Inhibiting Platelets Aggregation

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Summary

Inhibiting Platelets Aggregation
As previously stated, platelet activation leading to the autocrine and paracrine release of active mediators and subsequent aggregation, represents one of the two main pathways for thrombus formation. Over the years, several molecules have been discovered and used to inhibit platelet activation, but all these compounds focus on three key stages of the process: inibition of TXA₂ formation, blockage of the P2Y₁₂ ADP receptor and blockage of the IIbIIIa integrin.

Aspirin
Acetylsalicylic acid (ASA) irreversibly blocks both COX-1 and COX-2 (more weakly) by acetylation of their active site,¹⁵ thus preventing prostaglandin (PGs) and thromboxane production from platelets-membrane arachidonate. In particular, COX-1 inhibition reduces prostaglandin H2 (PGH2), which is a metabolic precursor of TXA₂, a potent platelet activator. Being the first synthesised effective antithrombotic agent, ASA still plays an unquestionable role in the treatment of vascular thrombosis and major cardiovascular events prevention. In classic studies, such as the Physicians’ Health Study,¹⁶ ASA reduced acute MI (AMI) occurrence in a large cohort of male US physicians asymptomatic for cardiac ischaemia. ASA efficacy on hard endpoints in patients with AMI has been then confirmed in the large ISIS-2 trial,¹⁷ showing survival benefits comparable with those achieved by strepokinase fibrinolysis. Furthermore, ASA decreased rates of re-infarctions and non-fatal strokes at mid-term follow-up in the same study. Long-term benefits of chronic antithrombotic therapy with ASA has also been analysed and confirmed with dosages of 75–325 mg/day.¹⁸ In older studies, ASA proved useful for hard-endpoints prevention also in the setting of unstable angina.¹⁹ Therefore, for the treatment of both non-STEMI (NSTEMI) and STEMI patients undergoing PCI, the European Society of Cardiology (ESC) recommends administering an initial loading dose of 150–300 mg of ASA, unless contraindicated, followed by a long-term maintenance dose of 75–100 mg daily (Class:I; LOE:B). ASA is also recommended in ACS patients, independently of the treatment strategy.^5,6

Ticlopidine
The first-generation thienopydirine ticlopidine, usually administered at a dose of 250 mg twice daily, has been widely replaced by newer agents mainly due to its known adverse haematological effects (neutropenia, purpura).

Clopidogrel
The second-generation PDY₁₂ receptor blocker drug, clopidogrel bisulfate, is a prodrug activated in the liver by a cytochrome-mediated two-step oxidation. Importantly, 85 % of the administered dose is inactivated by estherase-mediated competing reactions.²⁰ The active compound binds permanently to a free cysteine on P2Y₁₂, inactivating it for all the platelet’s lifespan. The clinical use of clopidogrel in non-ST-elevation (NSTE)-ACS has been investigated in the large CURE trial, which evidenced a significant reduction in a composite of cardiovascular death, recurrent AMI or strokes when a 300 mg loading dose followed by 75 mg daily of the drug was associated to ASA in terms of ASA alone (9.3 % versus 11.4 %; p<0.001).²¹ In the CURRENT-OASIS 7 trial a double loading dose of 600 mg followed by 6 days of 150 mg daily of clopidogrel proved superior in preventing cardiovascular deaths/AMI and stroke (3.9 % versus 4.5 %; p=0.039), as well as stent thrombosis, in the subgroup of more than 17,000 patients undergoing PCI.²² This result is achieved at the price of more CURRENT-defined major bleedings (1.6 % versus 1.1 %; p=0.009), but without significant excess of intracranial or surgical bleedings. Due to relevant inter-individual absorption and metabolisation differences, the degree of platelet inhibition is not uniform among clopidogreltreated patients, leading to the need for more potent and reliable P2Y₁₂ blockers.²³ The current recommendations by the ESC suggest a loading dose of 300 (Class:I; LOE:A) or 600 mg of clopidogrel (Class I; LOE:B) followed by a maintenance of 75 mg daily (or 150 mg until day 8) in both STEMI and NSTEMI patients when it is not possible to administer newer molecules (prasugrel, ticagrelor).^4,5

