WO2018167447A1

WO2018167447A1 - Low dose aspirin (1-50 mg) together with antiplatelets such as ticagrelor of anticoagulants

Info

Publication number: WO2018167447A1
Application number: PCT/GB2017/050692
Authority: WO
Inventors: Robert Frederick STOREY; William Andrew Edison PARKER
Original assignee: University of Sheffield
Current assignee: University of Sheffield
Priority date: 2017-03-14
Filing date: 2017-03-14
Publication date: 2018-09-20
Anticipated expiration: 2019-09-14

Abstract

The present disclosure concerns a dosage regimen consisting of ultra-low doses of irreversible cyclooxygenase inhibitors in combination with platelet aggregation inhibitors or anticoagulant agents for the prevention and treatment of acute coronary syndromes and other ischaemic events.

Description

W DOSE ASPIRIN (1-50 MG) TOGETHER WITH ANTIPLATELETS SUCH AS TICAGRELOR OF

ANTICOAGULANTS

Field of the Invention The present disclosure concerns a dosage regimen consisting of low doses of irreversible cydooxygenase inhibitors in combination with blood anti-platelet or anti-coagulant agents for use in the prevention and treatment of cardiovascular diseases or conditions.

Background of the Invention

Unhealthy diet, physical inactivity, smoking, high cholesterol levels and harmful use of alcohol are the leading causes of heart attack and stroke. Cardiovascular diseases are disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular diseases, peripheral arterial diseases, deep vein thrombosis and pulmonary embolism. According to the WHO, approximately 17.5 million deaths are caused each year by cardiovascular diseases, with an estimated 7.4 million deaths due to coronary heart disease and 6.7 million due to stroke. Although many cardiovascular diseases can be prevented by adapting a healthy lifestyle, people with already established diseases or risk factors such as hypertension, diabetes or hyperlipidaemia require careful monitoring by health professionals and medication such as antiplatelet drugs, anti-coagulants, beta-blockers and statins to lower the risk of heart attack and stroke.

Platelet adhesion and aggregation play an important role in the repair of vascular damage; however, both events are also critical to the formation of arterial thrombus, which can result in myocardial infarction, stroke and critical leg ischaemia. Antiplatelet drugs are used to decrease platelet aggregation, thus preventing and treating thrombus formation, and are routinely given to stroke patients, patients receiving heart surgery or patients suffering from stable and unstable angina, heart attack, or peripheral arterial disease. There are various different antiplatelet drugs available that are based on different modes of action and include compounds such as irreversible cydooxygenase (COX) inhibitors, adenosine diphosphate receptor inhibitors, phosphodiesterase inhibitors, glycoprotein IIB/IIIA inhibitors, adenosine reuptake inhibitors and thromboxane synthase inhibitors. Anticoagulant drugs are used to inhibit the generation and/or action of thrombin, thus preventing and treating thrombus formation, and are routinely given to patients suffering from atrial fibrillation, pulmonary embolism, venous thrombosis, unstable angina, heart attack, stable coronary artery disease and peripheral arterial disease. There are various different anticoagulant drugs available that are based on different modes of action and include compounds such as vitamin K antagonists, direct thrombin inhibitors and factor Xa inhibitors.

Aspirin, or acetylsalicylic acid, belongs to the class of irreversible cyclooxygenase inhibitors and is commonly used to treat fever and pains and reduces, when given at low doses, the aggregation of platelets thus preventing blood clot formation, heart attacks, strokes and critical leg ischaemia. Cyclooxygenase is an enzyme required for the synthesis of prostaglandin and thromboxane A2, compounds involved in the aggregation of platelets and formation of blood clots.

The platelet P2Yi2 receptor plays a major role in platelet activation by amplifying and sustaining platelet activation as a consequence of the adenosine 5'-disphosphate binding to the receptor. A variety of P2Yi2 receptor antagonists such as clopidogrel, prasugrel, ticlopidine and ticagrelor have been identified and are commonly used in patients with acute coronary syndrome, cerebrovascular or peripheral vascular disease and stroke to reduce platelet aggregation. Ticagrelor, or a triazolo [4.5] pyrimidine, is disclosed in WO99/05143. Moreover, WO2016/120729 discloses a treatment regimen for human subjects suffering from cardiovascular disease or conditions that combine ticagrelor with daily low doses of aspirin in the range 75 to 150mg aspirin.

