Aspirin

Aspirin

• Mechanism of action
• Aspirin in Primary Prevention
• *ASPREE*
• ASCEND
• ARRIVE
• Bleeding risks
• Aspirin in Secondary Prevention

Aspirin Mechanism

• Willow bark contains salicylates and was used for analgesia > 3500 years ago by the Sumerians and Egyptians.
• Mechanism of action:
• Irreversibly inhibits Cyclooxygenase (COX-1 and COX-2)
• COX-1 leads to production of prostaglandins
• protect gastric mucosa
• maintain renal blood flow
• regulate platelet activation and aggregation.
• COX-2 expression is induced by inflammation
• promotes the inflammatory response.
• Blocking COX-1 and/or COX-2 leads to reduced production of prostaglandins and thromboxane
• Reduced inflammation
• Inhibition of platelet aggregation

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Aspirin | Circulation (ahajournals.org)

Aspirin Mechanism

• Plasma half-life of 20 minutes
• Platelets have no nucleus and limited mRNA/protein synthesis
• COX-1 inhibition in platelets is irreversible and lasts until the platelet is destroyed and replaced.
• Platelet life ~10 days
• May protect LDL from oxidation
• Improves endothelial dysfunction in atherosclerotic vessels
• Antioxidant effects
• probably other effects that lead to reduced inflammatory response

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Aspirin | Circulation (ahajournals.org)

Aspirin Mechanism

• Rapidly absorbed in upper GI tract
• inhibits platelet function within 60 minutes
• Enteric coating significantly delays absorption
• BUT, does not seem to reduce GI Bleeding risk
• Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product - PubMed (nih.gov)

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• Single 100mg dose stops Thromboxane synthesis
• Effect of daily dosing is cumulative.
• Higher doses not proven to be more effective for antiplatelet effects and increase GI side effects.

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Aspirin | Circulation (ahajournals.org)

The role of aspirin in primary and secondary prevention. COX: cyclooxygenase isoenzyme; CHD: coronary heart disease; P2Y12: a chemoreceptor for adenosine diphosphate; DAPT: dual antiplatelet therapy; GI: gastrointestinal.

Aspirin in the Modern Era of Cardiovascular Disease Prevention - PMC (nih.gov)

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Methodist Debakey Cardiovasc J. 2021; 17(4): 36–47.

Published online 2021 Sep 24. doi: 10.14797/mdcvj.293

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Aspirin for CVD Primary Prevention

�ASPREE Trial 2018�ASPirin in Reducing Events in the Elderly�

• Aspirin 100mg qd vs Placebo. n = 19,114; Median of 4.7 years of follow-up
• Randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults in US and Australia.
• Healthy individuals >70 y/o (or >65 y/o for blacks and Hispanics); avg age 74; female 56%; Diabetic 11%
• Public Funding: United States and Australian governments and is led by the Berman Centre for Outcomes and Clinical Research in the U.S. and Monash University in Australia.
• Exclusion criteria: cardiovascular or cerebrovascular disease, dementia, high bleeding risk
• Primary Outcome: all-cause death, dementia, or physical disability
• Secondary outcome: Hemorrhage, stroke, MI, hospitalization for heart failure, fatal CVD, cancer

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ASPREE Results

Aspirin did not prolong disability-free survival

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Primary outcomes (Events per 1000 person-years)

• All-cause death, dementia, or physical disability
• Aspirin did not prolong disability-free survival
• 12.7 aspirin vs 11.1 placebo
• HR 1.14; 95% CI 1.01 - 1.29
• Cancer contribution to death was higher in the aspirin group
• HR 1.31, 95% CI 1.10-1.56

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Secondary outcomes (Events per 1000 person-years)

• CVD event: 10.7 aspirin vs 11.3 placebo (p = 0.79)
• Major CV event: 7.8 aspirin vs 8.8 placebo (p=0.89)
• Major hemorrhage: 8.6 aspirin vs 6.2 placebo (p <0.001)
• Intracranial bleeding: 2.5 aspirin vs 1.7 placebo (p <0.05)
• Upper GI bleed: 2.1 aspirin vs 1.1 placebo (p <0.05)

