Aspirin

The regular use of aspirin has an inverse association between the risk of colorectal and other digestive tract cancers: The favorable effect of aspirin increases with the longer duration of use, and for colorectal cancer with increasing dose.

Recommended for prevention of CV disease is in the subset of patients with favorable risk-benefit profile.

Low dose prophylactic aspirin utilized to decrease vascular disease or malignancy is associated with one death and one disabling hemorrhagic stroke per year in every 10,000 people suggesting risks are minimal.

Does not antagonize the acute or long-term effects of captopril on infarct size or left ventricular dilation 1 year after acute myocardial infarction.

Provides no health benefits in healthy women below the age of 65 years.

Decreases risk of first myocardial infarction and death in women over the age of 65 years who take one to six aspirins per week.

In pooled data from more than 200 trials patients with vascular disease on long-term low-dose aspirin have a reduction in the risk of major vascular events by more than 20%, exceeding modest bleeding risks.

Low dose aspirin 75-100 mg per day should be used as secondary prevention of cardiovascular events in patients with known vascular disease.

Meta-analyses of low dose aspirin in primary prevention of coronary disease in diabetics, reduced coronary artery disease event disease events by only 9% while increasing extracranial bleeding by 55% relative to non-diabetic patients.

Aspirin use in patients with stable coronary artery disease and hypertension is associated with reduced risk for adverse cardiovascular outcomes among those with prior ischemic events, but among those without prior ischemic events it was not associated with the reduction in risk (Bavry AA et al).

Aspirin has utility in the setting of vascular procedures such as PCI, reducing the risk of restenosis, and is recommended for several months up to a year after the procedure.

Effective therapy in the secondary prevention of recurrent myocardial infarction.

In patients with ST segment elevation myocardial infarction mortality is decreased compared to placebo by 23% with aspirin, 25% with streptokinase and 41% for the combination of aspirin and streptokinase.

Among long term colorectal cancer survivors, regular use of nonsteroidal anti-inflammatory drugs after colorectal cancer diagnosis is significantly associated with improve survival in patients with KRAS wild-type tumors.

About 10% of patients do not demonstrate platelet responsiveness to 325 mg of aspirin given daily for 7 days.

Estimated that 5-9% of patients are aspirin resistant and 23% are aspirin semi-responders.

Aspirin resistant and semi-responders are older and have a higher percentage of female patients.

The Women’s health study showed females taking aspirin experience is 17% decrease in stroke risk, and significantly reduced major events in females age 65 years and greater.

Low dose aspirin has a roll in stroke prevention, particular among all the females, who account for the majority of American population at age 64 and above, and for stroke deaths in America.

Poor biological response to aspirin does not exceed 5-10% in healthy adults but reaches 25% in patients with diabetes.

Low-dose ASA results in injury to the small bowel mucosa and tends to persist for up to three months after its discontinuation.

Low-dose aspirin does not help to prevent cardiovascular events in men and women weighing more than 70 kg (~154 lbs) (Rothwell PM).

The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight, showing benefits in individuals weighing 50-69 kg but not in those weighing 70 kg or more.

Higher doses of aspirin, however, had the opposite interaction with bodyweight, reducing risk only in those of higher weight.

Aspirin-related reductions in colorectal cancer risk were also weight dependent.

Patients with peripheral, cerebral and coronary artery disease have aspirin resistance.

Use associated with a 2-3 fold increased risk of developing a serious gastrointestinal bleed.

A meta-analysis found the rate of UGI bleeding associated with aspirin use at doses less than 100 mg daily to be 1.1%, at doses 100-325 mg per day to be 2.4%, and doses greater than 325 mg to be 2.5% (Serebruany VJ et al).

Risk of gastrointestinal bleeding with aspirin increases with prior peptic ulcer disease, age greater than 70 years, concomitant use of clopidogrel, anticoagulants, corticosteroids, and nonsteroidal anti-inflammatory drugs.

ISIS-2 trial demonstrated that daily aspirin in the setting of acute myocardial infarction reduces the risk of vascular death or 23%.

The benefits of aspirin in aiding the dissolution of a thrombus over hours to days and restoring bloodflow in the setting of an acute stroke or myocardial infarction greatly outweighs any short-term bleeding risks.

Aspirin is the mainstay of early therapy in the settings of acute coronary syndromes and stroke.

In the British Doctors’ Trial and the Physicins Health Study and other studies involving more than 100,000 participants have shown modest reduction of major vascular events in patients without vascular disease, that is primary prevention.

