SWAP-5 - Pharmacodynamic and pharmacokinetic profiles of switching between cangrelor and ticagrelor following ticagrelor pre-treatment
Reported from AHA 2022
Daniele Giacoppo provides his take on SWAP-5, which was presented during AHA 2022 in Chicago.
Why this study? The rationale/objective
Cangrelor is an intravenous P2Y12 platelet receptor inhibitor with rapid, potent, and predictable anti-thrombotic effects and a short half-life. These favourable pharmacologic characteristics are particularly advantageous when a potent inhibition of the P2Y12 platelet receptor is required in P2Y12-naïve patients undergoing percutaneous coronary intervention (PCI), especially for ST-segment-elevation myocardial infarction (STEMI).
Cangrelor is currently approved for patients undergoing PCI who have not been pre-treated with an oral P2Y12 inhibitor.
Previous pharmacodynamics studies have shown that drug-drug interactions may reduce platelet inhibition in the periprocedural period, when an oral P2Y12 inhibitor is given during cangrelor infusion.
Since the active metabolites of thienopyridines - clopidogrel and prasugrel - have half-lives that do not exceed the duration of the recommended infusion of cangrelor, they are mostly cleared from the systemic circulation by the time the P2Y12 receptors become available for binding following discontinuation of cangrelor infusion. However, ticagrelor has a half-life of 6 to 12 hours and is still systemically available to bind with the P2Y12 receptors after discontinuation of cangrelor infusion.
The Cangrelor and Crushed Ticagrelor in STEMI Patients Undergoing Primary Percutaneous Coronary Intervention (CANTIC) trial showed for the first time that, in patients with STEMI undergoing primary PCI, crushed ticagrelor during cangrelor infusion was not associated with any apparent drug-drug interaction.
However, available evidence on the absence of drug-drug interaction between ticagrelor and cangrelor derives from patients receiving ticagrelor at the time of cangrelor initiation or during cangrelor infusion. Thus far, there is no data on the effects of cangrelor in patients pre-treated with ticagrelor.
Francesco Franchi, MD, of the University of Florida College of Medicine, Jacksonville, FL, United States, presented on November 7th, 2022, the main results of the Switching Antiplatelet Therapy-5 (SWAP-5) trial at the annual congress of the American Heart Association.
How was it executed? – the methodology
SWAP-5 was a prospective, randomized, double-blind, placebo-controlled, cross-over pharmacokinetics / pharmacodynamics trial conducted at the University of Florida Health Jacksonville, in which patients with stable coronary artery disease on low-dose aspirin (81 mg daily) for at least 1 month were randomly assigned in a 1:1 fashion to ticagrelor loading dose (180 mg) followed after 1 hour by cangrelor bolus (30 µg/kg) and infusion (4 µg/kg/min) for 2 hours, or ticagrelor loading dose (180 mg) followed after 1 hour by placebo bolus (30 µg/kg) and infusion (4 µg/kg/min) for 2 hours.
After completing the first phase, patients underwent a 1-4-week wash-out period and then crossed over to the alternative assignment in the second phase.
During each phase, pharmacokinetics and pharmacodynamics assessments were conducted at 7-time points: before ticagrelor loading dose, at the start of cangrelor / placebo bolus and infusion – 1 hour after ticagrelor loading dose, 30 minutes after cangrelor / placebo bolus, 1 hour after cangrelor / placebo bolus, 2 hours after cangrelor / placebo bolus – cangrelor infusion discontinuation, 1 hour after cangrelor infusion discontinuation, 2 hours after cangrelor infusion discontinuation.
Pharmacodynamics assessments were conducted using 4 different assays: VerifyNow system, with results as P2Y12 Reaction Units (PRU); light transmittance aggregometry (LTA) following adenosine diphosphate stimuli, with results as percentage maximum platelet aggregation (MPA); whole blood vasodilator-stimulated phosphoprotein (VASP), with results as percentage platelet reactivity index (PRI); total thrombus-formation analysis system (T-TAS), with results as area-under-the-curve (AUC). Pharmacodynamics assessments included the determination of the plasma concentration of ticagrelor and its major active metabolite.
