- ACRONYMS AND DEFINITIONS
- ABI - Ankle-brachial index
- ACCP- American College of Chest Physicians
- A fib - Atrial fibrillation
- ASA - Acetylsalicylic acid
- AHA - American Heart Association
- CABG - Coronary artery bypass grafting
- CAD - Coronary artery disease
- COX - Cyclooxygenase enzyme
- DVT - Deep vein thrombosis
- GI - Gastrointestinal
- MAP - Mean arterial pressure (MAP = 1/3 SBP + 2/3 DBP)
- NSAIDs - Nonsteroidal anti-inflammatory drugs
- PE - Pulmonary embolism
- PPI - Proton pump inhibitor (e.g. Prilosec®, omeprazole, Nexium®, Prevacid®, Protonix®)
- PUD - Peptic ulcer disease
- RCT - Randomized controlled trial
- TIA - Transient ischemic attack
- Triple therapy - Anticoagulation + P2Y12 inhibitor + aspirin (see triple therapy for more)
- USPSTF - United States Preventive Services Task Force
- VTE - Venous thromboembolism
- DRUGS IN CLASS
- Aspirin (acetylsalicylic acid, often abbreviated "ASA")
- Aspirin (Bayer®, Bufferin®, St. Joseph®)
- MECHANISM OF ACTION
- The antithrombotic effect of aspirin is through platelet inhibition
- Cyclooxygenase is an enzyme inside of platelets that converts arachidonic acid to thromboxane A2. Thromboxane A2 stimulates platelet activation and recruitment.
- Aspirin irreversibly inhibits cyclooxygenase (COX). Once a platelet is exposed to aspirin, it becomes inactive for the remainder of its life. The maximal antiplatelet effect of aspirin occurs within minutes of consumption.
- Because aspirin irreversibly inhibits platelets, platelets must be replenished in order for platelet function to be restored. In general, 10 - 14% of the normal platelet pool is produced each day which means it takes 7 - 10 days after stopping aspirin for normal platelet function to return.
- Cyclooxygenase is also an important enzyme in the production of inflammatory mediators
- Blocking cyclooxygenase inhibits inflammation and gives aspirin its analgesic/antipyretic effects 
- ACUTE CORONARY SYNDROME
- A large trial published in the 1980s found that aspirin significantly improved vascular mortality in patients with an acute coronary syndrome. [PMID 2899772] Since that study, aspirin has been universally recommended in acute coronary syndrome.
- Professional recommendations
- COLON CANCER PREVENTION
- Aspirin and other NSAIDs have been shown to reduce the incidence of colon polyps. Observational studies have also shown a decreased incidence of colorectal cancer in patients who take aspirin on a regular basis. Given these findings, there has been much interest in using aspirin to prevent colon cancer.
- The Women's Health Study detailed below was an enormous trial that compared aspirin to placebo for the prevention of all types of cancer
- The Women's Health Study enrolled 39,876 female healthcare professionals
Main inclusion criteria
- Female ≥ 45 years old
- No history of cancer (except nonmelanoma skin cancer), cardiovascular disease, or major chronic illness
Main exclusion criteria
- Taking aspirin or NSAIDs more than once a week
- Taking anticoagulants or corticosteroids
- Average age 55 years
- Average BMI - 26
- Current smoker - 13%
- First-degree relative with breast, colorectal, or ovarian cancer - 18%
Randomized treatment groups
- Group 1 (19,934 patients) - Aspirin 100 mg every other day
- Group 2 (19,942 patients) - Placebo every other day
Primary outcome: Any cancer (excluding nonmelanoma skin cancer)
|Duration: 10 years|
|Primary outcome (any cancer)||7.2%||7.15%||HR 1.01, 95%CI [0.94 - 1.08], p=0.87|
|Colorectal cancer||0.67%||0.68%||HR 0.97, 95%CI [0.77 - 1.24], p=0.83|
|Lung cancer||0.45%||0.58%||HR 0.78, 95%CI [0.59 - 1.03], p=0.08|
|Leukemia||0.19%||0.12%||HR 1.54, 95%CI [0.92 - 2.57], p=0.10|
|Overall mortality||3.1%||3.2%||HR 0.95, 95%CI [0.85 - 1.06], p=0.32|
Findings: Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.
- Professional recommendations
- In 2016, the USPSTF recommended aspirin for the primary prevention of colorectal cancer in certain groups. See USPSTF aspirin recommendations below.
