Is it Time to Tailor the Dose of Aspirin for Primary Prevention of Cardiovascular Events and Cancer?

[Or…Why I changed my aspirin dosing schedule]

Henry I. Bussey, Pharm.D., FCCP

I just read one of the most complex and confusing studies that I’ve ever read.  This well-written article was complex and confusing because of the amount of data presented and the number of endpoints, dosing regimens, and patient subgroups addressed. The data, however, are important and, I believe, should be practice-changing.  After reading the article twice and discussing it with a hematologist on the ClotCare Editorial Board, I made a substantial change in my aspirin dosing schedule; and I believe that there is a good chance that most others taking aspirin for primary prevention are taking a dose that may be ineffective and/or harmful.

If you would like to review the article for yourself, it is available at https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31307-2/fulltext

Here are some of the key points that I got from this paper that analyzed individual patient data for 117,279 patients who were enrolled in trials of aspirin for primary prevention:

In the primary prevention of cardiovascular events:

1. Low-dose aspirin (75 to 100 mg daily) is effective only in individuals who weigh less than 70 Kg (Hazard Ratio, HR = 0.77) with no benefit in those who weigh 70 kg or more (HR = 0.95). Furthermore, for those who weigh 70 Kg or more, there is a trend for low-dose aspirin to increase cardiovascular events if the individual has diabetes, smokes, or is at least 70 years old.
2. Low-dose aspirin may be harmful in those who weigh less than 50 Kg. (including an increased risk of sudden death).
3. Enteric coated or sustained release aspirin products may be less effective.
4. Alternate day dosing may be less effective.
5. High-dose aspirin (300 – 325 mg or 500 mg or more) is effective in those who weigh more than 70 Kg (where low-dose is ineffective), but high-dose may be harmful in those who weigh less than 60 Kg.
6. Twice a day dosing may be desirable based on (1) the impressive reduction in cardiovascular events (HR = 0.74) among patients weighing less than 70 kg. in the ESPS-2 secondary stroke prevention trial that used a regimen of 25 mg of aspirin twice a day and (2) the theory that systemic availability of aspirin may be necessary to inhibit the 10-15% of new platelets that are released daily. Patients who weighed 70 Kg or more in the ESPS-2 did not exhibit a reduction in cardiovascular events with this regimen which led the authors of the current paper to suggest that 50 – 100 mg twice a day might be effective in heavier individuals.  Whether such a twice daily regimen would carry any bleeding risk in those weighing 90 kg or more is uncertain.

In the primary prevention of cancer:

1. Low-dose aspirin did not alter the rate of cancer in those who weighed 70 Kg or more.
2. Low-dose aspirin in those weighing less than 70 Kg increased cancer rates during the first 3 years of follow-up and this effect was especially evident in those with diabetes (HR = 1.32) and those over 70 years of age (HR = 1.35).
3. High-dose aspirin seemed to have a similar impact on cancer rates as that seen with low-dose aspirin.
4. Aspirin (regardless of dose or patient age) appeared to reduce the incidence of colorectal cancer at 20 years of follow-up in patients who weighed more than 50 kg and less than 80 Kg. No clear benefit was seen outside of that weight range.
5. Women younger than 50 years of age who had diabetes and were taking aspirin had an especially high rate of cancer (HR = 4.35) due in part to a high rate of breast cancer (HR = 2.60).

The risk of major or significant bleeding with aspirin:

1. Low-dose aspirin increases major bleeding up to a body weight of 90 Kg, above which bleeding risk disappears.
2. High-dose aspirin carried an increased risk of major bleeding that not only persisted but increased at weights above 90 Kg.

 

Reference:

Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: Analysis of individual patient data from randomized trials. The Lancet 2018; 392:387-399. http://dx.di.org/10.1016/S0140-6736(18)31133-4