Dual antiplatelet therapy, the combined administration of aspirin and a platelet P2Yi2 receptor antagonist, is considered an effective way to manage cardiovascular disease conditions or to provide post-operative care after coronary artery bypass surgery, procedures to widen the arteries by balloon angioplasty and stenting or after repairing and replacing a valve. Ticagrelor (Brilinta) is recommended to be given in combination with aspirin at a dose of 75-1 OOmg once daily. However, although dual antiplatelet therapy is more effective in preventing heart attack and stroke than aspirin alone, administration of platelet inhibitors, especially the regular use of aspirin, bears risk of excessive bleeding which can lead to death. This disclosure relates to a dosage regimen that combines ultra-low-dose irreversible cyclooxygenase inhibitors such as aspirin with anti-thrombotic agents such as ticagrelor. Aspirin 75-100 mg once daily and ticagrelor 90 mg twice daily represent a current recommended regimen of dual antiplatelet therapy in acute coronary syndromes. Despite potent antiplatelet therapy, the risk of further ischaemic events remains significant, but bleeding is also a frequent complication. Data suggests that higher doses of aspirin may be less beneficial in ACS patients treated with ticagrelor; Mahaffey et al, 2011 . Twice-daily administration of aspirin is known to improve consistency of effect, but has not been studied in those receiving ticagrelor. This disclosure characterises the effects on arachidonic acid metabolites, platelet inhibition and haemostasis of a novel regimen of ultra-low dose aspirin given twice-daily in combination with standard ticagrelor therapy in patients being treated for ACS.

Statement of the Invention

According to an aspect of the invention there is provided a treatment regimen comprising administering an effective dose of at least one antiplatelet or anticoagulant agent and a simultaneous, sequential or temporally separate dose of aspirin between 1 mg to 50mg for use in the treatment of a human subject that has a predisposition to or is suffering from a cardiovascular disease or condition.

In an embodiment of the invention aspirin is administered at a twice-daily dose of between 5mg to 30mg of aspirin.

In an embodiment of the invention aspirin is administered at a twice-daily dose of between 10mg to 30mg aspirin. In an embodiment of the invention aspirin is administered at a twice-daily dose of between 15mg and 25mg aspirin.

In a further embodiment of the invention aspirin is administered at a dose selected from the group consisting of: 16mg, 17mg, 18mg, 19mg, 20mg, 21 mg, 22mg, 23mg or 24mg aspirin.

In an embodiment of the invention aspirin is administered at a twice-daily dose of about 20mg.

In an embodiment of the invention aspirin is administered simultaneously with said antiplatelet or anticoagulant agent.

In an alternative embodiment of the invention aspirin is administered sequentially with said antiplatelet or anticoagulant agent.

In a further alternative embodiment of the invention aspirin is administered in temporally separate doses from administration of said antiplatelet or anticoagulant agent. In an alternative embodiment of the invention said dose of aspirin is administered three times within a 24 hour period.

In an embodiment of the invention said dose of aspirin is administered twice within a 24 hour period.

In an embodiment of the invention said dose of aspirin is administered at least 1 h after administration of said antiplatelet or anticoagulant agent. In an embodiment of the invention said dose of aspirin is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12h or greater after said antiplatelet or anticoagulant agent.

In an embodiment of the invention said antiplatelet agent is a P2Yi2 receptor antagonist. In an embodiment of the invention said P2Yi2 receptor antagonist is selected from the group consisting of: clopidogrel, prasugrel, or ticagrelor.

Preferably, said P2Yi2 receptor antagonist is ticagrelor. In an embodiment of the invention said P2Yi2 receptor antagonist is administered twice or three times daily.