- A number of observational studies have shown that aspirin may prevent colon cancer in the general population. Unfortunately, large randomized controlled trials that have looked for an effect have been mostly disappointing. Much like the Women's Health Study detailed above, a study published in 1993 that compared aspirin to placebo in men also failed to find a protective effect [PMID 8331682]. And lastly, a prespecified secondary analysis from the ASCEND trial [PMID 30146931] found no effect of aspirin on any type of cancer including gastrointestinal cancers.
- The Women's Health Study was an enormous study (39,876 subjects) that found no effect of aspirin in preventing any type of cancer. If aspirin had even the slightest effect, a study this large would have given a significant result.
- There is no evidence that aspirin prevents colon cancer in the general population. A study published in 2020 did find a protective effect of aspirin in patients with Lynch syndrome. [PMID 32534647]
- USPSTF ASPIRIN RECOMMENDATIONS
- In 2016, the USPSTF issued new recommendations regarding the use of aspirin for the primary prevention of cardiovascular disease and colorectal cancer
- The recommendations are detailed below. The USPSTF statement lumps the cardiovascular and colorectal recommendations together.
- For a review of primary prevention studies involving aspirin, see the following - colon cancer, coronary artery disease, stroke and TIA
|Aspirin for the primary prevention of cardiovascular disease and colorectal cancer|
|50 - 59 years||
Low-dose aspirin is recommended in patients who meet the following criteria:
|60 - 69 years||
|< 50 years or ≥ 70 years||
- SIDE EFFECTS
- The therapeutic effect of aspirin is to inhibit clot formation, therefore it will inherently increase the risk of unwanted bleeding
- Aspirin also inhibits COX-1 in the stomach lining. COX-1 plays an important role in the stomach's ability to protect itself from the acid it produces. Aspirin increases the risk of stomach ulcers and bleeding.
- A person's bleeding risk on aspirin will depend on their concurrent medical problems and risk factors. A review of bleeding risk factors is available here - bleeding risk factors
- Bleeding risk with aspirin has been evaluated in a number of primary prevention trials. See aspirin in CAD prevention and aspirin in stroke prevention for a review.
- A cohort study that followed a large group of aspirin users is presented below
- A cohort study in the JAMA compared the incidence of major GI bleeds and any cerebral hemorrhage between low-dose aspirin users (≤ 300 mg/day) and nonusers in the general population
- The study included 186,425 individuals who were followed for a median of 5.7 years
- Incidence rates of GI bleed or cerebral hemorrhage were as follows:
- Aspirin group: 5.58 events/1000 person-years (95%CI [5.39 - 5.77])
- Non-aspirin group: 3.60 events/1000 person-years (95%CI [3.48 - 3.72])
- Findings: In a population-based cohort, aspirin use was significantly associated with an increased risk of major gastrointestinal or cerebral bleeding episodes. Patients with diabetes had a high rate of bleeding that was not independently associated with aspirin use.
- Low-dose aspirin undoubtedly increases the risk of significant bleeding
- Whether or not the benefits of aspirin outweigh this risk will depend on the patient and indication
- Peptic ulcers
- Aspirin inhibits COX-1 in the stomach lining. COX-1 plays an important role in the stomach's ability to protect itself from the acid it produces. Aspirin increases the risk of ulcers and bleeding.
- In one study, the average annual increase in stomach ulcer risk among aspirin users (75 - 325 mg daily) when compared to placebo was 0.12% 
- In another study, the estimated average increase in risk for symptomatic stomach ulcers in patients taking cardioprotective doses (75 - 325 mg daily) of aspirin was 5 cases per 1000 people taking aspirin for a year. The risk was higher in patients who were at increased risk of peptic ulcer disease. 
- See aspirin in peptic ulcer disease for recommendations on preventing peptic ulcers during aspirin use
- Stomach upset (dyspepsia)
- Aspirin may cause stomach upset in some individuals
- At lower doses (< 100 mg), the incidence of stomach upset is comparable to placebo in trials 
- Kidney disease
- All NSAIDs including aspirin can have a number of detrimental effects on the kidneys. In the kidneys, prostaglandins cause kidney blood vessels to dilate which leads to increased blood flow. The COX enzyme is required to make prostaglandins. Aspirin inhibits the COX enzyme and decreases prostaglandin synthesis.
- Aspirin and other NSAIDs may also cause acute interstitial nephritis, but this is less common
- The safety of aspirin use in kidney disease depends on the indication and dosage
- Daily aspirin (81 - 325 mg)
- A large number of patients with chronic kidney disease also have indications for daily aspirin (e.g. stroke, heart disease, etc.)
