Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial

Magnani G, Storey F, Steg G, et al.
Eur Heart J published 5 October 2015, 10.1093/eurheartj/ehv482

Background

Renal dysfunction is common among patients with ST segment elevation myocardial infarction (STEMI) and non-STEMI [1]. An inverse, graded association has been described between estimated glomerular filtration rate (eGFR) and major adverse cardiovascular (CV) events (MACE) [2]. Increased ischaemic risk in relation to renal dysfunction may be the result of accelerated atherosclerosis, inflammation, oxidative stress and a prothrombotic state [3]. Renal dysfunction is also connected to other CV risk factors including age, hypertension and diabetes, and bleeding risk. Platelet dysfunction, compounded by an increased risk of overdosing with some antithrombotic drugs, can lead to an association between worsening renal function and bleeding [4].
This makes the benefit-risk balance of chronic antithrombotic therapies in patients with prior MI and concomitant renal dysfunction a complex issue. Contradicting study results have been published about the benefit of platelet inhibition on patients with reduced renal function.
Ticagrelor is an oral P2Y12 receptor antagonist that provides more potent and less variable P2Y12 inhibition compared with clopidogrel. Ticagrelor had been shown to reduce CV death, MI or stroke in comparison with clopidogrel in patients with acute coronary syndrome [5].
In the PEGASUS-TIMI 54 trial, ticagrelor lowered MACE in stable outpatients with prior MI, while an increase in thrombolysis in MI (TIMI) bleeding was seen [6]. This study evaluates the relationship of ischaemic and bleeding risk with renal function and whether renal dysfunction modifies the efficacy and safety of ticagrelor.

Main results

• After adjusting for baseline characteristics, eGFR was an independent predictor of ischaemic risk (MACE through 3 years, in placebo group), notably when eGFR was below 60 ml/min/1.73mm2. Patients with eGFR<60 mL/min/1.73m2 had a higher risk of MACE than those with eGFR>60 mL/min/1.73m2 (adjHR: 1.54, 95%CI: 1.27-1.85, P<0.001).
• No difference in TIMI major bleeding was seen between those with eGFR<60 vs eGFR >60 (Adj HR: 1.19, 95%CI: 0.64-2.24, P=0.58), while risk of TIMI minor bleeding was higher in those with eGFR>60 (adj. HR: 3.02, 95%CI: 1.07-8.48, P=0.04).
• No interaction was seen between the relative MACE risk reduction obtained with ticagrelor (doses pooled) and eGFR <60 or >60 (P(interaction)=0.44), both in dichotomised analyses and when eGFR was considered as a continuous variable.
  Absolute risk reduction in MACE at 3 years was greater in patients with renal dysfunction (2.7%, 95%CI: 0.49-4.93) than in those without (0.63%, 95%CI: -0.32-1.57).
• Relative risk of TIMI major bleeding on ticagrelor did not differ between those with and without renal dysfunction (eGFR<60: HR: 1.98 vs. eGFR<60: HR: 2.65, P(interaction)=0.38). Absolute risk of TIMI major bleeding was similar in both eGFR categories.
  No interaction was seen between the relative risk of TIMI minor bleeding with ticagrelor and renal dysfunction , but the absolute increase was higher in those with eGFR<60 (1.93%) vs. eGFR>60 (0.68%).
• Ticagrelor did not increase the risk of renal adverse events, and no interaction was seen with eGFR category (P(interaction)=0.22)

Conclusion

In stable outpatients with a history of MI, renal dysfunction was an independent predictor of MACE. Relative reduction of MACE risk with ticagrelor was not affected by renal function. However, due to their higher ischaemic risk, patients with renal dysfunction showed a greater absolute MACE risk reduction when treated with ticagrelor.
The relative and absolute risk of TIMI major bleeding with ticagrelor did not differ between patients with or without renal dysfunction. A greater absolute risk of TIMI minor bleeding with ticagrelor was observed those with renal dysfunction.
This study extends previous observations in patients with a recent MI to stable outpatients

Find this article online at Eur Heart J

References

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