Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An <i>ex vivo</i> study

Bonhomme, Fanny; Bonvini, Robert F.; Reny, Jean-Luc; Poncet, Antoine; Fontana, Pierre

doi:10.3109/09537104.2015.1035247

Cited by 35 publications

(34 citation statements)

References 41 publications

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“…16 It indicates inhibition of the newly added platelets by residual drug metabolite and is in concordance with the findings of earlier studies that had different patient populations and testing methodologies, but assessment times identical or very close to the 4 and 6 hour time-points of our study. 11, 13 By 24 hours, the improvements attained from adding fresh platelets appear much more substantial. The residual drug metabolite concentration around this time is too low to significantly affect new platelets 16 and as a result, gains attained at 24 hours shift platelet function safely away from the cutoff associated with increased bleeding risk as per the Working Group on On-Treatment Platelet Reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…10 The possibility of normalizing platelet reactivity after ticagrelor therapy has also been investigated in a few small studies with mixed outcomes, ranging from no recovery at all, 11, 12 to some restoration of function. 13 Clopidogrel and prasugrel are members of thienopyridine class, binding irreversibly to the P2Y 12 receptor and exerting long acting inhibitory effects, whereas ticagrelor is the first member of the cyclo-pentyl-triazolo-pyrimidine class, with reversible binding and short-acting effects, hence the twice-daily administration.…”

Section: Introductionmentioning

confidence: 99%

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Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Zafar

Smith

Baber

et al. 2017

Circ: Cardiovascular Interventions

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Background ACC/AHA guidelines advise waiting 5-7 days before operating on P2Y12 inhibitor-treated ACS patients, to allow dissipation of its antiplatelet effects. Platelet transfusion is often used to restore hemostasis during operations but its effectiveness and optimal timing are unclear. We investigated the degree of functional gains obtained from platelet-supplementation after loading and maintenance dual antiplatelet therapy [DAPT]with ticagrelor, and the influence of timing on this strategy. Methods and Results Following baseline platelet testing (Multiplate® Analyzer and VerifyNow®), CVD patients (n=20, 56.9±7.9 years, 65% male, 75% diabetic) received DAPT as a single loading-dose [LD: ticagrelor 180mg plus aspirin 325mg] and as daily/maintenance treatment for 5-7 days [MT: ticagrelor 90mg b.i.d. plus aspirin 81mg q.d.]. At 4-, 6-, 24- and 48-hours from (last) dosing, patients’ blood samples were supplemented with concentrated platelets from healthy donors in vitro, raising platelet counts by 0% (un-supplemented ‘control’), 25%, 50% and 75%, and the function retested. Reactivity in supplemented samples was compared with respective 0% sample and with the pre-treatment baseline. Results under LD and MT regimens were nearly identical. Platelet reactivity was higher (p<0.05) in nearly all supplemented samples vs. respective controls. Aggregations with supplementation were 59%-79% of baseline at 24-hours, and equal to baseline at 48-hours. Conclusions Platelet reactivity of ticagrelor-treated patients can be restored using concentrated platelets after a loading-dose/maintenance-therapy in a time-dependent manner under in vitro testing. Although statistically significant improvements are evident 6 hours after (last) dosing, up to 24 hours maybe needed for clinically meaningful restoration in platelet function.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Zafar

Smith

Baber

et al. 2017

Circ: Cardiovascular Interventions

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“…As long as this is not the case, we have to take the data coming from (in vitro) studies such as APTITUDE 5 and others [6][7][8][9][10] as the best available evidence for guidance of patient treatment. Second, the comparatively low sample size for prasugrel-treated patients (n=6) and ticagrelor-treated patients (n=3) in the APTITUDE-CABG cohort precludes from drawing definite conclusions on the feasibility of immediate and sustained platelet restoration after platelet transfusion with these 2 agents.…”

Section: Sibbing and Massberg Restoring Platelet Function On Antiplatmentioning

confidence: 99%

“…Although the authors observed a partial restoration of platelet aggregation in patients on maintenance treatment with these drugs, other studies and case reports provided conflicting data. 6,7,[9][10][11] The complete inefficacy of platelet transfusions to reverse the antiplatelet action of ticagrelor was nicely highlighted in a case report of a patient with intracranial hemorrhage, where platelet reactivity levels remained virtually unchanged despite transfusion of 17 U of platelets. 7 Other reports provided similar results.…”

