Aspirin for primary prevention of CVD

role of Aspirin for primary prevention of CV events. ASPREE, ARRIVE, ASCEND trials

1. Aspirin for Primary Prevention of Cardiovascular Events MODERATOR – DR. SHARAD JAIN PRESENTOR – DR. PINKESH PARMAR

2. INTRODUCTION Often hailed as “ the wonder drug ” story of aspirin dates back >3500 years when willow bark was used as a painkiller and antipyretics by Hippocrates and other people . Its use as antiplatelet drug started in the late 1960s and early 1970s. Since then, role of low‑dose aspirin in cardiovascular (CV) protection has been supported by >200 studies involving >200,000 patients.

3. INTRODUCTION The role of aspirin for secondary prevention of myocardial infarction (MI), stroke, or transient ischemic attack (TIA) is well established. However, the efficacy and safety of aspirin for primary prevention varied among multiple randomized controlled trials (RCTs ), creating significant variability in societal guidelines. Hence despite multiple studies , the role of aspirin for the primary prevention remains controversial .

4. ASPIRIN FOR PRIMARY PREVENTION: THE GOLDEN PHASE Six large randomized studies have tested the role of aspirin for the primary prevention of CVDs since the late 1980s.

5. Antithrombotic Trialists Collaboration The pivotal Antithrombotic Trialists Collaboration meta‑analysis pooled individual patient data of 95,000 patients from these six primary prevention studies . The collaborative meta‑analysis demonstrated 12% reduction in serious vascular events with the use of aspirin which was driven principally by 23% reduction in nonfatal MI. There was also a 14% reduction in ischemic strokes which was counterbalanced by increase in hemorrhagic strokes by 32 %. The net effect on strokes was not significant, while the effect on vascular mortality was not different from placebo. These benefits were accrued at the cost of almost 50% increase in bleeding which were chiefly gastrointestinal ( GI) and extracranial in location.

6. FALLOUT OF ASPIRIN After 2008, many negative studies came into the picture. Two studies (POPADAD and JPAD studies) assessed effects of aspirin in diabetes. Aspirin was not found to reduce the risk of adverse CV events in diabetic patients in these studies . Subsequently, aspirin was not found to reduce the risk of CV events in those with an Ankle–Brachial Index <0.95 in The Aspirin for Asymptomatic Atherosclerosis trial.

7. FALLOUT OF ASPIRIN However, the updated systematic review of 11 randomized controlled trials (incorporating the above trials), published by the US Preventive Services Task Force in 2016, still revealed an impressive 22% relative risk reduction in nonfatal MI with aspirin but only minor reduction in nonfatal stroke, CV death, and total mortality [Figure 2 ]. Interestingly , elderly patients demonstrated more robust reduction in MI. At lower doses of aspirin (<100 mg), 14% reduction in nonfatal strokes were seen , while reduction on MI was sustained. However , aspirin use increased major GI bleeding risk by 58% and hemorrhagic stroke risk by 27 %.

8. FALLOUT OF ASPIRIN Such conflicting results with aspirin studies have led to inconsistent guidelines for aspirin use in primary prevention. Some societies were in favor of aspirin use, while others were against its use. The US. Preventive Services Task Force recommends low‑dose aspirin use for the primary prevention of CVD in adults aged 50–59 years who have a 10% or greater 10‑year CVD risk. While in adults aged 60–69 years who have a 10% or greater 10‑year CVD risk, aspirin initiation was advised on individual basis . Use of aspirin for the primary prevention of CVD was not endorsed by European Guidelines due to lack of clear evidence in support of its efficacy and increase in bleeding events.

9. FALLOUT OF ASPIRIN In the background of emerging equivocal data about the role of aspirin primary prevention, three large randomized trials involving close to 47,000 patients were published recently . These three trials tried to address the unresolved issues of aspirin in primary prevention to some extent.

