Aspirin in Primary Prevention- The Verdict is NOT Straightforward!

Aspirin In Primary Prevention of CVD - Eliminate Or Individualize?

In India, Aspirin is a popular drug choice, commonly used by physicians for both primary and secondary prevention of Cardiovascular Diseases including heart attack and stroke.

Aspirin is a proven drug for the secondary prevention of cardiovascular diseases (CVD). However, recent clinical trials have criticized the use of aspirin in primary prevention, thereby questioning its significant use in this patient population, which has been a pervasive practice pattern in India over the years. In recent times there have been three important Trials that have focused on the role of Aspirin in primary prevention. This article attempts to bring out some lesser-known perspectives from these trials.

Aspirin and ASCEND Study

A randomized trial called the ASCEND (A Study of Cardiovascular Events in Diabetes) included a total of 15,480 patients (aged ≥ 4 0 years) receiving 100 mg of enteric-coated aspirin daily or matching placebo. For the first .4 years of follow-up, the baseline characteristics between the two groups were similar. However, later the patients in the aspirin group showed a 29 % increase in bleeding events and a reduction in the risk of the composite primary efficacy endpoints (myocardial infarction, stroke, transient ischemic attack, or death from vascular cause) by 12 % compared to placebo (8 .5 % vs. 9.6 %; 9 5 % CI 0.79 to 0.97; P = 0.01 ).

Critical Limitations of ASCEND Study:

The ASCEND study had several limitations as follows:

Patients having a high risk of vascular events were not accurately captured.

All the patients did not have type 2 diabetes (94 .1 % type 2 diabetes patients).

The glycemic control was comparable between all the groups (A1 C <6 % in 2 1 %, ≥ 6 to 8 % in 3 0%, and ≥ 8 % in 1 2 %). However, a considerable number of patients did not achieve the desired glycemic control (defined as A1C ≤ 7 %).

Analysis of specific subgroups of CVD such as hypertension, glycemic control, etc. was not performed individually.

The potential of aspirin was underestimated as the adherence to an antiplatelet drug in the aspirin group decreased over time, while the use of an antplatelet increased in the placebo group.

Diabetic patients have increased platelet turnover. In such patients, once daily dose of aspirin (100 mg) may not be adequate as the half-life of aspirin is very short. Moreover, several studies have demonstrated that the response to low-dose aspirin is dependent on the weight of the patient and those patients weighing more than 70 kgs may not be benefitted from 100 mg dose (low dose) of aspirin. ASCEND trial constituted of 47 % obese patients. Thus, there is a likely chance that some patients might not have benefited from 100 mg of daily dose of aspirin.

Aspirin and ARRIVE Study

Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study involved a total of 12,546 patients who were estimated to have a moderate cardiovascular risk. The estimation was based on a 10-year atherosclerotic event risk of 1 0 to 2 0%. These patients were randomly divided into two groups (mean age = 63 .9 ±7.1 years in both groups) receiving enteric-coated aspirin 1 00 mg daily and placebo, respectively. The complete trial was initially, followed for a mean of 6 0 months. However, because of lower than anticipated event rates, the study duration was extended to 72 months.

Similarly, the primary efficacy endpoint of this trial was initially a composite of time to the first occurrence of death by the cardiovascular event such as stroke and myocardial infarction. However, the efficacy endpoint was updated in the middle of the trial to include transient ischemic attack and unstable angina as the event rate was found out to be lower than expected.

Critical Aspects of ARRIVE Study:

One of the limitations of the trial was that the majority of patients were natives of Western Europe and North America (white males). Moreover, the study did not represent patients in most ambulatory care hospitals as the study involved the patients within the Veterans Health Administration. Furthermore, the study did not involve patients with diabetes.

Aspirin and ASPREE Trial

A Questionable Study In the aspirin in reducing events in the elderly (ASPREE) trial, a total of 19,114 healthy elderly individuals (>70 years of age) were randomly divided into two groups receiving enteric-coated aspirin 100 mg daily and placebo respectively. It was observed that all-cause death was increased by 1 4 % in the aspirin group over a median of 4.7 years.

The ASPREE trial too had several limitations. For example, 3 0% of the patients participating in the trial were obese. As previously stated, the response of 100 mg of aspirin (low-dose) is weight dependent. Therefore, there is a high possibility that a majority of the obese patient might not have been benefitted by the 100 mg daily dose of aspirin. Also, this age group itself is at an increased bleeding risk, just confounding the actual benefit-risk index of aspirin.

Give Aspirin A Fair Trial:

All clinical trials were performed on elderly patients. Thus, further research on middle age patients is required.

Aspirin is a relatively weak antiplatelet agent, due to which it has been observed as a safety hazard for the use in primary prevention. However, it should be noted that this effect would be an issue in higher risk individuals and not in the mild to moderate risk patients as the antiplatelet activity of aspirin is very weak.

A single dose of aspirin in diabetes (due to increased platelet turnover) might not be enough as the half-life of aspirin is very short.

There is evidence to demonstrate that response to low-dose aspirin is dependent on the weight of the patients. Thus, the patient weighing >70 kg may not be benefitted by the low-dose of aspirin.

Studies involving restructured dosages of aspirin as per weight and platelet activity measurement of the patient should be considered.

"American Diabetes Association (ADA) 2019 Guideline Recommendations on Aspirin: Individualize - Do not Eliminate

Aspirin (75 –1 6 2 mg/day) may be considered as primary prevention therapy in diabetic patients who are at increased cardiovascular risk, after a discussion with the patient on the benefits versus increased risk of bleeding.

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Way Forward

Looking at the evidence through a rational spectacle, it can be stated that permanent dismissal of aspirin is not straightforward. Therefore, use of aspirin in primary prevention could be individualized, rather than eliminated; while an opportunity to derive an "Aspirin Risk Score" to identify categorically high-risk primary prevention candidates who qualify for Aspirin therapy is certainly knocking doors!!

References:
1. ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. New England Journal of Medicine. 2018 Oct 18;379(16):1529-39.
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3. Nelson MR, Reid CM, Ames DA, Beilin LJ, Donnan GA, Gibbs P, Johnston CI, Krum H, Storey E, Tonkin A, Wolfe R. Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: Results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study--Research. Medical Journal of Australia. 2008 Jul 21;189(2):105-9.
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