Antithrombotic Outcome Trials in ACS
Antithrombotic Outcome Trials in ACS
The optimal antithrombotic regimen should achieve the greatest reduction in thrombotic events at the lowest bleeding risk. This balance is often difficult to achieve because efficacy and safety are related to the same pharmacodynamic effect. It is further complicated by the limited ability to compare data across studies. These concepts are illustrated using several relevant clinical trials.
In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial, TIMI major bleeding not related to CABG was increased with prasugrel when compared with clopidogrel (Supplementary material online, FigureS1a, Table 2 and Table 3). Further analysis revealed a statistically significant increased risk of life-threatening bleeding with prasugrel that was driven by fatal and spontaneous non-fatal events. In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, there was no difference in major bleeding between groups. However, this included and was dominated by bleeding related to CABG. When the bleeding criteria used in the TRITON-TIMI 38 study were applied to PLATO (i.e. excluding CABG-related bleeding), statistically significant increases in bleeding and fatal intracranial bleeding were noted with ticagrelor (Supplementary material online, Figure S1a).
In both trials, death from vascular causes, MI or stroke was lower in patients randomized to prasugrel or ticagrelor when compared with clopidogrel (Supplementary material online, Figure S1b, Table 2 and Table 3). Myocardial infarction (both spontaneous and procedure related) was the main contributor to the primary endpoint in both studies (Table 2 and Table 3).
In ATLAS ACS 2-TIMI 51, rivaroxaban was associated with absolute increases in TIMI major non-CABG bleeding of 1.2% (2.5 mg) and 1.8% (5 mg) compared with placebo, and a 0.2% (2.5 mg b.i.d.) and 0.5% (5 mg b.i.d.) absolute increase in intracranial bleeding. Absolute reductions of 1.8% in the primary composite endpoint (cardiovascular death, MI, or stroke), 0.8% in all-cause mortality and 1.1% in MI were also observed (Table 2 and Table 3). The exact balance between risks and benefits is uncertain due to incomplete follow-up in some patients, which caused the FDA to withhold the approval of rivaroxaban for an ACS indication pending further data.
Although definite conclusions cannot be drawn from post hoc analyses of individual components of bleeding or thrombotic outcomes that occur with a low frequency, the importance of evaluating the totality of evidence becomes clear. Clinically meaningful increases or decreases in specific thrombotic or bleeding events may be masked by an overall neutral composite result (e.g. overall bleeding composite is neutral but life-threatening or intracranial bleeding is increased). Similarly, a composite may be driven by a factor with a lower degree of clinical importance (e.g. small non-fatal MI), without effect on more important events, particularly mortality. For this reason, net clinical benefit composite endpoints are problematic, since each outcome is considered clinically equivalent, while this assumption is obviously incorrect. Similar to other types of composite endpoints, net clinical benefit composites can hide components that go in divergent directions. As with all composites, the components should be reported individually.
New methodologies are being developed to deal with these limitations of composite endpoints. One major limitation is that time-to-first event analyses do not consider subsequent events. Less clinically important events often occur first and count towards the endpoint (e.g. non-fatal MI), whereas subsequent, often more severe events, are disregarded. The win ratio approach to analysing composite endpoints gives greater priority to the more clinically important components, such as mortality. With this method, the most important component of the composite is determined. For example, in a composite of cardiovascular death, MI or stroke, cardiovascular death would be the most important component, followed by stroke, and then MI. Patients in the active treatment and control (or standard) treatment are matched using a risk score or risk stratification, and compared to determine which patient experienced a cardiovascular death first. If neither experienced a death, then they would be compared to determine who experienced a stroke first, and so on. The 'win ratio' is the number of matched pairs where patients on standard therapy had worse outcomes. An alternative unmatched 'win ratio' approach compares every active with every control patient using the same principles; this may be preferred if the basis of matching cannot be clearly defined in advance. Although more research is needed to validate this approach and to determine its acceptance by regulatory bodies, it is encouraging that more robust and insightful methods of analysing composite endpoints are on the horizon.