In an embodiment of the invention said P2Yi2 receptor antagonist is administered at a twice- daily dose of between 40-180 mg.

In an embodiment of the invention said P2Yi2 receptor antagonist is administered at a twice- daily dose of 45mg, 60mg, 90mg or 180mg.

In an alternative embodiment of the invention said anti-coagulant agent is selected from the group consisting of: warfarin, phenprocoumon, dabigatran, rivaroxaban, apixaban and edoxaban.

In an embodiment said cardiovascular disease or condition is selected from the group consisting of: coronary heart disease, cerebrovascular diseases, peripheral arterial diseases, deep vein thrombosis, pulmonary embolism, rheumatic heart disease, congenital heart disease, acute coronary syndrome, myocardial infarction and acute ischaemic stroke. In an embodiment of the invention said human subject is monitored to determine blood platelet turnover wherein said treatment regimen is modified in accordance with the said subject's blood platelet turnover. In an embodiment of the invention said human subject is monitored to determine blood inflammatory status wherein said treatment regimen is modified in accordance with the said subject's blood inflammatory status.

Monitoring the inflammatory state of subjects undergoing the disclosed treatment regimen will be known to those skilled in the art. Examples of inflammatory biomarkers typically used to assess inflammatory status include, by example, blood white cell count, blood neutrophil count, serum high-sensitivity C-reactive protein (hsCRP) and plasma interleukin-6. Methods to monitor white cell count and differential neutrophil count are measured by haematology analyser/cell counter. Other methods include measurement of hsCRP by either ELISA or laser nephelometry and IL-6 is measured by ELISA. Growth differentiation factor-15 (GDF-15) is a known biomarker associated with cardiovascular failure; see WO2015/028469 and US2016/016991 , US2015/268251 and US7955854 each of which is incorporated by reference in their entirety. Methods to measure GDF-15 include by Elecsys electrochemiluminescence immunoassay on a Cobas Immunoanalyzer system (Roche Diagnostics).

In an embodiment of the invention said regimen comprises the detection, before, during or after of growth differentiation factor-15 as a measure of said subjects response to the regimen according to the invention. In an embodiment of the invention said treatment regimen is modified in response to the expression of growth differentiation factor-15.

In an embodiment of the invention said cardiovascular disease or condition is associated with type I or type II diabetes in said human subject.

In an embodiment of the invention said cardiovascular disease or condition is associated with obesity with said human subject.

In an embodiment of the invention said cardiovascular disease or condition is associated with smoking tobacco. In a further embodiment of the invention said cardiovascular disease or condition is associated or resulting from a percutaneous interventional or surgical procedure on said human subject.

In an embodiment said surgical procedure includes coronary artery bypass surgery, balloon angioplasty, stenting or after repairing and replacing a heart valve.

According to a further aspect of the invention there is provided an effective dose of aspirin and at least one other antiplatelet or anticoagulant agent wherein said agent and aspirin are formulated for the simultaneous, sequential or temporal administration of the agent and aspiri n wherein aspirin is in a dose of between 1 mg to 50mg, for use in the manufacture of a medicament in the treatment of a cardiovascular disease or condition.

When administered the compositions comprising the antiplatelet or anticoagulant agent and aspirin as herein disclosed are administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives and compatible carriers. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. The pharmaceutical compositions used contain an effective amount of active agent for producing the desired response in a unit of weight or volume suitable for administration to a patient. The doses of agent administered to a subject can be chosen in accordance with different parameters, in particular the state of the subject, their body surface area, and also their weight. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.

When administered, the pharmaceutical composition is administered in pharmaceutically- acceptable amounts. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally additional, different therapeutic agents useful in the treatment of cardiovascular disease or conditions or disease or conditions that are associated with cardiovascular disease. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

Pharmaceutical compositions according to the invention may be combined, if desired, with a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human and are typically inert. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the agent, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

The pharmaceutical compositions may also include additional excipients, for example (a) fillers such as lactose, mannose, dicalcium phosphate, microcrystalline cellulose, (b) binders such as hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl acetate, (c) powder flow enhancers such colloidal silicon dioxide (d) lubricants such as magnesium stearate, sodium stearyl fumarate (e) disintegrants such as sodium starch glycollate and polyvinyl pyrrolidone and (f) anti-sticking agents such as talc (g) taste masking agents such as sucrose, cellulose acetate, cellulose butyrate, polyvinyl acetate, polyvinyl alcohol, polymetharylates. Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, mini-tablets, lozenges, each containing a predetermined amount of the active agent.