- A number of trials have looked at the safety of daily aspirin (81 - 325 mg) in patients with kidney disease
- In general, these trials have found aspirin to be safe and effective in patients with all degrees of kidney disease 
- The Renal Association (UK organization) recommends low-dose aspirin in patients with kidney disease who have an appropriate indication 
- The National Kidney Foundation states that the risks and benefits of NSAIDs must be weighed in patients with kidney disease, but makes no formal recommendation 
- Aspirin doses > 325 mg a day
- In general, frequent and higher doses of aspirin and other NSAIDs are not recommended in patients with kidney disease
- Liver disease
- Aspirin has not been studied extensively in patients with significant liver disease
- Advanced liver disease can cause both bleeding disorders and hypercoagulable states (see coagulopathy of liver disease for a review)
- Patients with advanced liver disease may also have low platelets
- Aspirin could potentially worsen bleeding disorders in patients with advanced liver disease and should be used with caution
- Gastrointestinal bleeding
- See GI bleeding/Peptic ulcer disease below
- Peptic ulcer disease
- See GI bleeding/Peptic ulcer disease below
- Aspirin has a dose-dependent effect on uric acid excretion
- Low-dose aspirin (≤ 325 mg/day) can raise uric acid levels. The effect is negligible, and the American College of Rheumatology does not recommend stopping daily prophylactic low-dose aspirin in patients with gout.
- Aspirin doses of 600 - 2400 mg/day can cause significant uric acid retention and should be avoided during acute gout attacks
- High-dose aspirin (> 4 grams/day) promotes uric acid excretion and can lower plasma uric acid levels [34,35]
- See gout for more
- Children and teenagers (Reye's syndrome)
- Aspirin should be avoided in children and teenagers who have a fever because it may increase the risk of Reye's syndrome
- Reye's syndrome is a rare condition characterized by rapidly progressive encephalopathy and liver dysfunction. It typically occurs after a viral infection in younger patients.
- ASPIRIN IN GASTROINTESTINAL (GI) BLEEDING / PEPTIC ULCER DISEASE
- Patients with a history of GI bleed or PUD
- Patients who have a history of GI bleeding and/or peptic ulcer disease often have medical indications (ex. stroke, heart disease) for daily low-dose aspirin
- In 2008, the AHA published recommendations for daily low-dose aspirin use in patients with a history of GI bleeding or peptic ulcers. Their treatment algorithm is detailed below.
|AHA recommendations for daily low-dose aspirin in patients with a history of GI bleed/PUD|
STEP 1 - Determine if patient has major risk factor for GI bleeding
STEP 2 - If any of the above are present, prescribe PPI with aspirin
STEP 3 - If none of the above are present, determine if other risk factors are present
STEP 4 - If two or more other risk factors are present, prescribe a PPI with aspirin
- Acute GI bleeding
- In the past, patients who experienced GI bleeding on aspirin were often taken off of aspirin indefinitely
- A trial published in 2010 randomized patients (n=156) with active peptic ulcer bleeding while taking aspirin to aspirin + PPI or placebo + PPI immediately after endoscopic therapy. The aspirin group had a greater risk of recurrent bleeding within 30 days than the placebo group (10.3% vs 5.4%), but at 8 weeks, all-cause mortality was significantly lower in the aspirin group (1.3% vs 12.9%) as was mortality from cardiovascular, cerebrovascular, or gastrointestinal complications (1.3% vs 10.3%). [PubMed abstract]
- In 2010, a multidisciplinary group of 34 experts developed a set of guidelines for patients with nonvariceal upper GI bleeding. Recommendations for aspirin are presented below.
- Expert consensus guidelines for aspirin use in patients with acute GI bleeding
- Patients who develop GI bleeding on low-dose aspirin should restart aspirin as soon as the risk for cardiac complications is thought to outweigh the risk for rebleeding. In trials, aspirin has been restarted immediately after endoscopy.
- Aspirin combined with a PPI is preferred over clopidogrel because clopidogrel alone has a higher risk of rebleeding 
- STOPPING BEFORE PROCEDURES
- REVERSING ASPIRIN
- Aspirin irreversibly inhibits cyclooxygenase in platelets. Once a platelet is exposed to aspirin, it becomes inactive for the remainder of its life. The maximal antiplatelet effect of aspirin occurs within minutes of consumption.
- Because aspirin irreversibly inhibits platelets, platelets must be replenished in order for platelet function to be restored. In general, 10 - 14% of the normal platelet pool is produced each day which means it takes 7 - 10 days after stopping aspirin for normal platelet function to return. 
- Platelet transfusions
- In emergency situations, platelet transfusion are often used to reverse the inhibitory effects of aspirin. The efficacy of this practice is not well supported in clinical trials.
