Inhibiting Platelets Aggregation

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Summary

Inhibiting Platelets Aggregation

Cangrelor and Elinogrel
Potential advantages of intravenous non-GPIIbIIIa blockers antiplatelet drugs may be appreciated in patients vomiting during the acute phase of ACS – patients unable to take oral therapy, need for rapid-onset or quick revesal of the drug action e.g. for bridge therapy to CABG interventions. Cangrelor is a new intravenous direct-acting P2Y₁₂ blocker characterised by almost immediate antiplatelet effect, a plasmatic half-life of 3–5 minutes and rapid restoration of platelet function just 1 hour after infusion cessation.³⁵ In the BRIDGE trial, 210 ACS or PCI patients planned for CABG were randomised to either Cangrelor or Placebo infusion after stopping ongoing P2Y₁₂ inhibitors. Cangrelor administration until 1–6 hours before CABG did not produce an excess in surgical bleeding compared with placebo (11.8 % versus 10.4 %; p=0.76), while maintaining effective antiplatelet action during the infusion.³⁶ In the CHAMPIONS-PHOENIX trial more than 11,000 patients scheduled for urgent or elective PCI were randomised to receive a 300–600 mg loading dose of clopidogrel or cangrelor infusion.³⁷ The primary endpoint, a composite of death, AMI, ischaemia-driven revascularisation and stent thrombosis at 48 hours after PCI, was significantly reduced in the cangrelor group (4.7 % versus 5.9 %, p=0.005) with no significant differences in the rate of major bleeding. Elinogrel is another reversible direct P2Y12 blocking agent available for both oral and intravenous administration. In the phase II INNOVATE-PCI trial³⁸ it was compared with clopidogrel in non-urgent PCI patients without relevant increase in major bleedings, but ad hoc phase III studies are still required to clarify its potential role in the clinical setting. Current ESC guidelines do not include specific recommendations for intravenous P2Y₁₂ blockers in ACS patients undergoing PCI.^4–6

Dual Antiplatelet Therapy
Although there is debate about the exact timing of administration of ADP-receptor blockers, the ESC recommends the initiation of dual antiplatelet therapy (DAPT) with ASA and a P2Y₁₂ inhibitor (ticagrelor, prasugrel or clopidogrel) as early as possible for both STEMI and NSTEMI patients, as previously detailed (Class:I; LOE:A). Unless contraindicated or discouraged by excessive risk of bleeding, DAPT should be maintained for 12 months.^4–6

Glycoprotein IIbIIIa inhibitors
As previously discussed, GP IIbIIIa binding to several adhesive molecules, such as fibrinogen, fibronectin, vitronectin and vWF, is a crucial step in aggregation and further platelet activation. Therefore, GPIIbIIIa was ‘destined’ to be the target of a class of promisingly powerful antiplatelet agents. The first to be developed was, indeed, a large chimeric murine/human monoclonal antibody with moderate immunogenic properties called abciximab,³⁹ which obtained US Food and Drug Administration (FDA) approval in 1994. Two years later a lower molecular weight cyclic-peptide drug based on extracts of snake venom (disintegrin, barbourin), acting as a competitive inhibitor for fibrinogen, was introduced with the name of eptifibatide.⁴⁰ The third approved GP IIbIIIa inhibitor (GPI) is tirofiban, a non-peptidic small-molecule compound containing an Arg-Gly-Asp sequence that binds to the receptor inactivating it.⁴¹ Early clinical trials supported the benefits of abciximab (EPIC⁴² and EPILOG⁴³), eptifibatide (IMPACT II⁴⁴ and ESPRIT⁴⁵) and tirofiban (PRISM⁴⁶ and PRISM- PLUS⁴⁷) for reduction of hard endpoints in urgent and elective PCI patients, at the price of an acceptable increment in bleedings. GPIs have been tested either in the context of early-revascularisation strategy or conservative approach. The PURSUIT trial⁴⁸ randomised 109⁴⁸ NTSE intermediate to high-risk patients to receive 180 μg/kg bolus and 1.3 or 2.0 μg/kg/min maintenance dose of eptifibatide or placebo over standard therapy with unfractioned heparin (UFH) and ASA. Around 60 % of the patients underwent invasive assessment with coronary angiography while around 40 % of the patients received mechanical revascularisation either with PCI or CABG. The composite primary endpoint of death and AMI was significantly reduced in high-dose eptifibatide patients up to 30 days (8.1 % versus 10.0 %; p=0.001), with a 31 % event reduction in patients treated with early (<72 hour) PCI (11.6 % versus 16.7 %; p=0.01). Bleeding was higher in the treatment group, with a significantly higher need for blood transfusion than in the placebo group (11.6 % versus 9.2 %), with no significant differences in stroke occurrence. The GUSTO IV-ACS trial⁴⁹ enrolled 7,800 NSTE patients not scheduled for PCI to either bolus plus 24 or 48 hours Abciximab infusion or placebo over standard treatment with ASA and unfractioned or low molecular weight heparin (LMWH). The study failed to demonstrate benefits of GPI in this medically treated population, showing similar rates of the composite endpoint of death or AMI at 30 days in the placebo, 24- or 48-hour abciximab infusion groups (8.0 % versus 8.2 % versus 9.1 %), and slightly increased bleeding risk. Conversely, in a meta-analysis of more than 31,000 patients with NSTE-ACS not routinely scheduled for early PCI, GPIs performed better than placebo in reducing death or AMI at 30 days (10.8 % versus 11.8 %; p=0.015).⁵⁰ Another meta-analysis of 6,458 patients with diabetes enrolled in the major GPI trials suggested potential survival benefits in this subgroup that, in contrast with the without diabetes cohort, showed a significant mortality reduction at 30 days in GPI-treated subjects (6.2 % versus 4.6 %; p=0.007).⁵¹