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ASPREE�Cumulative Incidence of Cardiovascular Disease

ASPREE�Cumulative Incidence of Major Hemorrhage

ASPREE Trial Results

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• Effect of Aspirin on All-Cause Mortality in the Healthy Elderly - PubMed (nih.gov) N Engl J Med. 2018;379(16):1519. 
• Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death.
• Effect of Aspirin on Disability-free Survival in the Healthy Elderly - PubMed (nih.gov)�N Engl J Med. 2018;379(16):1499.
• Aspirin use in healthy elderly persons did not prolong disability-free survival over a period of 5 years but led to a higher rate of major hemorrhage than placebo. 

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• Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly | NEJM. N Engl J Med. 2018;379(16):1509.
• The use of low-dose aspirin as a primary prevention strategy in older adults resulted in a significantly higher risk of major hemorrhage and did not result in a significantly lower risk of cardiovascular disease than placebo.
• Higher mortality in aspirin group.

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Interpretation of ASPREE

Among HEALTHY elderly patients low-dose aspirin therapy for primary prevention was not beneficial at 4.7 years follow up.

• No improvement in disability-free survival, CVD events, cancer
• Increased risk of major bleeding and mortality

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BUT…the subjects were healthy elderly patients

• Exclusion criteria: cardiovascular or cerebrovascular disease, dementia, high bleeding risk
• Closer to our population than most studies but not quite there yet.

Summary of Study -- Aspirin in Reducing Events in the Elderly - American College of Cardiology (acc.org)

Safety of Ceasing Aspirin Used Without a Clinical Indication After Age 70 Years: A Subgroup Analysis of the ASPREE Randomized Trial

• ASPREE was interpreted by some to be relevant only to initiation of Aspirin and not discontinuation of Aspirin
• Study tried to use ASPREE data to answer if aspirin cessation among consistent users had an effect on survival
• Not enough statistical power – Inconclusive
• Perhaps the ASPREE-XT will improve statistical power

Safety of Ceasing Aspirin Used Without a Clinical Indication After Age 70 Years: A Subgroup Analysis of the ASPREE Randomized Trial | Annals of Internal Medicine (acpjournals.org)

ASPREE Project Continues�

• Big project with lots of sub-studies
• https://aspree.org/usa
• ASPREE-XT -- continuation of ASPREE trial beyond 4.7 years
• ASPREE Cancer Endpoints Study (ACES)
• ASPREE Cancer Treatment Study (ACTS)
• ASPREE-D (Depression)
• ASPREE-EWAS (Epigenetics)
• ASPREE-G (Genomics)
• ASPREE Longitudinal Study of Older Persons (ALSOP)
• ASPREE-XT Microbiome

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ASCEND Trial 2018�

Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus - NEJM

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• RCT of Aspirin 100mg qd vs placebo; N 15,480; type 2 DM w/out evidence of CVD; follow-up of 7.4 years
• Primary outcome: first serious vascular event ( MI, CVA/TIA, vascular related death, excluding intracranial hemorrhage)

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• Vascular events significantly lowered
• Aspirin 8.5% vs. Placebo 9.6% (rate ratio 0.88; 95% CI, 0.79 - 0.97; P=0.01)

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• Major bleeding events were significantly increased
• Aspirin 314 participants (4.1%) vs Placebo 245 (3.2%) (rate ratio 1.29; 95% CI, 1.09 - 1.52; P=0.003),
• Mostly GI bleeding and other extracranial bleeding.

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• No significant difference in the incidence of GI tract cancer

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• Aspirin use prevented serious vascular events in persons who had diabetes and no evident cardiovascular disease but caused major bleeding events. The absolute benefits were largely counterbalanced by the bleeding hazard. 