In the Japanese Primary Prevention Project low dose aspirin vs no aspirin for prevention of atherosclerotic events in 14,658 Japanese patients 60 years or older with hypertensioisn, dyslipidemia, or diabetes:after 5 years no significant difference in the rate of major athersclerotic events occurred (Ikeda Y et al).

In a study of community-dwelling persons 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 physical disability randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally.(Aspirin in Reducing Events in the Elderly (ASPREE) trial).

In the above study there was no benefit with continued aspirin use with regard to the primary end point: rate of the composite of death, dementia, or persistent physical disability, but the rate of major hemorrhage was higher in the aspirin group than in the placebo group (3.8% vs. 2.8%.

The risk of aspirin for primary protection in the elderly carries a risk of severe G.I. bleeding that is greater than a potential benefit for the prevention of a  first heart attack or stroke.

In contemporary practice the routine use of aspirin for the primary prevention of cardiovascular events may have a net harmful effect (Shah R).

In patients with very low risk for cardiovascular disease prophylactic aspirin is not indicated.

Coadministration of low dose aspirin and a PPI for prevention of cardiovascular events results in fewer lifetime upper G.I. bleeding events (3.4% vs. 7.2%) and fewer recurrent myocardial infarctions (26 fewer events per 10,000 patients), and an additional 38 days of life for patient compared with aspirin alone (Saini SD et al).

The most important risk for aspirin therapy is that of hemorrhagic stroke.

Relative risk of hemorrhagic stroke by 84% compared to placebo.

The balance between the benefits in preventing major vascular events and the risk of serious bleeding underlies the decision making process as to when to use aspirin.

Generally, the higher risk of vascular events, the more advantageous it is to use aspirin.

Patients most at risk for hemorrhagic stroke have had a prior stroke, cerebral bleeding history or hypertension.

Aspirin reduces the risk of recurrence when given to patients with unprovoked venous thromboembolism who have discontinued anticoagulant therapy, with no increase in the risk of major bleeding(Becattini Celia).

For average risk patients age 50-65 taking aspirin for 10 years, there is a relative reduction of between 7% for women, and 9% for men, in the number of cancer, myocardial infarction, stroke events over a 15 year, and overall 4% relative reduction in all deaths over 20 years.

Prophylactic aspirin for a minimum of five years between 75-325 mg a day has favorable benefits and favorable harm profile ( Cuzick J et al).

In a trial comparing patients with established cardiovascular disease, there was substantial though switching to 81 mg of daily aspirin and no significant differences in cardiovascular events with major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily (Jones WS).

In the above analysis aspirin protected against colorectal, esophageal, stomach, breast prostate and lung cancers.

Regular aspirin intake may reduce risk of death from prostate cancer.

Low-Dose Aspirin for Preventing Recurrent Venous Thromboembolism (ASPIRE Investigators) studied patients with a first episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued.

Long-term treatment with a vitamin K antagonists are very effective in preventing a recurrence of venous thromboembolism while treatment continues, but has not been shown to improve survival, is associated with an increased risk of bleeding, and is inconvenient.

Combined anticoagulant therapy and aspirin use is associated with the 1.5-2.5 fold increase in bleeding risk in patients with atrial fibrillation and a 2-3 fold increase in patients with ischemic disease and prosthetic heart valves.

Many patients who have had a first episode of unprovoked venous thromboembolism discontinue anticoagulant therapy after 3 to 6 months despite recommendations to prolong therapy.

Low-dose aspirin is a simple, inexpensive, and widely available treatment that is effective for the prevention of arterial vascular events and for the primary prevention of venous thromboembolism in high-risk surgical patients.

Aspirin may also be effective in preventing a recurrence of venous thromboembolism after a first event.

The Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study was a double-blind, randomized, placebo-controlled study of the use of low-dose aspirin in patients who had had a first-ever unprovoked venous thromboembolism and who had completed initial anticoagulation therapy: Random assignment of patients who had completed anticoagulation therapy to aspirin, at a dose of 100 mg daily, or placebo for a minimum of 2 years: Recurrent venous thromboembolism occurred in 73 of 411 patients (18%) assigned to placebo and 57 of 411 (14%) assigned to aspirin, a rate of 6.5% per year vs. 4.8% per year, respectively.

The rates of all bleeding episodes did not differ significantly between the study groups.