The primary endpoint was the noninferiority of cangrelor and ticagrelor compared to cangrelor and placebo in terms of the difference in PRU (upper margin of the 95 % confidence interval of least square means below 45 PRU – noninferiority margin) as assessed 2 hours after stopping cangrelor / placebo infusion.
Key exclusion criteria included any active bleeding, high risk for bleeding, use of an oral P2Y12 receptor inhibitor or an oral anticoagulant in the prior 30 days, end-stage renal disease on haemodialysis, and known allergies to ticagrelor or cangrelor.
Patients, research staff, and laboratory personnel were blinded to treatment assignments. Masking and randomization of medications were performed by the institutional research pharmacy
What is the main result?
Between February 2021 and August 2021, a total of 22 patients were enrolled. Of these, two screens failed and 20 patients were randomized and received study medications. All 20 patients completed phase 1 of the study and 19 patients completed the second phase of the study.
Platelet reactivity as assessed by VerifyNow significantly decreased at 1 hour after ticagrelor loading dose and the addiction of cangrelor produced an additional significant reduction at 30 minutes (p = 0.001) and 1 hour (p = 0.005) after cangrelor bolus compared with placebo.
No differences between groups were observed later and 2 hours after stopping cangrelor / placebo PRU of ticagrelor plus cangrelor was noninferior to those of ticagrelor plus placebo (16.9 vs 12.6, least square means difference 4.3, 95 % confidence interval -28.6–37.3, psuperiority = 0.797).
Platelet reactivity assessed by LTA, VASP, and T-TAS showed consistent findings. MPA and PRI at 30 minutes and 1 hour were significantly lower in ticagrelor plus cangrelor than in ticagrelor plus placebo. AUC measured by T-TAS was lower in ticagrelor plus cangrelor than ticagrelor plus placebo at 30 minutes, while no significant differences between groups were observed at the other time points.
Plasma levels of ticagrelor and its major active metabolite were not significantly different between cangrelor and placebo groups across prespecified time points. Ticagrelor AUC0-last in patients assigned to cangrelor showed a 44 % significant increase compared to that of patients assigned to placebo.
Main points of strength and weakness of the study - Interview with Francesco Franchi, MD., the primary investigator
Introduction:
"Let's discuss the main results of the SWAP-5 trial in an interview with the primary investigator, Francesco Franchi, MD.
The SWAP-5 trial not only provides further data on the absence of drug-drug interaction between ticagrelor and cangrelor, but also suggests that cangrelor administration in patients pretreated with ticagrelor produces faster platelet inhibition. I think this finding of the SWAP-5 trial is unique, and open the debate on new therapeutic hypotheses that warrant validation in terms of clinical endpoints.
However, the SWAP-5 trial includes patients with stable coronary artery disease pretreated with ticagrelor. As you know, accrued evidence on antithrombotic strategies does not support the systematic administration of a potent P2Y12 inhibitor such as ticagrelor in patients with stable coronary artery disease and current guidelines do not recommend pretreating patients without STEMI with a P2Y12 inhibitor.In light of these considerations, the enrolment of patients with STEMI would have provided a more realistic setting, though that would have also unavoidably implied feasibility issues and higher heterogeneity. In aggregate, I have several questions for you on these considerations."
Question 1: First, do you believe that the results of the SWAP-5 trial can be safely translated to the STEMI setting?
Response - Francesco Franchi:
"The decision to include patients with stable coronary artery disease was not driven by the need for ensuring a timely assessment of blood samples. We sought to conduct a methodologically-rigorous cross-over pharmacokinetic / pharmacodynamic trial to provide definitive answers on drug-drug interaction in patients pretreated with ticagrelor receiving supplemental cangrelor bolus and infusion. In STEMI patients, the cross-over design would not be possible, lowering the ability to truly rule out a drug-drug interaction.