- A randomized controlled trial published in 2016 compared platelet transfusion to standard care in 190 patients with intracerebral hemorrhage who were taking antiplatelet therapy (mostly aspirin). The primary outcome was a shift towards death or dependence rated on the modified Rankin scale at 3 months. The odds of death or dependence was significantly higher in the platelet transfusion group when compared to the control group (OR 2.05, 95%CI [1.18 - 3.56], p=0.0114). Adverse events and mortality were also more frequent in the platelet transfusion group. [PMID 27178479]
- Professional recommendations
- The 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants states that the routine administration of platelets for patients who are bleeding and on antiplatelet agents is not recommended, although this can be considered in specific cases, particularly after other measures such as reversal of oral anticoagulants have failed 
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- ACE Inhibitors - in some studies, the beneficial effect of ACE inhibitors appears to have been blunted by daily aspirin. In other studies, an effect has not been seen. A review of this topic can be found here - ACE Inhibitors and aspirin
- Acetazolamide (Diamox®) - aspirin may increase acetazolamide blood levels. Use caution when combining. 
- Drugs that increase the risk of bleeding - drugs that inhibit coagulation may increase the risk of bleeding when taken with aspirin
- Drugs that may increase the risk of bleeding include:
- Anagrelide (Agrylin®)
- Direct thrombin inhibitors (dabigatran)
- Factor Xa inhibitors (e.g. rivaroxaban, apixaban)
- Fish oil (e.g. Vascepa®)
- P2Y12 inhibitors (e.g. clopidogrel, ticagrelor, prasugrel)
- NSAIDs (e.g. ibuprofen, naproxen)
- SSRIs and SNRIs (e.g. fluoxetine, venlafaxine)
- Vorapaxar (Zontivity®)
- Warfarin (Coumadin®)
- Lesinurad - aspirin at doses > 325 mg/day may decrease the effectiveness of lesinurad. Doses ≤ 325 mg/day do not decrease the efficacy of lesinurad.
- Methotrexate - aspirin may increase methotrexate blood levels and enhance its toxicity. It's unclear if there is a significant risk with low-dose aspirin. 
- Nitroglycerin - aspirin has been shown to significantly increase blood levels of nitroglycerin. Vasodilatory and hemodynamic properties of nitroglycerin may be enhanced when taken with aspirin. 
- NSAIDs (ibuprofen, Motrin®, Aleve®, etc.)
- Aspirin is an NSAID. When aspirin is taken with other NSAIDs, the risk of side effects is increased.
- In 2006, the FDA issued a drug safety warning about the possibility that ibuprofen might interfere with the antiplatelet activity of daily aspirin. Ibuprofen and other NSAIDs reversibly bind COX-1 where aspirin irreversibly binds COX-1. In vitro studies have shown that ibuprofen competes with aspirin for its binding site on the COX-1 enzyme. This competitive inhibition may block the antiplatelet effect of aspirin. Studies that have looked at whether taking aspirin with other NSAIDs decreases the cardioprotective effect of aspirin have been mixed. [18,19,20]
- The FDA recommends the following when taking NSAIDs with aspirin:
- With occasional use of ibuprofen, the risk for an interaction is low because of the long-acting antiplatelet effect of aspirin
- Patients who use immediate-release aspirin (not enteric coated) should take doses of ibuprofen 400 mg ≥ 30 minutes after aspirin or more than 8 hours before aspirin ingestion. Proper dosing recommendations with enteric coated aspirin are unknown.
- Other NSAIDs may confer the same risk as ibuprofen and should be used with caution 
- Phenytoin (Dilantin®) - aspirin may affect phenytoin levels. This interaction is not well-defined, and it is unclear if it is relevant in patients taking low-dose aspirin. 
- Probenecid - aspirin may block the uricosuric effect of probenecid. Low-dose aspirin does not appear to have a significant effect. [9,25]
- Sulfonylureas (glyburide, glipizide, etc.) - aspirin may enhance the glucose-lowering effect of sulfonylureas. It's unclear if there is a significant effect with low-dose aspirin. 
- Valproic acid (Depakote®, Depakene®) - aspirin may increase valproic acid levels. The relevance of this interaction in patients taking low-dose aspirin is unknown. Patients taking aspirin with valproic acid should monitor valproic acid levels closely when starting or stopping aspirin. 
- Zafirlukast (Accolate®) - aspirin may increase zafirlukast levels
- Metabolism and clearance
- Aspirin is hydrolyzed to salicylic acid. Salicylic acid is conjugated in the liver to form salicyluric acid. Salicyluric acid is excreted by the kidneys. 