The analysis of net clinical benefit, defined as a reduction in the rate of the composite of venous thromboembolism, myocardial infarction, stroke, major bleeding, or death from any cause, showed that aspirin was associated with a reduction of 33% in that composite outcome, with an event rate of 9.0% per year in the placebo group as compared with 6.0% per year in the aspirin group.

Results of the ASPIRE trial did not show a significant reduction in the primary outcome of recurrent venous thromboembolism with aspirin as compared with placebo in patients who had had a first unprovoked venous thromboembolism, it did show that aspirin reduced the secondary composite outcome of major vascular events by 34% without increasing bleeding and resulted in a significant net clinical benefit.

The estimated reduction of 26% in the rate of recurrence of venous thromboembolism with aspirin is consistent with results from the recently reported WARFASA study,14 which showed a reduction of 42% in the rate of recurrence of venous thromboembolism.

The combined results of the WARFASA and ASPIRE trials show a highly significant reduction of 32% in the rate of recurrence of venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess of bleeding.

The addition of aspirin to an anticoagulant increases the risk of major bleeding by 50% compared with anticoagulant use alone, from 1.8 to 3% at six month follow-up (Steinberg KA et al).

For patients who discontinue anticoagulation, the risk of a late recurrence of venous thromboembolism after a first unprovoked event remains high: approximately 10% in the first year and 30% after 10 years.

Recurrent venous thromboembolism is associated with a case fatality rate of 5 to 10% and a risk of post-thrombotic syndrome that is increased by a factor of 6.

In this context, aspirin, although substantially less effective than warfarin, provides an attractive alternative because it is simple and inexpensive and its safety profile is well documented.

Patients who have had a first unprovoked event of venous thromboembolism appear to be at greater risk for arterial thrombosis and cardiovascular death, and an added appeal of aspirin is that it has been associated with an overall reduction in the risk of major thrombotic events (arterial and venous) and cardiovascular death.

The ASPIRE study suggests that for every 1000 patients treated for 1 year, aspirin can be expected to be associated with 17 fewer episodes of recurrent venous thromboembolism and 28 fewer major thrombotic events, at the cost of 5 nonfatal bleeding episodes.

Reduces significant reduction in all cause mortality, MI and ischemic stroke.

US Preventative Services Task Force (USPSTF).recommends adults age 50-59 years old with a 10 year CVD risk of 10% or greater should take daily low dose aspirin for the prevention of CVD and colorectal cancer.

Risk of cerebral bleeding varies with age, race, presence of amyloid angiopathy and bleeding disorder.

Meta analysis of 287 studies demonstrated 25-30% reduction in cardiovascular events such as myocardial infarction, stroke and deaths in aspirin treated patients with high risk.

Meta-analysis including 135,000 of patients at high risk for vascular disease events revealed a reduced relative risk of such events by 22%, absolute risk reduction of 2.5%, with an associated increased relative risk of major extracranial bleeding events by 60% (Antithrombotic Trialists’ Collaboration).

Meta-analysis for secondary prevention was associated with a reduced relative risk of myocardial infarction, by 31%, ischemic stroke by 22%, and cardiovascular deaths by 13% (Bigent C et al)).

Low-dose aspirin significantly reduces heart failure mortality and morbidity as demonstrated in a trial of 1400 older adults in a heart failure disease management program (Bermingham M et al).

Meta-analyses suggest that for every 1000 patients treated for a 5-year period aspirin therapy would be expected to result in 1 excess hemorrhagic stroke compared with prevention of 14 myocardial infarctions in patients at moderate risk for coronary heart disease, suggesting aspirin therapy outweighs elevated risk of hemorrhagic stroke.

10,000 patients on asa for secondary prevention would be expected to prevent approximately 250 major vascular events with approximately 40 major extracranial bleeding events: for 6 major vascular events prevented 1 major bleeding event will occur.

The Aspirin for Asymptomatic Atherosclerosis trial involving 28980 men and women age 50-75 years free of clinical cardiovascular disease, with 3350 patients with low ABI treated with 100 mg of daily aspirin compared to placebo: no difference was noted in vascular events.

The combination of aspirin and dipyridine compared to aspirin alone in patients with cerebrovascular disease is superior in preventing new strokes and other cardiovascular events without an increase in bleeding episodes.

10-20% of patients treated with aspirin experience a recurrent vascular event within 5 years of treatment.

Recommended to stop aspirin 7 days before surgery.

After temporary interruption of treatment for surgery it is suggested that resumption of treatment approximately 24 hours after surgery when there is adequate hemostasis.

