Physicians' Academy for Cardiovascular Education

DM subgroup analysis in PEGASUS-TIMI 54 trial shows significant MI risk reduction

Bhatt DL, et al. J Am Coll Cardiol 2016

Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS–TIMI 54


Bhatt DL, Bonaca MP, Bansilal S, et al.
J Am Coll Cardiol 2016;67:273240


Background

Diabetes mellitus (DM) patients with a history of myocardial infarction (MI) belong to a high-risk group and should be treated with more potent antiplatelet therapy for longer periods of time [1,2]. Clinical and observational data show that patients with DM and MI have additional benefit in terms of risk reduction from several antiplatelet regimens, including [3,4]:  
  • clopidogrel versus aspirin
  • intravenous glycoprotein inhibitors versus placebo
  • clopidogrel plus aspirin versus aspirin alone
  • prasugrel versus clopidogrel
  • ticagrelor versus clopidogrel
In part, this additional benefit can be explained by the higher absolute risk of these patients due to eg. their higher platelet reactivity, compared with patients without DM [5-7].
 
In 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), a significant reduction in the primary endpoint of cardiovascular (CV) death, MI, or stroke was observed in a subgroup of patients that corresponded to aspirin-treated patients with prior MI, randomised to ticagrelor (60 or 90 mg twice daily) versus placebo, beyond one year [8,9].
 
This study hypothesised that DM patients in PEGASUS-TIMI 54 might have higher absolute risk reductions, given their generally higher event rates. To test this, the DM subgroup of this trial was extensively examined for the effects of antiplatelet therapy by evaluating the major adverse cardiovascular events (MACE) in a pre-specified analysis.
 

Main results

DM patients had higher rates of ischemic events compared with patients without DM. The risk of ischemic events in the placebo arm for DM patients versus non-DM patients was:
  • MACE: 11.60% versus 7.83% (adjusted HR: 1.45; 95% CI: 1.22 - 1.73; P < 0.001)
  • CV death: 4.97% versus 2.64%
  • MI: 6.51% versus 4.66%
  • Stroke: 2.46% versus 1.70%
The relative risk reduction in MACE for the pooled ticagrelor doses versus placebo was:
  • for DM patients: n = 6,806; HR: 0.84; 95% CI: 0.72 - 0.99; P = 0.035
  • for non-DM patients: n = 14,355; HR: 0.84; 95% CI: 0.74 - 0.96; P = 0.013; P interaction = 0.99
 
DM patients were at higher risk of MACE, and had a greater absolute risk reduction compared with non-DM patients: 1.5% vs. 1.1%, with corresponding 3-year number needed to treat with ticagrelor (pooled doses) of 67 vs. 91.
 
In DM patients, ticagrelor significantly reduced:  
  • CV death by 22%; HR: 0.78; 95% CI: 0.61 - 0.99; P = 0.0495
  • CHD death by 34%; HR: 0.66; 95% CI: 0.48 - 0.91; P = 0.01
The HR with ticagrelor versus placebo for all-cause mortality was 0.86; 95% CI: 0.70 - 1.05; P = 0.15.
 
In type 2 DM patients treated with ticagrelor but requiring pharmacological therapy to treat diabetes (n = 5,960):
  • MACE event rates were reduced from 12.3% to 10.4% (HR: 0.82; 95% CI: 0.69 - 0.97; P = 0.019)
  • the absolute risk reduction was 1.9%
  • the 3-year number needed to treat was 53
In type 2 DM patients treated with insulin at baseline (n = 1,480), the rate of CV death, MI, or stroke was 16.9% in the pooled ticagrelor group and 18.2% in the placebo group (HR: 0.88; 95% CI: 0.67 - 1.15; P = 0.35).
 
Thrombolysis in Myocardial Infarction (TIMI) major bleeding was significantly increased with ticagrelor compared with placebo in:
  • DM patients: 2.56% vs. 0.98%; HR: 2.56; 95% CI: 1.52 - 4.33; P = 0.0004
  • non-DM patients: 2.39% vs. 1.09%; HR: 2.47; 95% CI: 1.73 - 3.53; P < 0.0001; P interaction = 0.89
There was no significant difference between ticagrelor and placebo in DM patients in the rate of fatal or intracranial bleeding: 0.62% vs. 0.63%; HR: 0.90; 95% CI: 0.42 - 1.90; P = 0.78.
 

Conclusion

In the PEGASUS-TIMI 54 trial, ticagrelor on top of aspirin significantly reduced the risk of recurrent ischemic events of which the absolute risk was higher in DM patients compared to non-DM patients, but increased the risk of TIMI major bleeding but not intracranial or fatal bleedings, in DM patients with a history of MI.
 

Editorial comment [10]

In his editorial article, Domanski discusses the implications of the PEGASUS-TIMI 54 and DM subgroup analysis on clinical decision making: ‘The PEGASUS-TIMI 54 study adds the additional insight that even for patients who had dual antiplatelet therapy stopped (doing so at 1 year being a common practice), restarting dual antiplatelet therapy is indicated. We also know that although significant bleeding is more common with dual antiplatelet therapy than with aspirin monotherapy, intracranial hemorrhage and hemorrhagic death are not statistically significantly increased. So, although there is a bleeding price to be paid for efficacy, catastrophic complications are not increased and even the increase is, numerically, strikingly modest.’ And he concludes: ‘There is a huge population of patients with diabetes and prior infarction and the report of Bhatt et al. extends the reassurance of data reported with the main study that this pre-specified subgroup of patients with diabetes derive benefit that is similar (in relative terms) to that enjoyed by other groups. Other high-risk subgroups could be explored in addition to this one (such as patients with renal insufficiency). More pertinent is whether there is any time threshold beyond which dual antiplatelet therapy does not provide additional benefit beyond that offered by aspirin monotherapy. Also of importance is whether there are lower-risk populations than those with prior MI that can be identified who do not now receive dual antiplatelet therapy but who would benefit from such treatment.’
 
Find this article online
Find this editorial online
 

References

1. Cavender MA, Steg PG, Smith SC Jr., et al. Impact of diabetes mellitus on hospitalization for heart failure, cardiovascular events, and death: outcomes at 4 years from the Reduction of Atherothrombosis for Continued Health (REACH) Registry. Circulation 2015;132:923–31.
2. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304:1350–7.
3. Bhatt DL. Antiplatelet therapy following myocardial infarction in patients with diabetes. JAMA 2012;308:921–2.
4. Udell JA, Bonaca MP, Collet JP, et al. Longterm dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J 2016;37:390–9.
5. Bhatt DL. What makes platelets angry: diabetes, fibrinogen, obesity, and impaired response to antiplatelet therapy? J Am Coll Cardiol 2008;52:1060–1.
6. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013;62:2261–73.
7. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005;54:2430–5.
8. Bonaca MP, Bhatt DL, Cohen M, et al. Longterm use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791–800.
9. Bonaca MP, Bhatt DL, Braunwald E, et al. Design and rationale for the 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 (PEGASUS–TIMI 54) trial. Am Heart J 2014;167:437–44.e5.
10. Domanski MJ. Dual Antiplatelet Therapy in the Prevention of Recurrent Ischemic Events. J Am Coll Cardiol 2016;67:2741-43