10. ASCEND TRIAL- Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus Eligibility : Age ≥ 40 years, any DIABETES and no baseline cardiovascular disease Participants : 15,480 UK patients Factorial randomization : Aspirin 100 mg daily vs placebo (& to omega-3 fatty acid supplements vs placebo ) Follow-up : Mean 7.4 years, >99% complete for morbidity and mortality Published in NEJM on August 26, 2018

11. KEY OUTCOMES Primary efficacy outcome : Serious Vascular Event (SVE) Non-fatal myocardial infarction, Non-haemorrhagic stroke or transient ischaemic attack, or Cardiovascular death, excluding any intracranial haemorrhage Primary safety outcome : Major bleed Intra-cranial haemorrhage, Sight-threatening eye bleed, Serious gastrointestinal bleed, or Other serious bleed Key secondary outcomes : SVE or any revascularization (pre-specified for subgroup analyses) Gastrointestinal tract cancer

12. SUMMARY As Aspirin did not reduce the risk of gastrointestinal or any other cancer with no apparent effect emerging with longer follow-up Aspirin significantly reduced the risk of serious vascular events but also significantly increased the risk of major bleeding The absolute benefits from avoiding serious vascular events were largely counterbalanced by the increased risk of bleeding There was no group in which the benefits clearly outweighed the risks

13. ARRIVE- Use of aspirin to reduce risk of initial vascular events In patients at moderate risk of cardiovascular disease Published in LANCET on 26 August 2018 DESIGN - randomised, double-blind, placebo-controlled, multicentre study done in seven countries . (Germany, Italy, Ireland, Poland, Spain , the UK, and the USA). The study setting was largely primary care offices . Eligible male patients were aged 55 years and older and had between two and four risk factors; eligible female patients were aged 60 years or older and had three or more risk factors . Participants had an average cardiovascular risk (10-year risk of coronary heart disease of 10–20%), deemed to be moderate on the basis of the risk factors.

14. ARRIVE Risk factors were high cholesterol (total cholesterol >200 mg/ dL or LDL >130 mg/ dL for men; total cholesterol >240 mg/ dL or LDL >160 mg/ dL for women) irrespective of current treatment, current smoking (any cigarette smoking in the past 12 months), low HDL cholesterol (< 40 mg/ dL ), high blood pressure (systolic blood pressure >140 mm Hg), receiving medication to treat high blood pressure, and a positive family history of cardiovascular heart disease . Patients were excluded if they had a history of a vascular event , such as stroke, myocardial infarction, coronary artery angioplasty or stenting, coronary artery bypass graft , relevant arrhythmias, congestive heart failure, or vascular intervention.

15. ENDPOINTS The primary efficacy endpoint was a composite outcome consisting of time to first occurrence of confirmed myocardial infarction, stroke, cardiovascular death, unstable angina , or transient ischaemic attack . Secondary endpoints were a composite of the time to first occurrence of cardiovascular death, myocardial infarction , or stroke; time to individual components of this composite secondary outcome; time to first occurrence of unstable angina; time to first occurrence of transient ischaemic attack; and time to and incidence of all-cause mortality . Safety endpoints were haemorrhagic events and incidence of other adverse events,

16. RESULTS Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months.

17. EFFICACY END POINTS

18. SUMMARY

19. ASPREE- Effect of Aspirin on All-Cause Mortality in the Healthy Elderly Published in NEJM 16 September 2018 Randomized Multi-center placebo controlled Trial With Multi Year Follow-up ASPREE trial was a primary prevention trial that was established to investigate whether the daily use of 100 mg of enteric-coated aspirin would prolong the healthy life span of older adults. The trial, which was conducted in Australia and the United States, recruited 19,114 relatively healthy older persons from community settings.

