Aspirin Therapy Guidelines

Aspirin belongs to a class of medications called nonsteroidal anti-inflammatory drugs (NSAIDs). Aspirin and other NSAIDs like ibuprofen (Motrin, Advil, etc.) and naproxen (Aleve, etc.), are widely used to treat fever, pain, and inflammatory conditions such as arthritis, tendonitis, and bursitis. Aspirin has also been widely recommended for prevention of complications from athroscleotic disorders (heart attack, stroke and peripheral vascular disease). Aspirin is known chemically as acetyl salicylic acid and often abbreviated as ASA.

Aspirin also has an important inhibitory effect on platelets in the blood. This antiplatelet effect is used to prevent clotting of blood inside arteries, particularly in individuals who have atherosclerosis (narrowing of the arteries) or are otherwise prone to develop blood clots in their arteries.

Serious side effects of aspirin and other NSAIDs occur infrequently and generally tend to be more frequent with higher doses. It is advisable to use the lowest effective dose to minimize side effects.

The most common side effects of aspirin involve the gastrointestinal system, and include

• Ulcers of the stomach and duodenum (first part of the small intestine)
• Abdominal pain
• Nausea
• Gastritis (inflammation of the stomach)
• Even serious gastrointestinal bleeding from ulcers

Other side effects of aspirin include:

• Easy bruising
• Spinning sensation (vertigo)
• Ringing in the ears (tinnitus)
• Lightheadedness

Sometimes, ulcers of the stomach and bleeding occur without any abdominal pain, and the only signs of bleeding may be:

• Black tarry stools
• Weakness
• Dizziness upon standing (orthostatic hypotension)

Another serious but rare side effect of aspirin is intracranial hemorrhage (bleeding into the tissues of the brain), similar to a hemorrhagic stroke.

Aspirin can impair kidney and liver function, especially in patients who already have liver and kidney disease.

Occasionally, aspirin may be toxic to the liver.

Serious side effects of aspirin, such as bleeding ulcers or intracranial bleeding, are rare (less than 1% of patients) among patients taking moderate doses of aspirin (for example, 325 mg/day). Serious side effects of aspirin should be even lower with low doses such as 75-160 mg/day. However, the actual incidence of serious bleeding with long-term use of low dose aspirin has not been clearly determined.

These serious side effects also have been associated with aspirin:

• Thrombocytopenia (reduced blood platelets)
• Aplastic anemia (reduced production of red blood cells)
• Hemolytic anemia (increased destruction of red blood cells)
• Neutropenia (reduction of white blood cells)
• Pancytopenia (reduction of all cells in the blood
• Agranulocytosis (reduction of one type of white blood cell)
• Thromboembolism
• Hypoprothrombinemia
• Bronchospasm
• Angioedema
• Salicylism
• Serious allergic reactions

Some individuals are allergic to NSAIDs and may develop shortness of breath when an NSAID is taken. People with asthma are at a higher risk for experiencing serious allergic reaction to NSAIDs. Individuals with a serious allergy to one NSAID are likely to experience a similar reaction to a different NSAID.

In 2017, the U.S. Preventive Services Task Force (USPSTF) issued their final recommendations for the primary prevention of cardiovascular disease using aspirin. Based on their review of the published data:

• They encourage the use of low-dose aspirin in adults aged 50 to 59 years with a high risk of cardiovascular disease, who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years.
• Adults who are 60 to 69 and have high risk of cardiovascular disease may receive daily aspirin based on individual circumstances. According to the recommendations, persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin.
• In individuals younger than 50 years of age and older than 70 years of age, the data is insufficient to recommend daily aspirin.

In 2014 the FDA reviewed all the evidence on the use of aspirin for primary prevention and did not find sufficient evidence for use of aspirin for primary prevention.

An ideal dose of aspirin is one that maximizes its benefits but minimizes side effects. The ideal dose of aspirin for primary or secondary prevention of ischemic strokes and heart attacks has not been established firmly.

• In situations where an immediate antiplatelet effect is needed (for example, in the treatment of acute heart attacks, ischemic strokes, and unstable angina) aspirin at moderate doses (160–325 mg/day) will produce rapid and immediate antiplatelet effects. In the ISIS-2 trial, a dose of 160 mg/day given within 24 hours of the onset of symptoms of heart attack was shown to decrease deaths due to heart attacks by 23%. Therefore, this is the dose recommended for acute heart attacks and unstable angina.
• At lower doses, such as 75 mg/day, the antiplatelet effect of aspirin can be achieved in several days instead of minutes. Since the risk of serious bleeding from aspirin is lower at lower doses, 75 mg/day is an appropriate dose for long-term primary and secondary prevention. Even though aspirin at doses as low as 40 mg/d has been shown to have anti-platelet effects, there is insufficient and inconclusive data to show that such low doses are effective in preventing heart attacks and ischemic strokes.