Noncardiac surgery associated with platelet activation, and coronary artery thrombus with myocardial infarction may occur perioperatively.

Perioperative aspirin may prevent major vascular complications by inhibiting thrombus formation.

In randomized trials aspirin prevent MI and major vascular events in patients not undergoing surgery.

High dose aspirin not superior to low dose aspirin in preventing vascular complications.

Low dose aspirin associated with fewer gastric toxic effects.

In a randomized trial of 10,010 patients with cardiovascular risk, undergoing noncardiac surgery with administration of aspirin or placebo before and throughout early postoperative period: aspirin had no effect on the rate of composite death, or no fatal MI, but increased the risk of major bleeding .(POISE-2 Investigators).

Reduces risk of ischemic stroke by approximately 25%.

Use in the perioperative period associated with increased operative blood loss and increased transfusion requirements.

Although aspirin increases operative blood loss, evidence of significant effects on mortality and morbidity is lacking.

Aspirin increases the risk of bleeding complications by 1.5 times, but it does not increase the severity or mortality of patients in most surgical procedures(Chassot PG).

Aspirin use with intracranial or transurethral prostate surgeries are associated with significant bleeding complications from surgery.

Postoperatively aspirin may be restarted when risk of bleeding from surgery has diminished.

Physicians need to treat 278 patients to prevent one fatal MI, treat 256 patients to prevent one ischemic stroke and treat 833 patients to cause one hemorrhagic stroke.

Reduces incidence of colon cancer by 40-50% in regular aspirin users.

Regular use of aspirin in patients with history of colorectal adenomas or cancer reduces the risk of recurrent adenoma within 1-3 years.

Long-term regular use of 2 or more standard aspirin tablets is associated with a significant reduction in the risk of colorectal cancer in an average risk population.

Nurses’ Health Study revealed that the greatest reduction in the risk of colorectal cancer occurs in women with the use of 14 standard aspirin tablets per week but benefit only noted after 10 years of sustained use.

Randomized trials of cardiovascular prevention with aspirin reduces the 20 year risk of colorectal cancer by 24% and of associated mortality by 35% (Rothwell PM et al).

Long-term Aspirin Use and Lower Pancreatic Cancer Risk

The longer a person takes low-dose aspirin, the lower the risk for pancreatic cancer.

For every year of aspirin use, the risk for pancreatic cancer decreases by 6% with low-dose aspirin and by 2% with regular-dose aspirin.

The reduction in risk for pancreatic cancer is greater in people who started taking low-dose aspirin 20 years before study enrollment than in those who started 3 years before enrollment (60% vs 48%).

Discontinuation of aspirin use in the 2 years prior to the study enrollment was associated with a 3-fold increased risk for pancreatic cancer, compared with continued use.

People at increased risk for pancreatic cancer, such as those with appreciable family histories of pancreatic cancer or other cancers that might indicate an increased risk could benefit from low-dose aspirin.

Nurses’ Health Study 25% reduction in death from all causes associated with current use of aspirin compared to never users of aspirin.

Reduces vascular graft and arterial occlusion by 48%.

Reduces pulmonary embolism by 67% and deep vein thrombosis by 23% in patients treated with aspirin compared to controls.

Regular use associated with an inverse association of 0.8 breast cancer relative risk compared to nonusers.

Nurses’ Health Study by Holmes consising of 4164 female nurses diagnosed with breast cancer and suvived at least one year: aspirin use associated with a 74% reduction in risk of breast cancer death, compared to never users (Holmes MD.

In a metaanalysis of 42 reports involving 99,769 individuals, there was a significant decrease in breast cancer risk with aspirin use.

Nurses’ Health Study by Holmes indicated that a distant recurrence risk reduction of 43% for 6-7 day a week aspirin users, and a 60% reduction in risk for 2-5 day per week aspirin users compared to nonusers (Holmes, MD).

May act by inhibiting estrogen biosynthesis and be a breast cancer chemopreventative agent.

Among women living at least 1 year after the diagnosis of breast cancer aspirin use associated with decreased risk of distant recurrence and death (Holmes MD).

Efficacious against development of colorectal adenomas and cancer through its actions as a COX-2 inhibitor, which is overexpressd in 80-85% of colorectal cancers.

In sensitive patients a single dose can precipitate an asthmatic attack.

Should not be used in children or adolescents with viral syndromes because of the risk of Reye’s syndrome.

A dose of 75 mg per day doubles the risk of gastrointestinal bleeding by inhibiting cyclooxygenase and causing gastric ulceration, making it likely that all therapeutic dose levels have gastrointestinal risks.