Other compositions include suspensions in aqueous liquids or non-aqueous liquids. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents , sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof. According to a further aspect of the invention there is provided a method to treat a human subject in need of treatment for a cardiovascular disease or condition comprising the administration of aspirin with at least one other blood antiplatelet or anticoagulant agent wherein said agent and aspirin are formulated for the simultaneous, sequential or temporal administration of the agent and aspirin, wherein aspirin is in a dose of between 1 mg to 50mg and is administered to treat the cardiovascular disease or condition.

In an embodiment of the invention said treatment regimen, use or method is continued for at least 1 week. In an embodiment of the invention said treatment regimen, use or method is continued for at least 2, 3 or 4 weeks.

In an embodiment of the invention said treatment regimen, use or method is continued for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or in excess of 12 months.

In an embodiment of the invention said treatment regimen or method is continued after 12 months wherein administration of the blood antiplatelet or anticoagulant agent is ceased and aspirin administration continued.

In an embodiment of the invention the dosage of aspirin in said treatment regimen, use or method is increased to greater than 20mg twice daily.

In an embodiment of the invention said dosage of aspirin in said treatment regimen, use or method is increased to 75mg once or twice daily. In an embodiment of the invention the regimen, use or method according to the invention comprises administering aspirin in a soluble form.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps. "Consisting essentially" means having the essential integers but including integers which do not materially affect the function of the essential integers. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise. Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

A non-limiting embodiment of the invention will be described with reference to the following, figures,

Figure 1 illustrates serum thromboxane B2 levels determined pre and 2 hours post aspirin maintenance dose of either 20mg, using a 20mg twice-daily regimen, or 75 mg, using a 75 mg once-daily regimen, in patients receiving ticagrelor 90 mg twice-daily following acute coronary syndrome;

Figure 2 illustrates bleeding time determined by lancet method at 2 hours post aspirin maintenance dose of either 20mg, using a 20mg twice-daily (BD) regimen, or 75 mg, using a 75 mg once-daily (OD) regimen, in patients receiving ticagrelor 90 mg twice-daily following acute coronary syndrome;

Figure 3 illustrates Platelet aggregation determined as the maximum percentage aggregation response using light transmittance aggregometry and the following agonists and final concentrations: arachidonic acid (AA) 0.1 mM (yellow columns), 0.3mM (red columns), and 1 mM (blue columns); adenosine diphosphate (ADP) 20uM (green columns); and collagen 1 ug/ml (orange columns), 4ug/ml (pink columns) or 16 ug/ml (brown columns). Blood samples for preparation of platelet-rich plasma were collected pre aspirin maintenance dose ('Pre') and at 2 hours post aspirin maintenance dose ('Post') of either 20mg, using a 20mg twice-daily regimen, or 75 mg, using a 75 mg once-daily regimen, in patients receiving ticagrelor 90 mg twice-daily following acute coronary syndrome. Data are mean +/- SEM; and

Figure 4 illustrates urinary prostaglandin (prostacyclin) metabolite levels, corrected for urine creatinine concentration, determined from a urine sample collected at 2 hours after maintenance dose of aspirin of either 20mg, using a 20mg twice-daily (BD) regimen, or 75 mg, using a 75 mg once-daily (OD) regimen, in patients receiving ticagrelor 90 mg twice-daily following acute coronary syndrome.

