Aspirin and Antiplatelet Medications (cont.)

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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.

Treatment of 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. Accordingly, 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/d) 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. In fact, some studies suggest that long-term aspirin use may increase slightly the risk of developing hemorrhagic strokes.

It is important to recognize that 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 these strokes, such as in patients with atrial fibrillation. In these patients, warfarin (Coumadin), 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.

How effective is aspirin for preventing heart attacks among healthy subjects?

Long-term, low dose aspirin (75-160 mg/d) infrequently causes serious side effects. Therefore, among patients with advanced atherosclerosis (patients who already have heart attacks and strokes, patients with angina or TIAs, patients who need PTCA and coronary artery bypass surgery, and patients with symptoms of peripheral vascular disease) the benefits of low dose aspirin usually outweigh the risks of long-term aspirin (discussed below).

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.

Therefore, the potential benefits of long-term aspirin in healthy subjects may not justify the small 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. Most doctors recommend aspirin in healthy subjects who have one or more risk factors for developing atherosclerosis.

What are the latest recommendations on the use of aspirin in the primary prevention of cardiovascular disease?

As described below, the recommendations for the secondary prevention (in people who already have had a heart attack or stroke) of future attacks are more compelling.

In 2009, the U.S. Preventive Services Task Force (USPSTF) has come up with slightly modified recommendations for the primary prevention of cardiovascular disease using aspirin. Based on their review of the published data:

  • They encourage the use of aspirin in men between 45-79 years of age and women between 55-79.

  • In individuals older than 80, the treatment with aspirin was associated with more bleeding episodes which outweigh the protective benefits.

  • In men younger than 45 and women younger than 55, the benefits of aspirin seemed to too insignificant to warrant routine use for the prevention of cardiovascular disease.

What is the optimal dose of aspirin for treating and preventing heart attacks and strokes?

An ideal dose of aspirin is one that maximizes its benefits but minimizes side effects. However, 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/d, 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/d 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.

The USPSTF also looked into the optimal dose of aspirin for primary preventive purposes in 2009. They concluded that the low doses of 75-100mg daily were as effective as higher doses in preventing vascular disease and less associated with bleeding complications.

Who should be taking aspirin to prevent heart attacks and strokes?

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 (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)

  • peripheral vascular disease (poor artery blood flow to the legs)

  • vascular procedures such as PTCA and CABG

Doctors also consider low dose aspirin in patients at risk for atherosclerosis because they:

Who should not be taking aspirin?

Patients who should not be taking aspirin include:

  • Patients with an allergy to aspirin or other NSAIDs;

  • Patients with active ulcers, especially those with bleeding ulcers, because of the side effects of ulcers and bleeding with aspirin. Among patients who must take aspirin but have had intestinal ulcers, the lowest does 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 excreted 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;

  • Patients with advanced kidney or liver diseases since aspirin may cause toxicity to the kidney and liver;

  • Patients at risk for developing intracranial hemorrhage;

  • Some patients 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.)

What are the side effects of aspirin?

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

The most common side effects of aspirin involve the gastrointestinal system.

Aspirin can cause:

  • ulcers of the stomach and duodenum (first part of the small intestine),

  • abdominal pain,

  • nausea,

  • gastritis (inflammation of the stomach), and

  • even serious gastrointestinal bleeding from ulcers.

Occasionally, aspirin may be toxic to the liver.

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

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 function of the kidney and liver, especially in patients who already have liver and kidney disease. Other side effects of aspirin include easy bruising, vertigo, ringing in the ears (tinnitus), and lightheadedness.

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/d). Serious side effects of aspirin should be even lower with low doses such as 75-160 mg/d. However, the actual incidence of serious bleeding with long-term use of low dose aspirin has not been clearly determined.

What is aspirin allergy?

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. Clearly, 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.

What interactions might aspirin have with other medications?

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. Therefore, 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.

What can be done to reduce the risk of ulcers from long-term aspirin use?

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 for example, pantoprazole (Protonix), esomeprazole (Nexium), rabeprazole (Aciphex), or lansoprazole (Prevacid, Prevacid SoluTab), and omeprazole (Prilosec, Zegerid).

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 have any beneficial effect in preventing ulcers and ulcer bleeding.

What are the limitations of aspirin treatment?

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 interferes with the anti-platelet action of aspirin

  • Activation of platelet aggregation via pathways not blocked by aspirin

  • Aspirin resistance

What is 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 that 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 nonresponders identified by this method were found to have higher rates of heart attacks, strokes, and death than aspirin responders.

What is in the future for the research on aspirin resistance?

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)?

References:
U.S. Preventive Services Task Force; "Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement;" Annals of Internal Medicine; 17 March 2009. Volume 150 Issue 6. Pages 396-404.
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988), "Randomized Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither Among 17 187 Cases of Suspected Acute Myocardial Infarction: ISIS-2", The Lancet 332: 349-360
Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, et al.; "Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial." N Engl J Med. 1985 Nov 28;313(22):1369-75.
Theroux P; Ouimet H; McCans J; Latour JG; Joly P; Levy G; Pelletier E; Juneau M; Stasiak J; deGuise P; et al. "Aspirin, heparin, or both to treat acute unstable angina." Journal of Medicine Vol. 319:1105-1111
LC Wallentin; "Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden"J Am Coll Cardiol, 1991; 18:1587-1593
C. H. Hennekens, MD; M. L. Dyken, MD; V. Fuster, MD. "Aspirin as a Therapeutic Agent in Cardiovascular Disease;" Circulation. 1997;96:2751-2753

Previous contributing author: Dennis Lee, M.D.


Last Editorial Review: 4/3/2009



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