20. ASPREE From 2010 through 2014, they enrolled community-dwelling persons in Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States) and did not have cardiovascular disease, dementia , or disability. Participants were randomly assigned to receive 100 mg of enteric-coated aspirin or placebo . Followed Patients until Death/Disability Median 4.7 yrs

21. RESULTS

22. RESULTS

23. SUMMARY Aspirin has a beneficial profile for reducing nonfatal MI but not all cause or CV mortality in general Primary prophylaxis is not likely to result in decreased cardiovascular mortality, or all cause mortality/disability Aspirin use is significantly associated with serious hemorrhage A ll-cause mortality was apparently higher among those who received daily low-dose aspirin than among those who received placebo, with 1.6 excess deaths per 1000 person-years occurring in the aspirin group after a median of 4.7 years, and cancer was the principal cause of the excess deaths . Other primary prevention trials of aspirin have not identified similar results, which suggests that the mortality results reported here should be interpreted with caution.

24. These three studies used contemporary pharmacotherapy in the management of CVD. With large sample size and close to half‑decade follow‑up in these studies, the results would be hard to neglect. One can only speculate about the various possible reasons for contrasting results seen in the pristine trials . The initial aspirin trials occurred in an era when other risk factors of vascular diseases were not well controlled such as blood pressure and lipid profile. With development of statins , renin–angiotensin–aldosterone system blockers, and better management of CV risk factors, event rates are already on decline.

25. Aspirin for Primary Prevention of Cardiovascular Events – A Meta-analysis Published by Abdelaziz et al. in J ACC VOL .73, on JUNE 18, 2019 Randomized controlled trials comparing clinical outcomes with aspirin versus control for primary prevention with follow-up duration of >1 year were included . A total of 15 randomized controlled trials including 165,502 participants (aspirin n = 83,529, control n = 81,973) were available for analysis. The current meta-analysis represents the largest and most contemporary examination of long-term outcomes with aspirin use for primary prevention of CVD .

26. Efficacy outcomes included all-cause death, cardiovascular (CV ) death, myocardial infarction (MI), stroke, transient ischemic attack (TIA), and major adverse cardiovascular events. Safety outcomes included major bleeding, intracranial bleeding, fatal bleeding, and major gastrointestinal (GI) bleeding .

27. P rimary analysis found that: aspirin is not associated with a reduction in all-cause or non-CV death, but is associated with a modest, nonstatistically significant relative reduction of 7% in CV death ; aspirin (even <100 mg/day) is associated with lower rates of MI, nonfatal MI, TIA, and ischemic stroke; aspirin use is associated with a significant increase in the risk of nonfatal major bleeding events, intracranial bleeding, and major GI bleeding, with similar rates of fatal bleeding compared with the control subjects regardless of dose or population characteristics ; and aspirin does not affect the incidence of cancer or risk of cancer death within a median follow-up period of 6.46 years.

28. Secondary analysis revealed that: aspirin may reduce all cause death after 5 years of follow-up; the trend toward lower risk of CV death with aspirin is only observed in populations with high estimated 10-year ASCVD risk; and lower risk of total and nonfatal stroke with aspirin use is observed only when lowdose aspirin (<100 mg/day) is utilized.

29. 1. Low-dose aspirin (75-100 mg orally daily) might be considered for primary prevention of ASCVD among select adults 40 to 70 years of age wh are at higher ASCVD risk but not at increased bleeding risk To balance the benefits and risks, prior U.S. guidelines have recommended prophylactic aspirin only in the setting of elevated ASCVD risk. In this context, post hoc study of older trials suggests that the benefit–risk ratio for prophylactic aspirin generally becomes more favorable at >10% estimated 10-year ASCVD risk. However, the relative benefits of aspirin, specifically in preventing nonfatal MI and perhaps stroke (with a trend to lower mortality) have been less evident in more recent trials.

30. 1. Low-dose aspirin (75-100 mg orally daily) might be considered fo the primary prevention of ASCVD among select adults 40 to 70 years of age who are at higher ASCVD risk but not at increased bleeding risk Recent trials show that absolute risk for ASCVD events typically exceeds that of bleeding and, although the gap of relative benefit to relative harm for aspirin has narrowed, the number needed to treat to prevent an ASCVD event remains lower than the number needed to harm to cause bleeding . meta-analyses suggest that the ASCVD risk benefit for low-dose aspirin is equivalent to that for high-dose aspirin, but the bleeding risk is higher with high-dose aspirin . there was no evidence low-dose aspirin was any more effective in low-weight individuals than in high-weight individuals in the more recently published ASCEND (A Study of Cardiovascular Events iN Diabetes) trial.