Materials and Methods

20 patients receiving aspirin 75 mg once daily and ticagrelor 90 mg twice daily (Brilinta, AstraZeneca) for treatment of ACS (enrolled 1 -10 months after their event) were randomised in an open-label crossover design to receive aspirin 20 mg twice-daily during one of two 14 day treatment periods, and to continue 75 mg once-daily during the other. Both doses were administered using soluble aspirin (Aspegic) to ensure accurate dose titration and ticagrelor therapy (Brilinta) was continued during both periods. Principal metabolites of thromboxane A2 and prostacyclin were measured by ELISA in serum and urine respectively. Pre- and post- dose maximum aggregation (MA) and final platelet aggregation to arachidonic acid (AA, 0.1 , 0.3, 1 rtiM), collagen (1 , 4, 16 μg/ml) and 20 μΜ adenosine diphosphate (ADP) was assessed using light transmittance aggregometry. Post-dose bleeding time was determined using a standard lancet method.

Thromboxane B∑ ELISA

Venous blood was collected into a serum separator tube and immediately incubated at 37deg C for 30 minutes prior to centrifugation at 1500 RCF and storage of the supernatant serum at -80 degC prior to analysis of thromboxane B2 levels by ELISA kit (Cayman Chemicals, Michigan, USA), according to the manufacturer's instructions.

Bleeding time measurement

Bleeding time was measured pre aspirin maintenance dose and 2 hours post maintenance dose. A sphygmomanometer cuff was applied above the elbow and suitable sites for puncture were identified on the anterior aspect of the forearm, taking care to avoid any surface veins. The sphygmomanometer cuff was inflated to 40 mmHg and cuff pressure was maintained throughout the procedure. The first puncture was made at the most lateral aspect of the selected site with a sterile lancet and the stopwatch started. At 10 seconds, a second puncture was made with a second lancet, medial to the first. At 20 seconds, a third puncture was made with a third lancet, medial to the second. 30 seconds after each puncture, the edge of a sheet of filter paper was applied to the edge of the blood droplet collecting at each puncture site and removed. This was repeated at further 30 second intervals until bleeding ceased or 30 minutes post-puncture is reached, whichever occurred soonest. The first time after each puncture at which bleeding ceased was recorded or, if haemostasis was not achieved at 30 minutes, the time was recorded as 30 minutes.

Light transmittance aggregometry

Venous blood was collected into a citrate anticoagulant tube and then centrifuged at 200 RCF for 10 minutes at room temperature. Platelet-rich plasma was removed following which the sample was centrifugred at 1500 RCF to derive platelet-poor plasma. Light transmittance aggregometry was performed according to the manufacturer's instructions using a PAP8 aggregometer (BioData Corporation) and arachidonic acid (Chronolog Corporation, Havertown, USA), adenosine 5'-diphosphate (Sigma Aldrich, United Kingdom) and collagen (Horm collagen, Takeda, Japan) as agonists at the final concentrations indicated. The test was run for 6 minutes after addition of the agonist and the maximum and final percentage aggregation results were recorded.

Prostacyclin metabolite ELISA

Mid-stream urine was collected at 2 hours after aspirin maintenance dose and stored at -80 deg C prior to analysis of prostacyclin metabolite (PGI-M) levels using a commercial ELISA kit (Cayman Chemicals, Michigan, USA), according to the manufacturer's instructions. Creatinine concentration was also determined by the central pathology laboratory at Northern General Hospital, Sheffield. The PGI-M level was then expressed as pg per mg of creatinine.

Example

16 males and 4 females completed the study (mean age 64.3 [95% CI 58.7-69.8] years). Compared to the standard 75mg dose of aspirin, post-dose serum thromboxane B2 was significantly greater in those receiving the novel 20mg aspirin regimen (3.03 ng/ml [1.32 to 4.73] vs. 0.834 ng/ml [-0.068 to 1.74], p=0.018]), however there was no significant difference between pre-dose levels (3.51 ng/ml [1.61 to 5.42] vs. 2.48 [1.00 to 3.95], p=0.23) (Figure 1). Bleeding time was significantly shortened in those receiving the novel regimen compared to the standard (a mean reduction of 154.5s [6.5 - 302.4], p=0.02) (Figure 2). There were no significant differences between the regimens in pre- or post-dose platelet aggregation to AA or ADP (Figure 3). Post-dose MA response to collagen 1 and 4 μg/ml (but not 16μg/ml) was significantly reduced (mean difference -8.2% [-15.3 to -1.0], p=0.03; and -15.6% [-26.3 to - 4.8], p=0.007 respectively) when receiving 20 mg twice daily. Pre-dose MA was reduced when receiving the novel regimen only when using collagen 1 μg/ml as an agonist (mean difference -10.88 % [-20.7 to -1.07], p=0.03), but not 4 or 16 μg/ml. There was a non-significant trend towards lower level of prostacyclin inhibition with the novel aspirin regimen (Figure 4).

