Ignite Creation Date:
2024-05-06 @ 8:28 AM
Last Modification Date:
2024-10-26 @ 12:00 PM
Study NCT ID:
NCT02741817
Status:
COMPLETED
Last Update Posted:
2021-03-17
First Post:
2016-04-13
Brief Title:
WilL LOWer Dose Aspirin be More Effective Following ACS WILLOW-ACS
Sponsor:
Sheffield Teaching Hospitals NHS Foundation Trust
Organization:
Sheffield Teaching Hospitals NHS Foundation Trust
Study Overview
Official Title:
WilL LOWer Dose Aspirin be More Effective Following ACS WILLOW-ACS
Status:
COMPLETED
Status Verified Date:
2017-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
WILLOW-ACS
Brief Summary:
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
Detailed Description:
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
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None