Ticagrelor (2) – Brilique®

• Clinical trials
  • The PEGASUS-TIMI 54 trial was a completed, randomised, double-blind trial with three treatment arms, conducted on a multicentre basis in North and Latin America, Western and Eastern Europe, Asia, as well as in Australia and South Africa.

adult patients with a history of myocardial infarction and a high risk of developing an atherothrombotic event, for the prevention of atherothrombotic events

• In its summary assessment, the G-BA concludes that for ticagrelor in combination with ASA for the prevention of atherothrombotic events in adult patients with a history of myocardial infarction and a high risk of developing an atherothrombotic event, there is a hint of a minor additional benefit compared with the appropriate comparator, namely ASA monotherapy.
• The G-BA classifies the extent of the additional benefit of ticagrelor as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• mortality
  • All-cause mortality, cardiovascular mortality
  • For the endpoint of overall mortality (HR: 0.80, 95% CI [0.67; 0.96], p = 0.018), there was a statistically significant advantage of ticagrelor in combination with ASA.
  • This is mainly due to a difference in cardiovascular mortality (HR: 0.71, 95% CI [0.56; 0.90], p = 0.004).
  • The absolute effects on all-cause mortality (4.4% vs. 5.4%) and cardiovascular mortality (2.6% vs. 3.6%) are considered minor.
  • Overall, with regard to all-cause mortality, there is a minor additional benefit from ticagrelor in combination with ASA compared with the appropriate comparator therapy (ASA monotherapy).
• Morbidity – Cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke
  • For the composite endpoint comprising cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke, a statistically significant difference was observed in favour of ticagrelor in combination with ASA (HR: 0.80, 95% CI [0.70; 0.91], p = 0.001), which demonstrates a minor additional benefit of ticagrelor in combination with ASA.
• Morbidity – Myocardial infarction (fatal/non-fatal)
  • For the endpoint of myocardial infarction (fatal/non-fatal), there was a statistically significant advantage of ticagrelor in combination with ASA (HR: 0.83, 95% CI [0.70; 0.99], p = 0.041).
  • The additional benefit of ticagrelor for this endpoint is also considered to be minor.
• Morbidity – stroke (fatal/non-fatal)
  • For the endpoint of stroke (fatal/non-fatal), there is no statistically significant difference between the treatment groups.
  • However, there is a hint of an effect modification by the characteristic of age: for patients < 65 years (HR: 0.48, 95% CI [0.28; 0.81], p = 0.006; interaction: 0.055), there is an advantage of ticagrelor in combination with ASA, whilst for patients aged ≥ 65 years, no difference was observed between ticagrelor in combination with ASA and the appropriate comparator therapy (ASA monotherapy).
  • Overall, however, the reliability of the subgroup results is considered too minor to allow sufficiently robust conclusions to be drawn.
  • The additional benefit for this endpoint is therefore assessed on the basis of the entire relevant patient population and is thus considered not to have been proven.
• Morbidity – Health status (EQ-5D VAS)
  • For the health status endpoint (assessed using the EQ-5D VAS), no difference was observed between the treatment groups.
  • Consequently, the additional benefit of ticagrelor in combination with ASA compared with the appropriate comparator therapy for this endpoint is not proven.
  • The assessment is based on the analysis comprising all values recorded at the end of each patient’s treatment (‘End of Treatment’). This approach corresponds to the application of the Last Observation Carried Forward (LOCF) principle.
• Morbidity – Unstable angina pectoris; TIA
  • No significant difference was observed for either the endpoints of unstable angina pectoris or TIA.
  • The additional benefit is therefore not proven for these endpoints.
• quality of life
  • The health-related quality of life endpoint was not assessed.
• Side effects – Severe bleeding or clinically relevant non-severe bleeding
  • For the endpoint ‘severe bleeding or clinically relevant non-severe bleeding’ (all relevant bleeding events), a statistically significant effect was observed to the detriment of ticagrelor in combination with ASA (RR 2.55, 95% CI [2.22; 2.93], p < 0.001).
  • This results in a higher risk of harm, with a considerable extent, for ticagrelor in combination with ASA compared with the appropriate comparator therapy (ASA monotherapy).
• Side effects – Severe bleeding
  • For the endpoint of severe bleeding, a statistically significant effect was observed to the detriment of ticagrelor in combination with ASA (RR 2.46, 95% CI [1.82; 3.32], p < 0.001).
  • Furthermore, there is proof of an effect modification by the characteristic of multivessel CHD.
  • However, as a higher risk was observed for ticagrelor in combination with ASA compared with the appropriate comparator therapy (ASA monotherapy) in both patients with and without multivessel CHD, this effect modification has no impact on the overall result.
• Overall assessment
  • In the overall assessment of the results, an advantage of ticagrelor in combination with ASA, particularly with regard to all-cause mortality—primarily due to a difference in cardiovascular mortality— as well as advantages in the morbidity category for the composite endpoint comprising cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke, and for the endpoint of myocardial infarction (fatal/non-fatal), disadvantages in terms of side effects offset the advantages.
  • Disadvantages are derived in the category of serious side effects for the endpoint of severe bleeding.
  • However, an analysis of the underlying events for this endpoint shows that the effects are largely attributable to life-threatening or fatal events, some of which are already reflected in the all-cause mortality endpoint.
  • Overall, however, the negative effects do not entirely call into question the positive effects, particularly for the endpoint of all-cause mortality.
  • Compared with the appropriate comparator therapy, this represents, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, a moderate and not merely minor improvement in treatment-related benefit that has not previously been achieved, particularly as a moderate reduction in mortality is achieved.

Courtesy translation only, please refer to the German original.