WilL LOWer Dose Aspirin be More Effective Following ACS? (WILLOW-ACS)

Aspirin has an established role in the treatment of ACS and secondary prevention of ischaemic heart disease. In the landmark trial of aspirin in ACS, ISIS-2 (1988), it conferred a benefit of similar magnitude to thrombolysis. The addition of a second antiplatelet agent (a P2Y12 inhibitor) to aspirin is known to improve outcomes in both NSTE-ACS (Yusuf, Zhao et al. 2001) and STEMI (Chen, Jiang et al. 2005, Sabatine, Cannon et al. 2005). There are 2 major classes of oral P2Y12 inhibitor: irreversibly binding thienopyridine agents, such as clopidogrel or prasugrel, and reversibly-binding drugs, such as the cyclo-pentyl triazolopyrimidine ticagrelor.

A combination of aspirin and ticagrelor 90 milligrams (mg) twice daily for at least 1 year represents the current standard treatment for ACS recommended in European guidelines (Steg, James et al. 2012, Roffi, Patrono et al. 2015).

Aspirin inhibits cyclo-oxygenase (COX) enzymes by irreversible acetylation, and at lower doses exhibits relative selectivity for COX1, responsible for the synthesis of thromboxane A2 (TXA2), which is a pro-thrombotic and vasoconstrictive eicosanoid. At higher doses, aspirin is also able to inhibit COX2, leading to a reduction in release of the anti-thrombotic and vasodilatory compound prostacyclin (PGI2). Aspirin is able to inhibit platelet aggregation, therefore, by inhibiting TXA2 relatively more than PGI2. Due to its irreversible binding, COX is inhibited in platelets for their lifespan (typically 10-12 days) as, being without a nucleus, they cannot regenerate the enzyme (Patrono 1994). It is now thought that PGI2 acts locally rather than systemically and, in healthy individuals, COX1 may be responsible for the majority of PGI2 production (Kirkby, Lundberg et al. 2012). In patients with atheromatous disease, however, there is greater COX2 expression in diseased vessel walls (Schonbeck, Sukhova et al. 1999) therefore this may not apply in the areas most vulnerable to thrombosis. COX2 selective inhibitors have been associated with increased cardiovascular risk and this appears to be both a dose dependent and class effect (Mukherjee, Nissen et al. 2001, Bhala, Emberson et al. 2013).

All antithrombotic drugs confer a risk of bleeding. In addition to its antiplatelet effect, COX1 inhibition by aspirin in the stomach can lead to acid-induced inflammation and ulceration, resulting in bleeding. There is evidence that lower doses of aspirin are associated with lower rates of gastrointestinal bleeding (Valkhoff, Sturkenboom et al. 2012) including when combined with a P2Y12 inhibitor (Mehta, Tanguay et al. 2010).

In the UK, 75 mg od is the standard maintenance dose of aspirin and the consensus from the Antithrombotic Trialist Collaborators was that higher doses offer no added benefit and may increase complication rates when used for secondary prevention (2002). Use of this specific dose stems from its original formulation as an anti-inflammatory dose for paediatric use, and was chosen to approximate 1 grain in the formerly used unit. Only 1 study of aspirin dose in patients with ACS on DAPT has been carried out but this only included patients on clopidogrel rather than ticagrelor and did not evaluate aspirin doses lower than 75 mg (Mehta, Tanguay et al. 2010).