When compared to a standard regimen of aspirin 75 mg once-daily, ultra-low dose aspirin twice-daily provided consistent inhibition of thromboxane A2 release and platelet aggregation, reducing peak-trough variation and with evidence of significant haemostatic benefit.

Reference

Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF, Angiolillo DJ, Held C, Cannon CP, James S, Pieper KS, Horrow J, Harrington RA, Wallentin L. Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation. 201 1 ; 124:544-554

Claims

1. A treatment regimen comprising administering an effective dose of at least one antiplatelet or anticoagulant agent and a simultaneous, sequential or temporally separate dose of aspirin between 1 mg to 50mg for use in the treatment of a human subject that has a predisposition to or is suffering from a cardiovascular disease or condition.

2. The treatment regimen according to the use of claim 1 , wherein aspirin is administered twice daily at a dose of between 5mg to 40mg of aspirin.

3. The treatment regimen according to the use of claim 2, wherein aspirin is administered twice daily at a dose of between 10mg to 30mg aspirin.

4. The treatment regimen according to the use of claim 3, wherein aspirin is administered twice daily at a dose of between 15mg and 25mg aspirin.

5. The treatment regimen according to the use of claim 4, wherein aspirin is administered twice daily at a dose selected from the group consisting of: 16mg, 17mg, 18mg, 19mg, 20mg, 21 mg, 22mg, 23mg or 24mg aspirin.

6. The treatment regimen according to the use of claim 5, wherein aspirin is administered twice daily at a dose of about 20mg.

7. The treatment regimen according to the use of any one of claims 1 to 6, wherein aspirin is administered simultaneously with said antiplatelet or anticoagulant agent.

8. The treatment regimen according to the use of any one of claims 1 to 6 , wherein aspirin is administered sequentially with said antiplatelet or anticoagulant agent.

9. The treatment regimen according to the use of any one of claims 1 to 6, wherein aspirin is administered in temporally separate doses from administration of said antiplatelet or anticoagulant agent.

10. The treatment regimen according to the use of any one of claims 1 to 9, wherein said dose of aspirin is administered twice or three times within a 24 hour period.

1 1. The treatment regimen according to claim 10, wherein said dose of aspirin is administered twice within a 24 hour period.

12. The treatment regimen according to the use of claim 10 or 11 , wherein said dose of aspirin is administered at least 1 h after administration of said antiplatelet or anticoagulant agent.

13. The treatment regimen according to the use of claim 12, wherein said dose of aspirin is administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12h or greater after said antiplatelet or anticoagulant agent.

14. The treatment regimen according to the use of any one of claims 1 to 13, wherein said antiplatelet agent is a P2Yi2 receptor antagonist.

15. The treatment regimen according to the use of claim 14, wherein said P2Yi2 receptor antagonist is selected from the group consisting of clopidogrel, prasugrel, or ticagrelor.

16. The treatment regimen according to the use of claim 15, wherein said P2Yi2 receptor antagonist is ticagrelor.

17. The treatment regimen according to the use of any one of claims 14 to 16 , wherein said P2Yi2 receptor antagonist is administered once, twice or three times daily.

18. The treatment regimen according to the use of any one of claims 14 to 17 , wherein said P2Yi2 receptor antagonist is administered at a dose of between 40-200 mg.

