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

The study is going to compare two different doses of aspirin for the treatment of heart disease in combination with the anticlotting medication ticagrelor. One of these doses of aspirin, 75 milligrams (mg) once a day, is the current standard treatment dose of aspirin used to treat heart attacks and angina. The other, 20 mg twice a day, is lower than the standard but there is growing scientific evidence that, when given with ticagrelor, this might offer advantages over the usual dose.

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). Aspirin and ticagrelor are superior to aspirin and clopidogrel in preventing ischaemic complications in ACS but there is an increased rate of bleeding complications (Wallentin, Becker et al. 2009). There is some evidence that the benefit of ticagrelor over clopidogrel was diminished in patients taking higher doses of aspirin compared to lower doses (Mahaffey, Wojdyla et al. 2011). The P2Y12 and arachidonic acid pathways appear to be linked. P2Y12 inhibition has been shown to reduce TXA2 release from platelets (Armstrong, Leadbeater et al. 2011) and potentiates the antiplatelet effect of PGI2 in vitro (Cattaneo and Lecchi 2007). Ticagrelor acts as a more potent P2Y12 inhibitor than clopidogrel (Storey, Angiolillo et al. 2010) and therefore may contribute more to this. Ticagrelor has pleiotropic effects not seen with clopidogrel, including inhibition of erythrocyte adenosine uptake (Bonello, Laine et al. 2014) and, in a preclinical model, reduction of infarct size, an adenosine and COX2 dependent effect that is inhibited by high but not low dose aspirin (Nanhwan, Ling et al. 2014). Chronic, but not acute, ticagrelor treatment may upregulate COX2 expression (Nanhwan, Ling et al. 2014) and ticagrelor, but not clopidogrel, improves post-infarct remodeling (Ye, Birnbaum et al. 2015) and has an anticontractile effect on vascular smooth muscle cells when exposed to ADP which is inhibited by high dose, but not low dose, aspirin (Grzesk, Kozinski et al. 2013). Additionally, statins, given to the majority of patients with ACS, reduce infarct size by a COX2 dependent mechanism and, again, this effect is inhibited by aspirin in a dose-dependent manner (Birnbaum, Lin et al. 2007). Inhibition of COX2 by higher doses of aspirin therefore may reduce these benefits. In healthy volunteer studies, aspirin at a dose of 75 mg once daily provided only a small additional effect on platelets to prasugrel ex vivo (Leadbeater et al 2011) and similar findings have been shown with prasugrel (Armstrong et al 2011) and ticagrelor (Kirkby et al 2011) in vitro, however the clinical significance of this additional effect is not known as studies have not been made in patients with acute coronary syndrome, in whom platelet activation occurs and persists after the acute period (Ault, Cannon et al. 1999). It has been suggested that ticagrelor monotherapy may in fact offer advantages over DAPT (Warner, Armstrong et al. 2010) and 2 trials including ACS patients after the very early period are currently in progress (National Institutes of Health 2014, National Institutes of Health 2015). However, given the fact that aspirin still possesses some antiplatelet effect in the presence of potent P2Y12 inhibition, its total omission may not prove to be the optimum strategy in higher risk patients, particularly given the current lack of evidence in patients rather than healthy individuals. Aspirin inhibits TXA2 and PGI2 in vivo in a dose dependent manner and daily doses as low as 20 mg have been shown to significantly inhibit TXA2 release (Warner, Nylander et al. 2011), whilst similar doses provide minimal PGI2 inhibition and no significant prolongation of the bleeding time (Kallmann, Nieuwenhuis et al. 1987). Aspirin doses of less than 75mg OD have not been studied in combination with P2Y12 inhibitors. A strategy to reduce the effect of aspirin on beneficial COX2 whilst maintaining its antiplatelet effect in the presence of ticagrelor may therefore be a lower dose than the current standard. Dosing frequency may also be open to optimization. Aspirin is cleared from the plasma quickly after administration but its effect lasts for the lifespan of a platelet due to its properties as an irreversible inhibitor (Patrono 1994). However, a significant proportion of the population have a high rate of platelet turnover that therefore reduces the duration of effect and may lead to inadequate platelet inhibition. This has been shown to be the case in patients with ischaemic heart disease and is most frequently a problem in those with diabetes mellitus, obesity and smokers (Henry, Vermillet et al. 2011). Twice-daily dosing may offer more consistency (Rocca, Santilli et al. 2012, Paikin, Hirsh et al. 2015). Again, this has not been studied when in combination with a P2Y12 inhibitor. As ticagrelor is taken twice daily, it would not significantly inconvenience patients to receive doses of aspirin in this way.

Supplied with sachets of 100mg soluble aspirin and training, instructions and equipment will be provided to prepare 20 mg dose twice daily x14 then aspirin 75mg once daily x14

This is the standard dose of aspirin the participant will already be taking. The study will require the participants to switch to soluble aspirin for two weeks to enable accurate comparison with the other dose and to take their aspirin dose in the morning. Participants will be provided with a supply of soluble aspirin, along with training, instructions and equipment to help prepare it. They should not take their usual aspirin tablets whilst receiving the study medication, but should continue all other usual medications.

The intervention has been described previously in both arms individually. Group A will receive 20mg of soluble Aspirin and group B with 75mg of soluble Aspirin. As this is a crossover study, all patients will fall under both groups throughout the duration and be un-blinded.

Post-dose serum thromboxane B2, compared within-patients between the 2 dosing regimens by a paired t test.

Ratio of post-dose serum TXB2:urinary PGI-M, compared within-patients between the 2 dosing regimens by a paired t test.

Pre-dose serum thromboxane B2, compared within-patients between the 2 dosing regimens by a paired t test.

Maximum and final post-dose platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP compared within-patients between the 2 dosing regimens by paired t tests.

Maximum and final pre-dose platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP compared within-patients between the 2 dosing regimens by paired t tests.

Ratio of pre-:post-dose serum TXB2, compared within-patients between the 2 dosing regimens by a paired t test.

Ratio of pre-:post-dose maximum and final platelet aggregation induced by 0.1, 0.3 and 1 mM arachidonic acid; 1, 4 and 16 µg/ml collagen; and 20 µM ADP compared within-patients between the 2 dosing regimens by paired t tests.

Inclusion Criteria: For inclusion in the study, subjects should fulfill the following criteria: Provision of informed consent prior to any study specific procedures Male or female aged greater than 18 years Previous diagnosis of acute coronary syndrome greater than 30 days and less than 10 months before enrollment Receiving dual antiplatelet therapy with aspirin 75 mg once daily and ticagrelor 90 mg twice daily Exclusion Criteria: Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Presence of an indication for dual antiplatelet therapy other than ischaemic heart disease PCI with drug eluting or bare metal stent(s) within 30 days of randomization Any history of stent implantation to the left main coronary artery Any history of stent thrombosis during dual antiplatelet therapy Planned procedure for coronary revascularization Any planned surgery or other procedure that may require suspension or discontinuation of dual antiplatelet therapy expected to occur within 3 months of randomisation Prior intention by patient or physician to discontinue aspirin and/or ticagrelor within the study period Receiving doses of aspirin and ticagrelor other than 75 mg once daily and 90mg twice daily respectively

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