There also is no evidence that higher doses of aspirin, such as 1000 mg/day or higher, is more effective than lower doses. Some studies even suggest that higher doses may not be as effective as lower doses. Since the side effects of aspirin are more frequent with higher doses, doctors generally do not recommend higher doses for long-term use.

Long-term, low dose aspirin (75-160 mg/day) infrequently causes serious side effects. Among people with advanced atherosclerosis (people who already have heart attacks and strokes, patients with angina or TIAs, and patients who need PTCA and coronary artery bypass surgery). The benefits of low dose aspirin usually outweigh the risks of long-term aspirin (discussed in this article).

Unlike the treatment of patients with advanced atherosclerosis, aspirin use among healthy subjects (for example, individuals with no prior heart attacks or strokes) is more controversial. In the U.S. Physicians' Health Study (a study comparing 325 mg of aspirin every other day to placebo among more than 20,000 healthy male doctors), there were fewer heart attacks among aspirin users as compared to placebo users. However, the overall rate of death from heart disease was no different between aspirin users and men on placebo. Furthermore, there is insufficient data to evaluate the benefit of aspirin among healthy women.

The potential benefits of long-term aspirin in healthy subjects may not justify the risks of serious side effects of aspirin, including bleeding from ulcers and blood vessels in the brain. Healthy individuals should discuss long-term therapy with aspirin with their doctors before they start taking aspirin.

Even though aspirin is available without a doctor's prescription and has been used safely for many years by patients for fever and pain, patients should NOT take aspirin on a long-term basis without consulting with their doctor.

Aspirin prevents blood clots from forming inside arteries affected by atherosclerosis, but aspirin does not prevent atherosclerosis. Other measures (such as losing excess weight, controlling high blood pressure and diabetes, lowering LDL cholesterol, increasing HDL cholesterol, and stopping cigarette smoking) are necessary to prevent atherosclerosis.

Most doctors now recommend low doses of aspirin long-term for patients with advanced atherosclerosis for secondary prevention purposes. Such patients include those with:

• Prior heart attacks
• Prior strokes
• Exertional and unstable angina
• TIAs (transient ischemic attack, mini-stroke)
• Vascular procedures such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass surgery (CABG).

People who have not had a heart attack or stroke but have a high risk for developing a heart attack or stroke should also receive long-term low dose aspirin. For example, the American Diabetes Association recommends that people 50 years of age or older with type 1 or type 2 diabetes who have a high risk for heart attacks or strokes because of hypertension, smoking, a family history of stroke or heart attacks, or abnormal lipid levels should receive aspirin daily. Adults age 50 to 59 with a high risk of cardiovascular disease may also be considered for low dose aspirin treatment.

People who should not take aspirin include:

• People with an allergy to aspirin or other NSAIDs.
• People with active ulcers, especially those with bleeding ulcers, because of the side effects of ulcers and bleeding with aspirin. Among people who must take aspirin but have had intestinal ulcers, the lowest doses of aspirin should be used only after the ulcers heal. It should also be taken together with a proton pump inhibitor such as pantoprazole (Protonix), esomeprazole (Nexium), rabeprazole (Aciphex), or lansoprazole (Prevacid, Prevacid SoluTab) to decrease the risk of recurrent ulcers.
• Pregnant women and nursing mothers (since aspirin is secreted into breast milk).
• Teenagers and children with the flu or chickenpox because of the associated risk of Reye's syndrome, a serious disease of the liver and nervous system that can lead to coma and death.
• People with advanced kidney or liver diseases since aspirin may cause toxicity to the kidney and liver.
• People at risk for developing intracranial hemorrhage.
• Some people undergoing elective surgery or procedures. (Patients taking aspirin should discuss with their doctors whether to stop aspirin for several days to up to two weeks before surgery and procedures to avoid excess bleeding.)

According to the FDA there is no good evidence supporting the use of aspirin to prevent a heart attack or stroke in people who have a low risk of developing a heart attack or stroke.