Prasugrel
The third-generation thienopyridine prasugrel guarantees more rapid and predictable platelet inhibition than clopidogrel even sharing an almost identical mechanism of action based on irreversible disulphide bridging on the P2Y₁₂ receptor.²⁴ Unlike clopidogrel, cytochromial and uptake molecules polimorphisms do not have a great effect on the prasugrel metabolism, while an estherase-mediated intestinal reaction forms thyolactones that are then rapidly converted to the active form by the P450 cytochrome system, leading to a greater bioavailability of the active compound.²⁵ Standard oral loading dosages of 60 mg produce peak plasmatic concentration after just 30 minutes, while 60–70 % of platelet activity is inhibited in 2–4 hours.²⁶ In the PRINCIPLE-TIMI (‘Thrombolysis In Myocardial Infarction’) 44 phase II trial, 60 mg loading dose and 10 mg maintenance dose of prasugrel achieved superior results in terms of platelet inhibition compared with a 600 mg loading dose and a 150 mg maintenance dose of clopidogrel.²⁷ In the setting of STEMI or NSTEMI treated with PCI, the TRITON-TIMI 38 study compared a 60 mg loading dose followed by 10 mg daily maintenance of prasugrel with a 300 mg loading dose and 75 mg daily maintenance of clopidogrel, with the loading dose administered after coronary angiography.²⁸ The trial demonstrated a significant reduction of the composite endpoint of cardiovascular death, non-fatal AMI and non-fatal stroke in the prasugrel group (9.9 % versus 12.1 %; p<0.001), with early survival advantages after only 3 days persisting at a mean follow-up of 14.5 months. Although this result was mainly driven by AMI reduction (7.3 % versus 9.5 %; p<0.001), the prasugrel-treated group also had less need for target vessel revascularisation (TVR) or definite or probable stent thrombosis. Patients with diabetes had the greatest reduction of the primary endpoint (12.2 % versus 17.0 %; p<0.001) with a relative risk (RR) reduction of 34 % compared with 13 % in the cohort without diabetes. This powerful antiplatelet action has the cost of increased major non-coronary artery bypass graft (CABG)-related TIMI bleedings (2.4 % versus 1.8 %; p=0.03) determining a net clinical harm in patients with previous stroke or transient ischaemic attack and no benefits in patients older than 75 or weghing less than 60 kg. In the overall study population the net balance between primary endpoint reduction and major non-CABG bleedings still favoured prasugrel treatment (12.2 % versus 13.9 %; p=0.004). The TRILOGY ACS trial investigated prasugrel in ACS patients not planned for PCI, failing to demonstrate reductions in a composite of cardiovascular death, non-fatal AMI and non-fatal stroke at 30 months.²⁹ Therefore ESC recommends a 60 mg loading dose and 10 mg daily maintenance of prasugrel in P2Y₁₂ naive patients undergoing PCI (Class:I; LOE:B) after visualisation of the coronary arteries.^5,6 Ticlopidine or clopidogrel pre-treated patients may also receive prasugrel before PCI (Class:IIa; LOE:B).⁴

Ticagrelor
Ticagrelor is the first representative of a new class of ADP blockers, triazolopyrimidines, which act as ADP analogues directly binding to P2Y₁₂ causing allosteric reversible blockage of the receptor. This compound has a more powerful, rapid and predictable effect on platelet inibition than clopidogrel. Being an ADP-mimicking molecule, the drug could bind bronchial A₁ receptors, possibly accounting for a unique side effect, dyspnoea, which may also be provoked by ADP accumulation and reversible P2Y₁₂ inhibition on sensory neurons.³⁰ Although ticagrelor is active itself, its main metabolite, produced by de-hydroxyethylation via CYP3A4, accounts for part of the effect.³¹ The drug peaks at 1–3 hours post loading dose, with an half-life of 6–13 hours that justifies its bi-daily administration. After 2–4 hours from an oral loading dose of 180 mg, ticagrelor inhibits platelets aggregation by 50–60 %, an effect that can be maintained with b.i.d. doses of 90 mg.³² Further increases of maintenance dosages over 90 mg produce a relatively small increment of platelet inhibition. Clinical use in intermediate to high-risk NSTE-ACS (either treated invasively or conservatively) or STEMI patients planned for primary PCI was evaluated in the PLATO trial, comparing a standard 300–600 mg loading dose and 75 mg daily maintenance dosages of clopidogrel with a 180 mg loading dose and 90 mg b.i.d. maintenance of ticagrelor.³³ The ADP blocker drug was continued for 6–12 months (mean 9 months). In the overall population, the study demonstrated a significant reduction in the composite primary endpoint of cardiovascular deaths, AMI and non-fatal strokes (9.8 % ticagrelor group versus 11.7 % clopidogrel group; p<0.001), mainly driven by a reduction of deaths (4.0 % versus 5.1 %) and AMI (5.8 % versus 6.9 %). In PLATO overall major bleedings were similar in both groups (11.6 % versus 11.2 %; p=0.43), treatment with ticagrelor was associated with significantly higer rates of non- CABG related bleedings (4.5 % versus 3.8 %; p=0.03) or spontaneous bleedings (3.1 % versus 2.3 %; p=0.01).³⁴ Rare fatal intracranial bleedings were also more frequent in the ticagrelor group (0.21 % versus 0.03 %; p=0.02), as were non-procedure-elated bleedings after 30 days. Like for prasugrel, the overall clinical benefit analysis in PLATO was in favour of the ticagrelor group (7.9 % versus 9.0 %; p=0.026). In CABG-treated patients, ticagrelor versus clopidogrel reduced total mortality (4.7 % versus 9.7 %; p<0.001) by decreasing both cardiovascular and noncardiovascular deaths, while CABG-related bleedings were similar in the two treatment arms. As expected, dyspnoea was more frequent in ticagrelor-treated patients (13.8 % versus 7.8 %; p<0.001), even if this was not a significant cause of treatment dyscontinuation. Benign, early phase (transient) ventricular pauses were also more frequent in the ticagrelor group.

ESC guidelines recommend a ticagrelor 180 mg loading dose followed by 90 mg b.i.d. in all intermediate to high-risk ACS patients (Class I; LOE:B), regardless of the initial treatment strategy and including clopidogrel pre-treated patients, suspending clopidogrel at drug shift.^{4– 6}