31. 2. Low-dose aspirin (75-100 mg orally daily) should not be administered on routine basis for the primary prevention of ASCVD among adults >70 years of age Prophylactic aspirin in primary-prevention adults >70 years of age is potentially harmful and, given the higher risk of bleeding in this age group, difficult to justify for routine use. In addition, for adults <40 years of age, there is insufficient evidence to judge the risk–benefit ratio of routine aspirin for the primary prevention of ASCVD . As inferred from the first recommendation, there is also no justification for the routine administration of low-dose aspirin for the primary prevention of ASCVD among adults at low estimated ASCVD risk.

32. 3. Low-dose aspirin (75-100 mg orally daily) should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding The accumulated trial and observational data to date support avoiding prophylactic aspirin in the setting of known risk factors for increased bleeding outcomes. A nonexhaustive list of scenarios associated with increased risk of bleeding includes: a history of previous gastrointestinal bleeding or peptic ulcer disease or bleeding from other sites, age >70 years, thrombocytopenia, coagulopathy, CKD, and concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs, steroids, direct oral anticoagulants, and warfarin.

33. CONCLUSIONS Aspirin use for primary prevention decreased nonfatal ischemic events and increased nonfatal bleeding events. The benefits were more pronounced when estimated ASCVD risk was > 7.5 % over 10 years. These findings suggest that the decision to use aspirin for primary prevention should be tailored to the individual patient based on estimated ASCVD risk and perceived bleeding risk, as well as patient preferences regarding types of events prevented versus potential bleeding caused. When aspirin is used for primary prevention, a low dose (<100 mg/day) should be recommended.

34. ASPIRIN RESISTANCE

35. INTRODUCTION Despite the development of new molecules, aspirin remains a mainstay of the antiplatelet therapy, indispensable for treatment and the secondary prevention of cardiovascular and cerebrovascular diseases. A significant number of these patients manifest breakthrough events despite regular intake of aspirin. It is estimated that one in eight high risk patients suffers from the recurrence of a vascular event within the next 2 years .

36. MECHANISMS OF ACTION OF ASPIRIN Aspirin mediates its antithrombotic effect through inhibition of platelet aggregation. It does this by inhibition of cyclooxygenase- 1 (COX-1) which in turn inhibits the metabolism of arachidonic acid to cyclic prostanoids such as thromboxane A2, prostacycline and other prostaglandins. Because platelets have minimal capacity for protein synthesis, the inactivation of COX-1 by aspirin is irreversible for the life of the platelet (8-10 days)

37. DEFINITION OF ASPIRIN RESISTANCE Aspirin resistance is a poorly defined term. It could mean a clinical inability of aspirin to protect individuals from arterial thrombotic events or laboratory indication of failure of aspirin to inhibit platelet activity, mainly platelet aggregation or a close to normal urinary concentration of thromboxane metabolites.

38. PREVALENCE OF ASPIRIN RESISTANCE There are no standard criteria or method by which aspirin resistance can be assessed. Aspirin resistance has been reported to occur in 5% to 45% of the general population

39. METHODS OF ASSESSING ASPIRIN RESISTANCE Platelet aggregation studies using platelet rich plasma (optical aggregometer ) or whole blood (platelet function analyzer-100 ; PFA-100) are the usually employed method. Optical aggregometer is widely available, however it is neither reproducible nor user-friendly. Whereas whole blood aggregometer allows more rapid assessment and results are easily reproducible. Other method used is rapid platelet function analysis (RPFA) using Ultegra RPFA instrument. Bleeding time Urinary metabolites of thromboxane metabolism- urinary 11-dehdrothromboxane B2 levels, a stable metabolite of TXA2. As the urinary levels depend on platelet and nonplatelet sources of thromboxane generation, this test lacks specificity . Selectin -P overexpression.