Determining Therapeutic Benefit and Risk Profiles
The optimal antithrombotic regimen should achieve the greatest reduction in thrombotic events at the lowest bleeding risk. This balance is often difficult to achieve because efficacy and safety are related to the same pharmacodynamic effect. It is further complicated by the limited ability to compare data across studies. These concepts are illustrated using several relevant clinical trials.
P2Y12 Inhibitors
In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) trial, TIMI major bleeding not related to CABG was increased with prasugrel when compared with clopidogrel (Supplementary material online, FigureS1a, Table 2 and Table 3). Further analysis revealed a statistically significant increased risk of life-threatening bleeding with prasugrel that was driven by fatal and spontaneous non-fatal events. In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, there was no difference in major bleeding between groups. However, this included and was dominated by bleeding related to CABG. When the bleeding criteria used in the TRITON-TIMI 38 study were applied to PLATO (i.e. excluding CABG-related bleeding), statistically significant increases in bleeding and fatal intracranial bleeding were noted with ticagrelor (Supplementary material online, Figure S1a).
In both trials, death from vascular causes, MI or stroke was lower in patients randomized to prasugrel or ticagrelor when compared with clopidogrel (Supplementary material online, Figure S1b, Table 2 and Table 3). Myocardial infarction (both spontaneous and procedure related) was the main contributor to the primary endpoint in both studies (Table 2 and Table 3).
Factor Xa Inhibitors
In ATLAS ACS 2-TIMI 51, rivaroxaban was associated with absolute increases in TIMI major non-CABG bleeding of 1.2% (2.5 mg) and 1.8% (5 mg) compared with placebo, and a 0.2% (2.5 mg b.i.d.) and 0.5% (5 mg b.i.d.) absolute increase in intracranial bleeding. Absolute reductions of 1.8% in the primary composite endpoint (cardiovascular death, MI, or stroke), 0.8% in all-cause mortality and 1.1% in MI were also observed (Table 2 and Table 3). The exact balance between risks and benefits is uncertain due to incomplete follow-up in some patients, which caused the FDA to withhold the approval of rivaroxaban for an ACS indication pending further data.
Although definite conclusions cannot be drawn from post hoc analyses of individual components of bleeding or thrombotic outcomes that occur with a low frequency, the importance of evaluating the totality of evidence becomes clear. Clinically meaningful increases or decreases in specific thrombotic or bleeding events may be masked by an overall neutral composite result (e.g. overall bleeding composite is neutral but life-threatening or intracranial bleeding is increased). Similarly, a composite may be driven by a factor with a lower degree of clinical importance (e.g. small non-fatal MI), without effect on more important events, particularly mortality. For this reason, net clinical benefit composite endpoints are problematic, since each outcome is considered clinically equivalent, while this assumption is obviously incorrect. Similar to other types of composite endpoints, net clinical benefit composites can hide components that go in divergent directions. As with all composites, the components should be reported individually.
New methodologies are being developed to deal with these limitations of composite endpoints. One major limitation is that time-to-first event analyses do not consider subsequent events. Less clinically important events often occur first and count towards the endpoint (e.g. non-fatal MI), whereas subsequent, often more severe events, are disregarded. The win ratio approach to analysing composite endpoints gives greater priority to the more clinically important components, such as mortality. With this method, the most important component of the composite is determined. For example, in a composite of cardiovascular death, MI or stroke, cardiovascular death would be the most important component, followed by stroke, and then MI. Patients in the active treatment and control (or standard) treatment are matched using a risk score or risk stratification, and compared to determine which patient experienced a cardiovascular death first. If neither experienced a death, then they would be compared to determine who experienced a stroke first, and so on. The 'win ratio' is the number of matched pairs where patients on standard therapy had worse outcomes. An alternative unmatched 'win ratio' approach compares every active with every control patient using the same principles; this may be preferred if the basis of matching cannot be clearly defined in advance. Although more research is needed to validate this approach and to determine its acceptance by regulatory bodies, it is encouraging that more robust and insightful methods of analysing composite endpoints are on the horizon.