Aspirin is widely used either alone or in combination with other antiplatelet agents to prevent blood clots from forming in arteries. Aspirin is used specifically in several situations including:

1. Aspirin often is prescribed in moderate doses (160-325 mg/day) for people who are having heart attacks to limit the extent of damage to the heart's muscle (by preventing further blood clot formation in the blood vessels of the heart and reduction of blood flow), prevent additional heart attacks, and improve survival.
2. Aspirin often is prescribed to patients undergoing surgery to open or bypass blocked arteries, including percutaneous transluminal coronary angioplasty (PTCA) with or without placement of coronary stents and coronary artery bypass surgery (CABG). Aspirin also is prescribed on a long-term basis to prevent clotting in the stents and/or the bypassed blood vessels.
3. Aspirin often is prescribed in low doses (75-160 mg/day) on a long-term basis to patients with prior heart attacks or strokes and to patients with TIAs (transient ischemic attacks or mini-strokes) and exertional angina to prevent heart attacks and ischemic strokes.
4. Aspirin is prescribed in moderate doses (160-325 mg/day) to patients who are having unstable angina to prevent heart attacks and improve survival.
5. Aspirin is prescribed in moderate doses (160-325 mg/day) to selected patients who are having ischemic strokes to limit damage to the brain, prevent a second stroke, and improve survival.

In a large multi-center study (Second International Study of Infarct Survival of the ISIS-2 trial) of patients having acute heart attacks, early treatment (within 24 hours of the onset of symptoms) with aspirin (160 mg/d) was found to reduce deaths from the heart attacks by 23%. The improved survival is believed to be due to aspirin's ability to quickly prevent further blood clots and the extension of existing clots and thus limit the amount of damage to the heart's muscle.

Aspirin is easy to use, safe at the low doses used for its antiplatelet action, and fast acting. Aspirin at moderate doses (160-325 mg/day) produces an antiplatelet effect rapidly (within 30 minutes). The current recommendation is to give aspirin immediately to almost all patients as soon as a heart attack is recognized at a dose of 160-325 mg/d and to continue it for one month. The only reason for not using aspirin is a history of intolerance or allergy to aspirin or evidence of obvious active bleeding (such as actively bleeding stomach ulcers) that might be worsened by aspirin.

Performance of vascular procedures

Aspirin is not the only treatment for heart attacks and unstable angina. Sometimes percutaneous transluminal coronary artery angioplasty (PTCA), with or without placement of an arterial stent, is necessary to open narrowed or blocked coronary arteries. In rare instances, PTCA may be technically impossible, or not practical, to do, and coronary artery bypass graft surgery (CABG) becomes necessary to improve the flow of blood to the heart.

Some patients with heart attacks also may be treated with thrombolytic agents (medications that dissolve clots) to open blocked arteries. It is important to make the distinction that aspirin generally does not dissolve an existing blood clot, but it acts to prevent growth of the existing clot and the formation of new ones. In all of these instances, there is a risk blood clots will form again inside the arteries, leading to further heart attacks. In all of these cases, aspirin has been shown to be beneficial in preventing new clots, thus reducing the risk of heart attacks and improving both short and long-term survival.

Prevention of further heart attacks

There are two types of heart attack prevention, primary and secondary. Preventing the first heart attack in people who do not have a history of heart disease is called primary prevention. Preventing further heart attacks among patients who already have had a heart attack or another heart related condition is called secondary prevention.

Within six years after the first heart attack, 16% of men and 35% of women will have a second heart attack. Long-term, daily aspirin (75-325 mg/d) has been shown to reduce the risk of second heart attacks and improve survival among both men and women. Additionally, long-term secondary prevention with aspirin also has resulted in fewer ischemic (lack of blood flow due to blockage in blood vessels from clot formation) strokes. Survivors of heart attacks usually take daily low dose (75 mg-160 mg/d) aspirin indefinitely to prevent further heart attacks as well as strokes.

Aspirin taken long-term is an important part but NOT the only measure for preventing heart attacks. Aspirin is not recommended for primary prevention of heart attacks because available evidence does not support its use for primary prevention.

Aspirin is particularly useful in preventing heart attacks and heart attack related deaths in patients with unstable angina. The Canadian Multicenter Trial, and the Montreal Heart Institute study all demonstrated significant reductions (approximately 50%) in the risk of heart attack among patients with unstable angina treated with aspirin. A study by the Research on Instability in Coronary Artery Disease Group (RISC) showed a 70% reduction in the risk of death or heart attack in patients with unstable angina treated with aspirin. Aspirin usually is started as soon as the diagnosis of unstable angina is made and then continued indefinitely.