Eradication of H. pylori and long-term treatment with proton pump inhibitors are effective in the prevention of aspirin induced GI lesions and symptoms in patients with aspirin induced erosions or peptic ulcers.

In a randomized, double-blind, controlled study comparing the efficacy of famotidine with pantoprazole in the prevention of recurrent dyspeptic or complicated ulcer/erosions. In patients taking low-dose aspirin: the prevalence of significant dyspepsia or peptic alteration was significantly higher in the famotidine group compared with the pantoprozole group (20% vs. 0%)(Ng FH).

The above the study demonstrates that famotidine is inferior to proton pump inhibitor therapy in preventing aspirin related peptic ulcer/erosions in the upper G.I. tract.

In patients unable to take aspirin because of gastrointestinal toxicity clopidogrel is recommended.

Recommend for the secondary prevention of cardiovascular disease in patients with prior cardiovascular these because it decreases the risk of cardiovascular disease events and mortality in clinical trials of men and women with cardiovascular disease and (Baigent C et al).

The Antithrombotic Trialists’ (ATT) compared with placebo, aspirin resulted in an approximate 10% relative risk reduction of cardiovascular disease mortality and total mortality and an approximate 20% relative reduction of cardiovascular events, with similar reduction in coronary event and ischemic strokes.

Adding clopidogrel to aspirin increases the relative risk of major bleeding perioperatively by 30 to 50% compared to aspirin alone.

Dual antiplatelet therapy does not increase operative mortality, except for intracranial neurosurgery, but is associated with a slight increase in the need for re-operation and a 30% increase in the need for transfusions (Douketis JD).

Most surgical procedures, with the exception of intracranial neurosurgery, can be performed while the patient is receiving dual antiplatelet therapy without significantly increasing morbidity or mortality.

Other surgical procedures that should be avoided, while on antiplatelet therapy, include operations on the spinal cord or posterior chamber of the eye.

In a dual antiplatelet study (ASA vs. ASA + clopidogrel) of greater than 12 months in patients with drug eluting stents, dual treatment was not significantly more effective than aspirin monotherapy in reducing rate of myocardial infarction or death from cardiac causes (Park Seung-Jung).

The Beaver Dam Eye Study assessed the use of ASA for 5 years and was not associated with Age-related macular degeneration, but use for 10 years associated with small but significant increase in risk of incident late and neovasvular AMD (Klein BEK et al).

In patients with low cardiovascular disease risk and no prior events, aspirin use is not associated with reduced cardiovascular events.

In a low risk primary prevention population, the increased risk of gastrointestinal bleeding and hemorrhagic stroke associated with aspirin use outweighs any potential benefit in cardiovascular risk reduction.

A randomized trial among Japanese seniors showed no impact of daily low-dose aspirin on cardiovascular and stroke risk over 5 years.

The US Preventive Services Task Force recommends aspirin use if the 5-year coronary heart disease risk is 3% or greater, or 10-year risk 6% or greater.

The American Heart Association and American College of Cardiology recommend aspirin use if the 10-year cardiovascular disease risk is at least 6% to 10%.

The combination of aspirin and oral anticoagulants is appropriate for up to 12 months after acute coronary syndromes, percutaneous coronary intervention, or stenting procedurals.

With stable vascular disease use of anticoagulants alone is recommended, GI ven the lack of substantial benefit in the increased risk of bleeding from combination of agents.

For mechanical heart valves aspirin plus oral anticoagulant therapy is appropriate but only with warfarin and not direct oral anticoagulants.

In a study of community-dwelling persons 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 physical disability randomly assigned to receive 100 mg per day of enteric-coated aspirin or placebo orally.(Aspirin in Reducing Events in the Elderly (ASPREE) trial).

In the above study there was no benefit with continued aspirin use with regard to the primary end point: rate of the composite of death, dementia, or persistent physical disability, but the rate of major hemorrhage was higher in the aspirin group than in the placebo group, 3.8% vs. 2.8%.

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.

Randomized trials have shown the efficacy of aspirin for the secondary prevention of cardiovascular disease among persons with a history of coronary heart disease or stroke.

Evidence supporting a benefit of aspirin therapy in the primary prevention of cardiovascular or other chronic disease is less conclusive despite favorable trends suggesting that aspirin use reduces the incidence of cardiovascular events and possibly reduces the incidence of cancer and cancer-related mortality, particularly from colorectal cancer.