Section: Sibbing and Massberg Restoring Platelet Function On Antiplatmentioning

confidence: 99%

Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment

Sibbing

Maßberg

2015

Circ: Cardiovascular Interventions

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Dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 receptor inhibitor is the current mainstay of pharmacological treatment in both patients with stable coronary artery disease and acute coronary syndrome managed invasively by percutaneous coronary intervention (PCI). 1 The primary goal of DAPT is to reduce the risk of ischemic events including (re)-infarction and stent thrombosis. Contrary, this well-recognized ischemic benefit of DAPT is cut down by an increased on-treatment bleeding risk including major and fatal bleeding in both a nonoperative and operative setting like coronary artery bypass grafting (CABG).2,3 Bleeding risks differ for the currently available oral P2Y 12 receptor inhibitors. On the basis of the results of large-scale clinical trials and the clinical experience in recent years, we considered that the risk of bleeding to be modest for the second-generation thienopyridine clopidogrel, whereas more potent platelet inhibition, such as it is delivered by the third-generation thienopyridine prasugrel or the cyclo-pentyl-triazolo-pyrimidine ticagrelor, comes along with a substantially higher risk of bleeding. 2-4Immediate and sustained restoration of platelet function in patients on DAPT may become mandatory in a nonoperative setting with acute bleeding (eg, intracranial bleeding) or during cardiac and noncardiac surgery. From a pharmacological point of view, the ability to restore platelet function may differ for the irreversibly acting P2Y 12 receptor inhibitors clopidogrel and prasugrel when compared with the directacting reversibly binding antiplatelet agent ticagrelor. This is because of the circumstance that active metabolites of both clopidogrel and prasugrel exhibit a short plasma half-life and their binding to the P2Y 12 receptor is irreversible. Hence, transfused allogeneic platelet concentrates remain uninhibited in patients on thienopyridine maintenance treatment. In contrast and because of its pharmacological properties, ticagrelor and its active metabolite may inhibit fresh platelets after allogeneic platelet transfusion. ) and in an in vivo setting with allogeneic platelet transfusion in cardiac surgery patients on DAPT who had excessive bleeding during surgery (APTITUDE-CABG). As a key result of the APTITUDE-ACS study (n=59 patients), the authors were able to show that the level of restoration of platelet function by ex vivo administration of autologous platelet-rich plasma significantly decreased with increasing potency of the antiplatelet agent. In clopidogrel-treated patients, platelet function restoration was highest, whereas restoration was lower in prasugreltreated subjects and by comparison lowest in the subgroup of ticagrelor-treated patients. In APTITUDE-CABG (n=52 patients), platelet transfusion resulted in a significant 23% relative increase (42.2±23.6% platelet reactivity index [PRI] before transfusion versus 56.6±23.6% PRI after transfusion; P=0.008) of the VASP PRI and the primary study end point was met. Of note, for the merged subgroup of patients (n=9) treat...

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“…Hobl et al found that in vitro autologous platelets reversed the antiplatelet effect of ticagrelor as measured by whole blood multiple‐electrode aggregometry. However, most other studies found that autologous, donor, and pooled platelets had minimal effect on reversal of ticagrelor …”

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confidence: 96%

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

Zhang

Mei

et al. 2019

Transfusion

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BACKGROUND Reversal of antiplatelet therapy is desirable in patients presenting with life‐threatening bleeding or requiring urgent surgery. This study aimed to examine ticagrelor reversal using donor platelets and to explore the effects of residual ticagrelor on donor platelets. STUDY DESIGN AND METHODS In Cohort 1, 16 healthy subjects were treated with ticagrelor 90 mg twice daily alone or in combination with aspirin 100 mg once daily for 7 days followed by single blood sampling for preparation of platelet‐rich plasma. An additional 16 healthy subjects served as controls. In Cohort 2, 16 healthy subjects were treated with ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 7 days followed by serial blood samplings for preparation of platelet‐poor plasma (PPP). An additional 16 healthy subjects served as controls. RESULTS In Cohort 1, inhibition of adenosine diphosphate–induced platelet aggregation (PLADP) by ticagrelor could not be fully reversed by mixing with up to 90% control platelets, whereas inhibition of arachidonic acid–induced platelet aggregation by aspirin was fully reversed with the addition of 60% control platelets. In Cohort 2, 10% PPP obtained from ticagrelor‐treated subjects reduced PLADP from 74% to 40% at 2 hours, 72% to 58% at 6 hours, and 73% to 59% at 10 hours, while 10% or 20% PPP obtained from clopidogrel‐treated subjects did not inhibit PLADP. CONCLUSION The antiplatelet effect of ticagrelor cannot be fully reversed by donor platelets, which could be explained by the presence of active drug. The effect of residual drug on donor platelets appears to be evident for at least 10 hours after ticagrelor ingestion.

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Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Cited by 35 publications

References 41 publications

Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

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Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study

Cited by 35 publications

References 41 publications

Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Impact of Timing on the Functional Recovery Achieved With Platelet Supplementation After Treatment With Ticagrelor

Restoring Platelet Function in Patients on P2Y 12 Receptor Inhibitor Treatment

Reversal of the antiplatelet effect of ticagrelor by simulated platelet transfusion

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Product

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Restoring Platelet Function in Patients on P2Y ₁₂ Receptor Inhibitor Treatment