In patients with prolonged chest pain due to unstable angina (a situation in which heart attacks are frequent), percutaneous transluminal coronary artery angioplasty (PTCA) with or without stenting may be necessary to open blocked coronary arteries. Aspirin is often used in combination with another antiplatelet agent, such as eptifibatide (Integrilin), and an anti-coagulant (heparin or low molecular weight heparin) to prevent heart attacks while awaiting the PTCA procedure. Aspirin then is used long-term (either alone or in combination with another antiplatelet agent) to prevent blood clots from forming inside the coronary arteries and stents.

In patients with exertional angina (chest pain brought on by exertion), low dose aspirin (75 mg-325 mg daily) given long-term has been shown to significantly reduce the risk of heart attacks, sudden death, and ischemic strokes.

Ischemic stroke is a process similar to a heart attack. In general, ischemia means injury to a tissue in the body due to lack of blood flow, and an ischemic stroke is injury to the brain tissue due to lack of blood perfusion. This usually happens because of atherosclerosis (narrowing and hardening of the blood vessels) of the arteries in the brain. Heart attack is the ischemia of the heart caused by similar process. Another major process for ischemic stroke may be due to an embolism (a blood clot that dislodges and travels from some other location in the body) to the blood vessels in the brain stopping blood from passing through the blood vessel.

When aspirin at moderate doses (160-350 mg/day) is given to patients as soon as an ischemic stroke is recognized (usually within the first 48 hours of the onset of symptoms), survival is improved, and the risk of additional strokes is reduced. Aspirin is believed to benefit patients having acute ischemic strokes by preventing the propagation (extension or growth) of the blood clots and preventing the complete obstruction of the arteries. However, aspirin is not effective in treating or preventing hemorrhagic strokes. Some studies suggest that long-term aspirin use may increase slightly the risk of developing hemorrhagic strokes.

Aspirin is not the preferred treatment for ischemic strokes. Thrombolytic medications (medications that dissolve clots) are used early (as soon as an ischemic stroke is recognized) to open blocked cerebral arteries.

The major limitation for using these medications is time. For example, for an ischemic stroke, thrombolytics must be given within the first three hours after the first symptoms of a stroke. Many people with strokes may not recognize the symptoms and may delay medical attention for several hours if not days after the onset of stroke symptoms.

Another limitation in their use is that only certain patients qualify to receive these medications. As a result, for patients in whom thrombolytic medications cannot be used (most often because of underlying conditions that can cause excessive bleeding), doctors may consider using aspirin. Thus, aspirin is often the drug that patients with stroke will receive when they are seen in the emergency room.

Prevention of strokes

Patients with prior strokes and TIAs (mini-strokes) usually have significant atherosclerosis of the carotid and /or the smaller arteries within the brain and are at risk of further strokes. (These patients often have coronary atherosclerosis as well and are at risk for heart attacks.) Long-term low-to-moderate doses of aspirin (50-325 mg/d) have been found to reduce the risk of strokes as well as heart attacks in these patients.

Aspirin is not the only medication to prevent strokes among patients with atherosclerosis. Another anti-platelet agent, clopidogrel (Plavix), also has been used, especially in patients who are intolerant or allergic to aspirin. Aspirin is sometimes combined with a second anti-platelet agent, dipyridamole (Persantine, Aggrenox), to prevent strokes.

Antiplatelet agents are not the only measures that prevent strokes. For example, aspirin alone may not be sufficient to prevent embolic strokes in patients at risk for this type of stroke, such as in patients with atrial fibrillation. In these patients, warfarin (Coumadin, Jantoven), an oral anti-coagulant that is a stronger anti-clotting medication than aspirin, may be necessary.

In patients with ischemic strokes or TIAs who have advanced atherosclerosis and narrowing of the carotid arteries, carotid endarterectomy (a surgical procedure to widen the narrowed carotid artery, the main blood vessel feeding the brain) or the introduction of stents within the carotid artery may be necessary to prevent strokes.

Allergy to aspirin is a rare condition in which a patient can develop swelling of tissues, spasm of the airways (bronchospasm) that causes difficulty breathing, and even anaphylaxis, a life-threatening condition. Patients with a history of allergy to aspirin should not take aspirin. Since aspirin is related chemically to the other NSAIDs, patients who are allergic to the other NSAIDs, such as ibuprofen (Motrin) and naproxen (Aleve), also should not take aspirin.