40. Criteria used for the diagnosis of aspirin resistance also varies among different authors. Using platelet aggregation Gum et al defined resistance as aggregation of >70% with 10μm ADP and >20 % with 0.5mg/ml arachidonic acid. Aspirin semiresponder was defined as meeting one criteria but not both. With PFA-100 aspirin resistance was defined in terms of normal collagen and/or epinephrine closure time <186 sec and with RPFA- as aspirin resistance units >550.

41. MECHANISMS OF ASPIRIN RESISTANCE CLINICAL Non-compliance Drug interaction: Most important is with ibuprofen. Ibuprofen is able to bind the COX-1 binding site of aspirin and via stearic hindrance may prevent aspirin from binding and exerting its antiplatelet effect Cigarette smoking enhances platelet function. Diabetes and hypercholesterolemia – by means of producing free radicals decreases response to antiplatelet therapy.

42. MECHANISMS OF ASPIRIN RESISTANCE BIOLOGIC/ CELLULAR FACTORS Alternate pathways of platelet activation . Failure to inhibit catecholamine-mediated platelet activation e.g . exercise, mental stress, epinephrine . Overexpression of COX-2 mRNA Regenerated COX-1 activity in macrophages and vascular endothelial cells Erythrocyte-induced platelet activation Generation of B2-isoPGF2 alpha binds to thromboxane receptors

43. MECHANISMS OF ASPIRIN RESISTANCE GENETIC Polymorphism of vWF receptor gene Polymorphism collagen receptor Functional single nucleotide polymorphism of COX-1 gene Platelet glycoprotein IIIa polymorphism. The platelet glycoprotein IIb / IIIa complex is the receptor for fibrinogen and mediates platelet aggregation. Polymorphism exists in the IIIa subunit of this receptor with patients being PI A1/A1 homozygous, Pl A1/A2 heterozygous or Pl A2/A2 homozygous . Patients displaying either the Pl A1/A2 or Pl A2/A2 polymorphism have been shown to be less responsive to the antiplatelet effect of aspirin. But, the main cause for aspirin resistance may be a yet undiscribed genetic abnormality .

44. TYPES OF ASPIRIN RESISTANCE Aspirin resistance type I (pharmacokinetic type) – There is no effect on collagen-induced platelet aggregation or thromboxane formation while taking aspirin 100 mg/da for at least 5 days. While there is inhibition of platelet aggregation in vitro suggesting intra- and inter-individual variability in pharmacokinetics when aspirin is used at low doses . Aspirin resistance type II ( pharmacodynamic type ) - It is characterized by the inability of aspirin to inhibit platelet thromboxane formation both in vivo and in vitro. Aspirin resistance type III (pseudo-resistance ) - It is characterized by inhibition of thromboxane formation in vivo but not in vitro. This type of aspirin resistance was designated ‘pseudo-resistance’, because, in these patients, aspirin exerted the expected pharmacodynamic effect, i.e ., inhibition of platelet thromboxane formation.

45. MANAGEMENT OF ASPIRIN RESISTANCE There are no specific recommendations regarding the management of aspirin resistance. General measures- Patient compliance Increasing aspirin dose- Data from Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) and Blockage of the Glycoprotein IIb / IIIa Receptor to Avoid Vascular Occlusion (BRAVO) studies show that increasing aspirin dose is not useful.

46. MANAGEMENT OF ASPIRIN RESISTANCE Combining with other antiplatelet agents- Clopidogrel inhibits platelet aggregation via ADP receptor and therefore may represent an important therapeutic alternative . trial Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE)) has shown a modest superiority of clopidogrel monotherapy over aspirin monotherapy . Both CURE and Clopidogrel for the Reduction of Events During Observation (CREDO) support the superiority of dual antiplatelet therapy over monotherapy . However resistance to other antiplatelet agents has also been reported. In a recent study up to 4.7% of the patients undergoing coronary stenting developed thrombotic stent occlusion despite intensive clopidogrel treatment.

47. THANK YOU