An important point regarding the management of GPIs was to clarify whether these drugs should be initiated as early as possible prior to PCI (upstream treatment) or in the cath lab after the visualisation of the coronary tree (downstream treatment). To answer this question two major trials were conducted: ACUITY-timing⁵² and EARLY- ACS.⁵³ In ACUITY-timing, 9,207 patients with NSTE-ACS were randomised to upstream or downstream strategy with any GPI, being 64 % of the overall population under thienopyridines prior to PCI. Despite non-significantly different rates of a composite of death, AMI or unplanned revascularisation at 30 days (7.9 % downstream versus 7.1 % upstream) the downstream strategy did not meet the noninferiority goal, but major bleedings were more common in upstreamstrategy patients (4.9 % versus 6.1 %; p<0.001). Similarily, in the EARLYACS trial, upstream use of eptifibatide was not different from deferred treatment in terms of death, AMI, recurrent ischaemia or thrombotic complications during PCI (9.3 % versus 10.0 %; p=0.23). Again, early GPI use was associated with significantly higher rates of TIMI major bleedings (2.6 % versus 1.8 %; p=0.015).

As many of the older studies on GPIs were conducted without the use of P2Y₁₂ blockers, there are limited data on the usefulness of GPIIbIIIa inhibitors in addition to ASA and ADP receptor blocker drugs. In the ISAR-REACT II trial,⁵⁴ 2,022 patients with high-risk NSTE-ACS pre-treated with ASA and a 600 mg loading dose of clopidogrel were randomised to receive either downstream abciximab or placebo. The primary composite endpoint of death, AMI or urgent TVR at 30 days was lower in abciximab-treated patients than in the placebo group (8.9 % versus 11.9 %; p=0.03), with the benefit concentrated in the higher-risk troponine-positive subgroup. The use of GPIs before primary PCI in STEMI patients, also known as ‘facilitated’ primary PCI, was not associated with a convincing improvement in outcomes, while relevant increments in bleedings were observed in the FINESSE trial.⁵⁵ Furthermore, in 800 STEMI patients pre-treated with clopidogrel 600 mg enrolled in the BRAVE-3 trial, there was no significant decrease of infarct size at single-photon emission computed tomography or 30-day hard endpoints with the addition of upstream abciximab therapy.⁵⁶

Overall, in ESC recommendations, usage of GPIIbIIIa inhibitors in ACS patients undergoing PCI and treated with a P2Y₁₂ blocker, may be considered in selected populations with low bleeding risk and elevated periprocedural AMI risk (Class:I; LOE:B). Eptifibatide or tirofiban may be considered in high-risk patients undergoing PCI, pretreated with ASA alone (Class:IIa; LOE:B). Pre-treatment with tirofiban or eptifibatide may be considered in selected, high-risk patients in DAPT before PCI if there is evidence of ongoing ischaemia and the bleeding risk is low (Class:IIb; LOE:C). In STEMI patients, ESC guidelines recommend GPIs as bailout therapy in highly thrombotic lesions or no-reflow situations (Class:IIa; LOE:C). There is modest recommendation also in patients treated with UFH and in case of patient transferral to an hub centre for primary PCI (Class:IIb; LOE:B). ESC guidelines do not currently recommend routine use of GPIs upstream before invasive treatment or in ACS patients treated with DAPT not scheduled for PCI (Class:III; LOE:A).^4–6