Aspirin may interact with other medications and cause undesirable side effects. For example:

• Aspirin, when taken together with an anti-coagulant such as warfarin (Coumadin) or enoxaparin (Lovenox), can greatly impair the body's ability to form blood clots, resulting in excessive bleeding spontaneously, from ulcers, or related to a procedure. Patients on such combinations must be closely monitored by a doctor.
• Aspirin can raise levels of uric acid in the blood and may need to be avoided in patients with increased uric acid levels or gout.
• Aspirin can increase the effect of medications used for lowering blood sugar levels in patients with diabetes, resulting in abnormally low blood sugar levels (hypoglycemia). Blood sugar levels may need to be more closely monitored.
• Certain NSAIDs, particularly ibuprofen (Motrin, Advil), if taken just before aspirin or in multiples doses each day, can reduce the anti-platelet effects of aspirin and theoretically render aspirin less effective in preventing heart attacks and ischemic strokes. The ibuprofen molecule is believed to adhere to the COX-1 enzyme, thus keeping aspirin from reaching the enzyme.

Long-term low dose aspirin use is generally safe. An estimated 10% of the patients taking long-term aspirin (75-325 mg/day) can develop ulcers. Most of these ulcers were asymptomatic (no abdominal pain or bleeding). Patients at a higher risk of developing ulcers with low dose aspirin included elderly patients age 70 years and older, and patients with H. pylori stomach infection (see below). The risk of significant ulcer bleeding from aspirin is low (approximately 1%). One can reduce the risk of bleeding by adding a daily dose of a proton pump inhibitor (PPI) that reduces stomach acid, for example, pantoprazole (Protonix), esomeprazole (Nexium), rabeprazole (Aciphex), or lansoprazole (Prevacid, Prevacid SoluTab), and omeprazole (Prilosec, Zegerid).

Misoprostil (Cytotec) is another type of drug that prevents ulcer formation by NSAIDs. It is a prostaglandin and probably prevents the detrimental effects of NSAIDs by replacing the prostaglandins that are not produced because of the inhibition of their formation by NSAIDs.

Chronic H. pylori infection of the stomach is found in up to 30% of adults in the U.S. Patients with gastritis due to H. pylori will have a higher risk of bleeding when given aspirin or NSAIDs long-term. Eradication of H. pylori from the stomach with antibiotics can reduce the risk of bleeding from chronic aspirin use.

Buffered and coated aspirin do not seem to prevent ulcers and ulcer bleeding.

Aspirin is not always effective in preventing strokes and heart attacks. Examples of possible causes of aspirin failure include:

• Poor patient compliance (not taking the medication regularly)
• Inadequate dosing
• Concurrent intake of other NSAIDs such as ibuprofen that interfere with the anti-platelet action of aspirin
• Activation of platelet aggregation via pathways not blocked by aspirin
• Aspirin resistance

Aspirin resistance can be defined as the lack of antiplatelet effect despite therapeutic doses of aspirin (75mg-150mg/day for at least five days). This lack of anti-platelet response to aspirin increases the risk of developing heart attacks, strokes, and related deaths. Aspirin resistance is different from other causes of aspirin failure (see above), such as patient non-compliance or drug interference from concomitant use of ibuprofen.

Some scientists believe a segment of the population is resistant to the antiplatelet effect of aspirin. In these aspirin-resistant individuals, aspirin does not inhibit the formation of thromboxane A-2. Resistant individuals can be identified in research settings by finding high levels of 11-dehydrothromboxane B2 (a metabolic breakdown product of thromboxane A-2) in the urine while taking aspirin. These individuals have a higher risk of heart attack and strokes than subjects with lower urine levels of 11-dehydrothromboxane B2.

Another way of identifying aspirin resistance in research settings is by optical platelet aggregation. Aspirin non-responders identified by this method were found to have higher rates of heart attacks, strokes, and death than aspirin responders.

While research scientists are increasingly convinced that aspirin resistance exists, there are no reliable and standardized tests that doctors in clinical practice can use to diagnose this condition. Large scale controlled studies are needed to validate and standardize laboratory tests of aspirin resistance, and link these tests results to clinical outcomes.

Clinical trials will also be needed to determine how best to treat aspirin resistance. For example, should patients diagnosed as having aspirin resistance be treated with higher doses of aspirin? Should they be treated with aspirin in combination with another anti-platelet agent? Or should they be treated with a different anti-platelet agent, such as clopidogrel bisulfate (Plavix)?