- ASPIRIN + ANTICOAGULATION
- In some cases, patients will have indications for both anticoagulation and an antiplatelet drug (e.g. atrial fibrillation with CAD)
- Recommendations for treating these patients are covered at the links below
- ENTERIC-COATED AND BUFFERED ASPIRIN
- Enteric coated aspirin has a coating that prevents the pill from dissolving in the stomach. The aspirin passes through the stomach and is then released in the first part of the small intestine called the duodenum.
- The enteric coating is meant to decrease the stomach upset caused by aspirin. Aspirin is believed to cause irritation of the gastric lining when it comes into contact with it.
- Buffered aspirin contains buffering agents (ex. calcium carbonate, magnesium oxide) that increase the pH of the stomach. Buffering agents increase the solubility of aspirin and decreased its exposure to the gastric mucosa.
- Gastrointestinal bleeding
- Several case-control studies have compared the risk of GI bleeding between patients taking regular aspirin, enteric coated aspirin, and buffered aspirin
- These studies have found no difference in the risk of GI bleeding [26, 27]
- Gastrointestinal bleeding caused by aspirin appears to be from a systemic effect and not a local one
- Acute coronary syndrome
- Enteric coated aspirin is not absorbed as quickly as regular aspirin. Regular aspirin reaches peak plasma levels in 30 - 40 minutes compared to 3 - 4 hours with enteric coated.
- Patients who are taking aspirin for an acute heart attack should take a regular aspirin
- If only enteric coated aspirin is available, it should be chewed 
- ASPIRIN/NSAID ALLERGY
- See NSAID allergy for a review
- LONG TERM SAFETY
- Aspirin has been used for over a hundred years by millions of people
- The risks and benefits of aspirin are well-defined
- Dosage forms
- Many different brands (ex. Bayer®, St. Joseph®, Bufferin®, etc.)
- Most common doses - 81, 325, 500 mg
- Aspirin comes in tablets, caplets, buffered forms, enteric coated forms, and chewable pills
- Acute coronary syndrome: One dose of nonenteric coated aspirin (162 - 325 mg). The aspirin may be chewed or swallowed.
- Daily low-dose: 75 - 325 mg once daily
- Analgesic/Antipyretic: 325 - 1000 mg every 6 hours. Do not exceed 4000 mg in 24 hours.
- Food does not affect absorption. Food may decrease stomach upset.
- Aspirin doses as low as 30 mg a day have been shown to fully inhibit platelet activity 
- Aspirin + Dipyridamole (Aggrenox®)
- Dosage form (capsule)
- Aspirin : Dipyridamole
- 25 mg : 200 mg
- Generic available. 60 capsules cost $50 - $100.
- Secondary prevention of stroke: 1 capsule twice daily
- In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there is no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.
- May give without regard to food
- Do not chew capsules
- Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes. This inhibition results in an increase in local concentrations of adenosine which stimulates the platelet A2-receptor and inhibits platelet activation.
- 1 - PMID 16908781
- 2 - PMID 15998890
- 3 - USPSTF website
- 4 - PMID 21444888 - AHA GL on MI 2011
- 5 - PMID 10371234 - Arch of IM study on stroke
- 6 - PMID 22706834 - JAMA cohort bleeding study
- 7 - PMID 20197530 - AAA study
- 8 - PMID 18836135 - AHA GL on NSAIDS and PUD
- 9 - AGGRENOX PI
- 10 - PMID 22093501
- 11 - The Renal Assoc website - Click here
- 12 - PMID 11904577
- 13 - PMID 18574054
- 14 - PMID 8435027
- 15 - PMID 18836135
- 16 - PMID 20083829
- 17 - PMID 21166368
- 18 - PMID 16319386 - ASA review
- 19 - PMID 15111370
- 20 - PMID 15028354
- 21 - PMID 18156036
- 22 - PMID 1831835
- 23 - Depakote PI
- 24 - Methotrexate PI
- 25 - PMID 11128679
- 26 - PMID 8937281
- 27 - PMID 11228592
- 28 - Anaphylaxis and Hypersensitivity Reactions, 2011, pp 107-125, ISBN 978-1-60327-951-2
- 29 - PMID 20214589
- 30 - Nitromist® PI
- 31 - PMID 25564918 - Case study on ticagrelor
- 32 - PMID 23609292 - platelet transfusion study
- 33 - FDA website
- 34 - PMID 17522099 - British Rheum Soc gout review
- 35 - PMID 23024028 - ACR Gout GL
- 36 - PMID 17693178 - BAFTA study
- 37 - PMID 21309657 - AVERROES study
- 38 - PMID 29203195 - PMID 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants
- 39 - PMID 22315266 - PMID 2012 Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
- 40 - PMID 30207919 - Aspirin-Exacerbated Respiratory Disease, NEJM (2018)