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ARRIVE Trial 2018�Aspirin to Reduce Risk of Initial Vascular Events

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE)

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• Aspirin 100mg qd vs placebo; n = 12,546; Median follow up 5 yrs
• Primary care setting, double-blinded, placebo-controlled, multicenter study (7 countries); nondiabetic patients with a moderate risk (ASCVD 10–20% 10-year risk) of CAD
• Men >50 y/o; Women >60 y/o; avg age 63.9
• Primary outcome: Cardiovascular death, MI, unstable angina, CVA/TIA
• Exclusion criteria: High risk of bleeding, diabetes

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• Aspirin did not lower the risk of major CV events
• Aspirin 4.3% vs placebo 4.5% (p=0.60)

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• Significant number of GI bleeds
• aspirin 61 (0.97%) vs Placebo 29 (0.46%) (p=0·0007)
• Even though high GI bleed risk was an exclusion criteria.

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Summary - Aspirin to Reduce Risk of Initial Vascular Events - American College of Cardiology (acc.org)

Do we see a trend?

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• Probably not much cardiovascular benefit

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• High risk of bleeding

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2019 ACC/AHA Guideline for Primary Prevention of CVD

IIb 🡪 Benefit equal to or greater than risk

A 🡪 High quality evidence

III: Harm 🡪 Risk > Benefit

B-R 🡪 Moderate quality evidence; 1 or more RCTs

III: Harm 🡪 Risk > Benefit

C-LD 🡪 Limited Data. Observational studies. Limitations in design.

2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines | Circulation (ahajournals.org)

USPSTF Update Pending

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Draft Recommendation: Aspirin Use to Prevent Cardiovascular Disease: Preventive Medication | United States Preventive Services Taskforce (uspreventiveservicestaskforce.org)

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USPSTF changing recommend from “insufficient evidence” to recommending against starting aspirin for primary prevention in > 60 y/o

Risk of Bleeding with Aspirin

• Significant number of bleeding events in ASPREE, ASCEND, and ARRIVE
• Mostly GI bleeding but some intracranial
• Mortality from non-traumatic intracranial bleeding ~ 40%
• Lower dose, lower risk of bleeding
• “…limited justification to use aspirin doses >100mg daily for primary prevention.” 2019 ACC/AHA Guideline of PP of CVD
• Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials - PubMed (nih.gov)

Risk of Bleeding with Aspirin

• Bleeding Risks With Aspirin Use for Primary Prevention in Adults: A Systematic Review for the U.S. Preventive Services Task Force - PubMed (nih.gov) 2016
• 58% increased risk in GI bleeding (OR 1.58, 95% CI 1.29 -1.95])
• 27% increase in hemorrhagic stroke risk  (OR 1.27, CI 0.96 - 1.68])

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• Frequency of Intracranial Hemorrhage With Low-Dose Aspirin in Individuals Without Symptomatic Cardiovascular Disease: A Systematic Review and Meta-analysis - PubMed (nih.gov)
• 13 RCTs including ASCEND, ARRIVE, ASPREE
• Assess risk of Intracranial hemorrhage in individuals without symptomatic CVD
• Low- dose aspirin vs placebo
• Increased risk of intracranial bleeding (RR 1.37, 95% CI 1.13-1.66)

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Risk of Bleeding with Aspirin

• Bleeding risk of aspirin is significant
• This same risk probably applies to secondary prevention as well.
• What factors trump the bleeding risk for primary prevention? Secondary prevention?
• Family hx
• Poorly controlled HTN/HLD
• Elevated Coronary Ca++ score
• ASCVD score >10%
• Does a PPI or H2 blocker reduce GI bleeding risk?
• Age-specific risks, severity, time course, and outcome of bleeding on long-term antiplatelet treatment after vascular events: a population-based cohort study - PMC (nih.gov)

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Aspirin for Secondary Prevention of CVD

• What about the data supporting aspirin for secondary prevention
• Acute MI, unstable angina
• Acute ischemic stroke, post stroke
• CAD, post CABG, post MI, PCI/stents
• PAD, Carotid artery disease
• Data showing efficacy of aspirin in the acute setting is strong
• Anti-Thrombotic Trialists’ Collaboration meta-analysis (1970s, 1980s)
• Data showing efficacy of aspirin for lifelong secondary prevention is lacking
• Follow periods of 4 years in most studies.
• Studies using various combinations of P2Y12 inhibitors, aspirin, and anticoagulants are underway.

