Prof. Giuseppe Tarantini, Chief of interventional Cardiology Unit - Associate Professor, University Medical school of Padua - GISE President speaks about Downstream or Upstream P2Y12 Receptor Blockers in NSTE-ACS: Primary Results of the DUBIUS Trial.
Link to Expert Analysis:
* In the case of various P2Y12 inhibitors, the available data on the clinical effect of pretreatment has been insufficient and heterogeneous.
* The DUBIUS (Downstream Vs Upstream Strategy for the Administration of P2Y12 Receptor Blockers in Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication) trial found that both downstream and upstream oral P2Y12 inhibitor administration strategies were correlated with low rates of ischemic and bleeding events and a small numeric disparity between treatment groups.
* The widespread use of a radial method may have led to the low adverse event rates observed.
A brief introduction
In patients with non-ST-segment elevation acute coronary syndrome, dual antiplatelet therapy with aspirin and an oral P2Y12 inhibitor is the preferred treatment (NSTE-ACS). Ticagrelor and prasugrel, among P2Y12 inhibitors, are associated with better clinical results in patients with the acute coronary syndrome (ACS) than clopidogrel and are therefore favored unless contraindicated. 1 The timing of P2Y12 inhibitor administration has been a point of contention in recent years. 2 Their use prior to coronary angiography (also known as pretreatment) may minimize periprocedural ischemic events in patients undergoing percutaneous coronary intervention (PCI), but it may also increase the risk of significant bleeding. Furthermore, the available data on the clinical effects of pretreatment has been sparse and inconsistent across various P2Y12 inhibitors. 2
The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial) and CREDO (Clopidogrel for the Reduction of Events During Observation) trials on clopidogrel inspired the idea of starting dual antiplatelet therapy early in patients with NSTE-ACS. However, a significant percentage of CURE patients did not have coronary angiography, and the median time between enrollment and angiography for those who were treated invasively was several days. Patients for the CREDO trial were chosen after an angiography examination of their coronary anatomy.
In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 18,624 patients with ACS were randomly assigned to receive ticagrelor or clopidogrel. The PLATO study presented evidence in support of early initiation of ticagrelor therapy based on the observed early gain of ticagrelor over clopidogrel in terms of ischemic events (without a rise in the rate of overall significant bleeding). The research medications, however, were given before coronary angiography, and the study did not look into the issue of pretreatment.
In TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38), 13,608 patients with ACS were randomly assigned to receive prasugrel or clopidogrel. Prasugrel decreased the number of ischemic cases, but it came with a higher risk of significant bleeding. Patients in this study, however, were given prasugrel after coronary angiography if the need for PCI was verified.
Pretreatment with prasugrel was explicitly tested in the ACCOAST analysis (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction). Before coronary angiography, a total of 4,033 patients were randomized to receive prasugrel (pretreatment group) or a placebo (control group). Pretreatment with prasugrel was linked to a higher risk of major bleeding without a reduction in major ischemic incidents after 30 days.
In the ISAR-REACT 5 study (Intracoronary Stenting and Antithrombotic Regimen 5) 4,018 patients with ACS were randomly assigned to receive either ticagrelor or prasugrel.
3 The loading dose for the ticagrelor community was given as soon as possible after randomization. The loading dose was given as soon as possible in patients with ST-segment elevation ACS (41%) and after coronary anatomy was known in patients with NSTE-ACS in the prasugrel community. At one year, prasugrel substantially decreased ischemic events without raising the rate of serious bleeding. Because of the research nature, both the study drugs and the administration approach may have had a mixed impact on the observed outcomes.
Design of the DUBIUS Trial Study
The DUBIUS trial was a multicenter, randomized, adaptive, open-label trial that compared downstream and upstream oral P2Y12 inhibitor administration strategies in patients with NSTE-ACS who were undergoing invasive treatment.
4,5 patients were randomly allocated to receive ticagrelor or no ticagrelor before angiography (upstream group) (downstream group). All patients undergoing PCI were randomized to receive either ticagrelor or prasugrel in the downstream community.
In terms of net clinical gain on ischemic and haemorrhagic cases, the primary hypothesis was that the downstream administration strategy would be superior to the upstream administration strategy. At 30 days after randomization, the primary outcome was a combination of death from vascular causes (death from cardiovascular or cerebrovascular causes, and any death without another known cause), nonfatal myocardial infarction, or nonfatal stroke, and serious or fatal bleeding (BARC types 3, 4, and 5)
The DUBIUS Trial's Primary Findings
From December 2015 to May 2020, 1,449 patients were randomized from 30 Italian centers. The occurrence of the primary endpoint was measured at the second interim review. The steering committee agreed to halt enrollment for a futility scenario based on a predetermined stopping law. The research arms is well-balanced in terms of patient characteristics. Both groups had a median GRACE score of 122, and the downstream group had a median CRUSADE score of 22 and the upstream group had a median CRUSADE score of 21. More than 99 percent of patients had coronary angiography (median time: 23.3 hours), with the radial approach being the most common (94.5 percent of patients). In 72 percent of patients, PCI was used for revascularization, while coronary artery bypass graft was used in 6%. In 22% of patients, no revascularization was required.
The downstream and upstream classes had no variations in the rate of the primary endpoint (2.9 percent and 3.3 percent, respectively; absolute risk reduction –0.46; 95 percent confidence interval, –2.87 to 1.89). Significant or fatal bleedings were the most common adverse events, with no variations between categories. The timing of coronary angiography (within or after 24 hours of enrollment) and treatment with or without PCI had no effect on the results. In an exploratory study, the incidence of the primary endpoint did not vary substantially between patients treated with prasugrel and those treated with ticagrelor in the PCI subgroup of the downstream arm (4.1 percent and 3.1 percent, respectively; absolute risk reduction 0.9; 95 percent confidence interval, –3 to 5).
The DUBIUS trial is the first to investigate the effects of ticagrelor pretreatment in patients with NSTE-ACS. Owing to the unlikelihood of detecting an advantage of one approach over the other with continued enrollments, the DUBIUS trial was prematurely stopped after an interim review due to a futility scenario. The DUBIUS trial found that both a downstream treatment approach with an oral P2Y12 inhibitor (prasugrel or ticagrelor) and a ticagrelor-based pretreatment strategy were correlated with low rates of ischemic and bleeding incidents in patients with NSTE-ACS who are undergoing scheduled invasive treatment. Several factors, including early coronary angiography and revascularization, very high rates of radial approach, and widespread adoption of secondary prevention steps, may have led to the trial's low adverse event rates.
Summary In patients with NSTE-ACS receiving early invasive care, both downstream and upstream oral P2Y12 inhibitor administration methods were linked to a low incidence of ischemic and bleeding events, with little numeric difference between treatment classes. The widespread use of a radial method may have led to the low adverse event rates observed.