 95% CI: 0.77-2.31, P=0.31) or fatal bleeding (HR 1.00, 95% CI: 0.44-2.27, P=1.00).
• Ticagrelor reduced the PEGASUS-TIMI 54 composite endpoint (HR 0.84, 95% CI: 0.74-0.95, P=0.0043) and all-cause mortality rates were not changed (HR 0.89, 95% CI: 0.76-1.04, P=0.14).
• A meta-analysis of 4 randomized, long-term, placebo-controlled trials that compared more with less intensive antiplatelet therapy (n=44,814 patients) demonstrated a 28% reduction in stroke in patients treated with more intensive therapy (HR 0.72, 95% CI: 0.60-0.85, P<0.001). The effect on reduction was more pronounced for ischemic stroke (34%) and there was no effect on haemorrhagic stroke.

Conclusion

Patients enrolled on the PEGASUS-TIMI 54 trial and at high risk for stroke but largely without a history of stroke had benefit from long-term secondary prevention with ticagrelor 60 mg twice daily in addition to low-dose aspirin, in terms of risk of stroke, in particular ischemic stroke. This was independent of severity scale. Furthermore, ticagrelor addition reduced the incidence of stroke that resulted in at least moderate persistent disability within 30 days after discharge. This long-term secondary prevention benefit of intensive antiplatelet treatment was consistent with the results found with other data sets that evaluated the effect of intensive antiplatelet strategies with regard to stroke reduction.

Find this article online at Circulation

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al, American Heart Association Statistics Committee, Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2016 Update: A Report From
the American Heart Association. Circulation. 2016;133:e38–e60.
2. Bhatt DL, Eagle KA, Ohman EM, et al, REACH Registry Investigators. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304:1350–1357. doi: 10.1001/jama.2010.1322.
3. Bonaca MP, Bhatt DL, Cohen M, et al, PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791–1800. doi: 10.1056/NEJMoa1500857.