Lifelong Aspirin for All in the Secondary Prevention of Chronic Coronary Syndrome | Circulation (ahajournals.org)

Is it time for a study looking at discontinuation of aspirin for secondary prevention in the elderly?

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Aspirin Topics for the future

Role of aspirin in

• PVD
• Primary/Secondary Prevention of Stroke
• Atrial Fibrillation
• Comparison of aspirin and DOACs
• DVT prophylaxis
• Post hip fracture
• Comparison of aspirin and DOACs

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Thank you for listening��David Shepherd

Aspirin in PVD

Antithrombotic Therapy for Peripheral Artery Disease in 2018 | Cardiology | JAMA | JAMA Network

Antithrombotic Therapy for Peripheral Artery Disease in 2018

• Of Life and Limb: Addition of Low-Dose Rivaroxaban for Secondary Prevention After Peripheral Artery Disease Surgery | Circulation (ahajournals.org)
• compared CAD+PAD patients, patients with PAD only are less likely to receive antiplatelet drugs, statins, or smoking-cessation interventions

Aspirin for CVA prevention

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients (nih.gov) – 1/12/2002

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• 2002 meta-analysis from Antithrombotic Trialists Collaboration included 195 randomized controlled trials of high risk patients
• Primary prevention: 25% RRR in nonfatal stroke compared to placebo
• Secondary prevention: 22% reduction
• Benefit independent of sex, age, diabetes, hypertension
• Low dose as effective as higher doses.

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• 🡪 So it is good for primary prevention? Right?

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Aspirin for CVA prevention

Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force - PubMed (nih.gov) -- 2016

• Aspirin has no significant benefit on non-fatal stroke
•  RR 0.95, 95% CI 0.85-1.06

Aspirin use in endovascular stroke treatment. �afety

MR CLEAN-MED Trial

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial - The LancetS

Interpretation

• Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome.

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DAPT for CVA

Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events - PubMed (nih.gov)

• RCCT, 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-dose aspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed them for a median of 28 months.
• Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes. 

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Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial - The Lancet

• Adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or transient ischaemic attack is associated with a non-significant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin.

Effects of clopidogrel added to aspirin in patients with recent lacunar stroke - PubMed (nih.gov)

• Double blind, multicenter trial, n=3020, pts with recent lacunar infarcts.
• Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. 

Aspirin early after CVA/TIA

• Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials - PubMed (nih.gov)
• Meta-analysis, 12 trials, randomized trials of aspirin vs control in secondary prevention after TIA or ischemic stroke. N=15,778.
• Aspirin reduced 6 week recurrence by 60%

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Summary: Aspirin for CVA

• Acute treatment 🡪 Aspirin or DAPT.
• Most important during the first 6 weeks after CVA
• primary prevention – ~20% reduction
• secondary prevention – ~20% reduction
• Low dose aspirin is as effective as higher dose with lower bleeding risk.
• Addition of second antiplatelet agent (clopidogrel) does not seem to reduce risk significantly.
• BUT, increases bleeding risk.

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Aspirin for DVT prophylaxis

• Can we use Aspirin for DVT prophy in hip fracture with non-surgical management?

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Aspirin for DVT prophylaxis after hip fracture surgery

Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial - PubMed (nih.gov)

• In a randomized trial of almost 18,000 patients, most of whom had hip fracture surgery/HFS, compared with placebo, aspirin administered for 35 days reduced the incidence of symptomatic DVT without an increase in major bleeding events but had no effect on the rate of clinically significant PE [98].