19. The treatment regimen according to the use of any one of claims 14 to 18, wherein said P2Yi2 receptor antagonist is administered at a dose of 45mg, 60mg, 90mg or 180mg.

20. The treatment regimen according to any one of claims 1 to 13 wherein said anticoagulant agent is selected from the group consisting of: warfarin, phenprocoumon, dabigatran, rivaroxaban, apixaban, and edoxaban.

21. The treatment regimen according to the use of any one of claims 1 to 20, wherein said cardiovascular disease or condition is selected from the group consisting of coronary heart disease, cerebrovascular diseases, peripheral arterial diseases, deep vein thrombosis, pulmonary embolism, rheumatic heart disease, congenital heart disease, acute coronary syndrome or myocardial infarction, or acute ischaemic stroke.

22. The treatment regimen according to the use of any one of claims 1 to 20, wherein said cardiovascular disease or condition is associated with type I or type II diabetes in said human subject.

23. The treatment regimen according to the use of any one of claims 1 to 20, wherein said cardiovascular disease or condition is associated with obesity in said human subject.

24. The treatment regimen according to the use of any one of claims 1 to 20, wherein said cardiovascular disease or condition is associated with said human subject smoking tobacco.

25. The treatment regimen according to the use of any one of claims 1 to 20, wherein said cardiovascular disease or condition is associated or resulting from a percutaneous interventional or surgical procedure on said human subject.

26. The treatment regimen according to any one of claims 1 to 20, wherein said percutaneous interventional or surgical procedure includes coronary artery bypass surgery, balloon angioplasty, stenting or after repairing and replacing a heart valve.

27. The treatment regimen according to the use of any one of claims 1 to 26, wherein said human subject is monitored to determine blood platelet turnover wherein said treatment regimen is modified in accordance with the turnover of said subject's blood platelet turnover.

28. The treatment regimen according to any one of claims 1 to 27 wherein said human subject is monitored to determine blood inflammatory status wherein said treatment regimen is modified in accordance with the said subject's blood inflammatory status.

29. The treatment regimen according to claim 28 wherein said regimen comprises the detection, before, during or after of growth differentiation factor-15 as a measure of said subjects response to the regimen according to any one of claims 1 to 26.

30. The treatment regimen according to claim 29 wherein said treatment regimen is modified in response to the expression of growth differentiation factor-15.

31. An effective dosage of at least one antiplatelet or anticoagulant agent and aspirin wherein said agent and aspirin are formulated for the simultaneous, sequential or temporal administration of the agent and aspirin wherein aspirin is in a dosage of between 1 mg to 50mg, in the manufacture of a medicament for use in the treatment of a cardiovascular disease or condition.

32. A method to treat a human subject in need of treatment for a cardiovascular disease or condition comprising the administration of at least one antiplatelet or anticoagulant agent and aspirin wherein said agent and aspirin are formulated for the simultaneous, sequential or temporal administration of the agent and aspirin, wherein aspirin is in a dosage of between 1 mg to 50mg and is administered to treat the cardiovascular disease or condition.

33. The treatment regimen, use or method according to any one of claims 1 to 32, wherein administration of at least one antiplatelet or anticoagulant agent and aspirin is continued for at least 1 week.

34. The treatment regimen, use or method according to claim 33, wherein said treatment regimen, use or method is continued for at least 2, 3 or 4 weeks.

35. The treatment regimen, use or method according to claim 33 or 34, wherein said treatment regimen, use or method is continued for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or in excess of 12 months.

36. The treatment regimen, use or method according to claim 35, wherein said treatment regimen, or method is continued after 12 months wherein administration of the antiplatelet or anticoagulant agent is ceased and aspirin administration continued.

37. The treatment regimen, use or method according to claim 36, wherein the dose of aspirin in said treatment regimen, use or method is increased to greater than 20mg once or twice daily.

38. The treatment regimen, use or method according to claim 37, wherein said dose of aspirin in said treatment regimen, use or method is increased from 75mg to 100mg once or twice daily.

39. The treatment regimen, use or method according to any one of claims 1 to 38, wherein aspirin is in soluble form.