Moving on to the question, I do believe that the results of the SWAP-5 trial are reproducible in the STEMI setting. In agreement with previous evidence from the CANTIC trial, in which patients received cangrelor and ticagrelor at the same time, the SWAP-5 trial indicates that drug-drug interaction between cangrelor and ticagrelor can be safely excluded regardless of the clinical presentation.
This finding is extremely important when faster and more powerful platelet inhibition with oral and intravenous P2Y12 inhibitors is required to reduce the incidence of early thrombotic events. In particular, stent thrombosis has the highest incidence in the first hours following stent implantation and a proportion of events can be attributed to insufficient levels of platelet inhibitions after P2Y12 inhibitor loading dose administration."Question 2: Second, do you believe that cangrelor should be added after coronary angiography in patients without high bleeding risk conditions according to the thrombotic burden and anatomic pattern of coronary artery disease, or that co-administration of ticagrelor and cangrelor should be employed upfront in any STEMI?
Response - Francesco Franchi:
"Honestly, I do not think that the thrombotic burden and anatomic complexity of coronary artery disease should guide the decision of adding cangrelor in patients receiving pretreatment with loading dose ticagrelor. In patients with STEMI undergoing primary PCI, cangrelor supplementation may significantly reduce thrombotic events, regardless of the thrombotic burden or anatomic pattern of coronary artery disease. Stent thrombosis is a dramatic event that is known to occur with the highest incidence in the first hours following stent implantation."
Question 3: Finally, do you think there is room for a selective pretreatment with ticagrelor followed by cangrelor in patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) requiring emergency PCI?
Response - Francesco Franchi:
Daniele continues the interview with this observation:
"The highest benefit of a ticagrelor-cangrelor strategy was essentially confined to the first hour and, as you know, door-to-balloon time can be longer in daily clinical practice, with patients admitted for STEMI that undergo primary PCI after 1 hour since ticagrelor administration."
Question 4: What is the pragmatic implication of the time elapsed from ticagrelor pretreatment to cangrelor administration?
According to Francesco Franchi:
Daniele adds that a combined strategy of two potent P2Y12 receptor inhibitors is expected to increase the risk of bleeding.
"As you know, in recent times several investigations have highlighted the strong prognostic impact of bleeding events after PCI and different strategies to reduce the risk of bleeding have emerged."
Question 5: Against this background, what is the implication of a ticagrelor plus cangrelor strategy in terms of bleeding events?
Response - Francesco Franchi:
"Adding cangrelor to patients pretreated with ticagrelor unavoidably increase the risk of bleeding. However, radial access has significantly reduced the incidence of bleeding during PCI and the rapid offset of cangrelor effects after infusion discontinuation reduces the impact on major bleeding."
Question 6: Finally, I have a provocative question for you. The FABULOUS FASTER trial has recently shown that tirofiban antithrombotic effect onset was faster than cangrelor. What is in your opinion the advantage of cangrelor on top of ticagrelor compared with tirofiban supplementation? Do you believe that the different plasma half-life of the two drugs may confer a superior clinical safety profile to cangrelor compared with tirofiban?
Response - Francesco Franchi:
"The results of the FABOLOUS FASTER trial show platelet inhibition by cangrelor overall tend to be lower compared with those of the SWAP-5 and CANTIC trials. These differences warrant further analysis. Regardless of the pharmacodynamic differences between the trials, cangrelor presents a superior safety profile compared with tirofiban. As you mentioned, the short half-life of cangrelor is key in preventing bleeding events. In contrast, tirofiban effects last several hours with relevant implications when a major or life-threatening bleeding event occurs."
Conclusion:
"I think we can complete this interesting interview. Thank you very much for presenting your trial and providing clear answers to the discussion on these promising findings."
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