Intermittent Pneumatic Compression for the Prevention of Venous Thromboembolism after Total Hip Arthroplasty - PubMed (nih.gov) Clin Orthop Surg . 2017 Mar;9(1):37-42. doi: 10.4055/cios.2017.9.1.37. Epub 2017 Feb 13.

• In a randomized trial of 275 patients undergoing TKA, when used in combination with pneumatic compression devices, four weeks of aspirin had similar rates of DVT when compared with LMW heparin (18 versus 14 percent) [78]. In another trial in patients with THA, IPC devices in combination with six weeks of aspirin did not result in a significant reduction in rates of VTE compared with aspirin alone [136].

Association of Aspirin With Prevention of Venous Thromboembolism in Patients After Total Knee Arthroplasty Compared With Other Anticoagulants: A Noninferiority Analysis - PubMed (nih.gov) JAMA Surg. 2019 Jan 1;154(1):65-72.

• In a review of the Michigan Arthroplasty registry of over 41,000 patients undergoing TKA, the overall incidence of VTE was 1.38 percent [142]. The incidence was 4.79 percent among those who received no pharmacologic prophylaxis, 1.42 percent for those treated with anticoagulation alone (various agents and combinations), 1.31 percent for those prescribed both anticoagulation and aspirin, and 1.16 percent for those treated with aspirin alone. Bleeding occurred in 1.10 percent of patients overall, and in 1.50, 1.35, 1.14 and 0.90 percent of the no prophylaxis, anticoagulation and aspirin, anticoagulation, and aspirin groups, respectively. Aspirin alone was noninferior for both the composite VTE outcome (unadjusted analysis) and for bleeding complications (unadjusted and adjusted analysis) compared with other nonaspirin treatment.

Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement: A Systematic Review and Meta-analysis of Randomized Clinical Trials | Orthopedics | JAMA Internal Medicine | JAMA Network - Feb 3, 2020

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Wide range of findings from RCTs. RCTs with Placebo control group excluded.

Primary outcome was postoperative DVT.

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No statistically significant difference between Aspirin and commonly used anticoagulants.

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No significant difference in the risk of adverse events.

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Most trials in the study had high rates of bias

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The Anderson et al RCT gave 5 days of rivaroxiban prior to aspirin.

Aspirin in healthy individuals to modify VTE risk

Effect of low-dose aspirin on the occurrence of venous thromboembolism: a randomized trial - PubMed (nih.gov)

• In the Women's Health Study, VTE rates were no different in healthy females that were randomly assigned to receive either low-dose aspirin (100 mg orally every other day) or placebo for 10 years (1.18 versus 1.25 events per 1000 patient-years) [60]. On subgroup analysis, no VTE risk factor (ie, age, obesity, menopausal status, reported VTE at baseline, factor V Leiden, prothrombin gene mutation) modified the relationship between aspirin and the overall risk of VTE. However, the use of aspirin was associated with an increased risk of gastrointestinal bleeding, peptic ulcer, hematuria, bruising, and epistaxis.

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1. do we need to give aspirin for secondary prophylaxis of CVA?
2. Is 81mg as good as 325mg?
3. Is plavix better?
4. Do we need to use plavix with aspirin in CVA?

�Aspirin for Afib

• Efficacy? ARe we really lowering risk of CVA with aspirin?
• Bleeding risk compared to warfarin and DOACs?

Extra Slides

Interesting facts

• Enteric coated aspirin does not protect against GI bleeding.
• Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product - PubMed (nih.gov)

Antithrombotic Trialists Collaboration

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients (nih.gov)

• 2002 meta-analysis from Antithrombotic Trialists Collaboration included 195 randomized controlled trials of high-risk patients
• Primary prevention: 25% RRR in nonfatal stroke compared to placebo
• Secondary prevention: 22% reduction
• Benefit independent of sex, age, diabetes, hypertension
• Low dose as effective as higher doses

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