Why Aspirin is Not Beneficial in Non-Diabetic Patients

Understanding the serious threat that cardiovascular disease poses and the various risk factors for developing this disease is fundamental to a patient’s health. Risks for cardiovascular disease can be due to a patient’s family history, gender, or age, but could also be indicative of their daily lifestyle. These factors can include hypertension, obesity, hyperlipidemia, unhealthy diet, and tobacco use. Prophylaxis with aspirin therapy or non-pharmacological treatment is a method in which patients can prevent adverse cardiovascular events, such as myocardial infarction or stroke.¹ Aspirin is a cyclooxygenase-II inhibitor that acts on the coagulation cascade leading to decreased thrombin activity and decreased clot formation as a result. It can also work to reduce inflammation, fever, and pain. It is vital to use aspirin in the secondary prevention of cardiovascular disease because the patients are at such a high risk of additional events. However, an ongoing debate is whether primary prevention with aspirin is beneficial in non-diabetic patients. Determining when to prescribe aspirin is important to ensure consistent guidelines across the board and to maximize patients’ safety and overall health since cardiovascular disease is the number one cause of death in both men and women.² Trials have been performed to determine whether aspirin is efficacious in certain patient populations, but no definite answer has been found in regards to primary prevention. The ARRIVE trial, the ASPREE trial, and lastly the Women’s Health study further explore the benefits and risks of using aspirin for primary prevention. From the primary literature, the use of aspirin in non-diabetic patients for the primary prevention of cardiovascular disease should not be given due to bleeding risks and increased death rates due to age.

  The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial was a double-blind, randomized controlled trial that studied the efficacy of 100 mg enteric-coated aspirin daily compared to a placebo. It was a six-year study that followed 12,456 patients over a total of nine doctor’s visits.³ These patients, both men and women, were 55 years or older with 2 or more cardiovascular risk factors. These risk factors could include high blood pressure, high cholesterol, or a positive family history of cardiovascular disease. Most patients had an ASCVD risk score between 10-20%, which was indicative of their risk factors. However, patients were excluded if they had diabetes, high bleeding risks, history of a vascular event, or required antiplatelet therapy. The primary outcome was the time to cardiovascular death, myocardial infarction, stroke, unstable angina, or transient ischemic attacks.³

As mentioned above, the trial was a double-blind, randomized control trial, which decreases bias because neither patient nor researcher knows which medication the patient is receiving so results will not be skewed. Also, patients with diabetes were excluded from the study, which proved to strengthen this trial because diabetes itself is a major cardiovascular risk factor. By only studying non-diabetics we are able to see if aspirin can truly lower cardiovascular risks without the presence of a major factor. ARRIVE included women and older age individuals who were at risk of developing cardiovascular disease within this trial, which was a strength that separated them from other trials performed in the past. The trials also performed comprehensive analyses through intention-to-treat and per protocol testing. This allowed thorough testing and follow-up with patients from beginning to end to ensure the most accurate conclusions could be determined even if the patients did not complete the full duration of the study. 

The ARRIVE trial’s funding is considered a weakness since Bayer manufactures aspirin and funded this trial. The trial did not seem to find statistically significant differences between the aspirin group and placebo group, but how can one trust these results if Bayer was responsible for some portions of the study design, the data collection, analysis and interpretation? In addition, they also had an independent statistician and were responsible for the final decision on whether to publish the study or not. Would Bayer release study results that poorly demote their product, which would ultimately prompt questions of bias within this study and how accurate the conclusions truly are? At first, the data seemed to be promising and consistent. However, upon further investigation, the data was sporadic, which proved to be a weakness. At first glance, the Kaplan-Meier curves regarding the cumulative incidence of the primary outcome would lead one to believe the lines showed separation, meaning there were statistically significant differences between the two groups, which were in favor of aspirin. But, these curves were misleading in that each y-axis only increased by two percent intervals. Overall, the readers must ask themselves how applicable this data is based on the small intervals of the y-axis. In addition, the Forest plots were also inaccurate upon further interpretation. For example, the cardiovascular disease risk score quartiles show individuals with risk scores less than 21.6% favoring aspirin, while the group with a risk percent greater than 21.6% favoring the placebo.³ The overall confidence interval should be on the far side of the aspirin side, however it is very close to favoring placebo. Realistically, the individuals with a greater cardiovascular risk percent should favor aspirin if the lower percent did, but this was not the case. Therefore, this prompts the reader to inquire why there would be a disconnection between the data. Is the data skewed from inconsistencies in data collection and analyses or did Bayer skew the data to provide better results for themselves? Perhaps Bayer is trying to hide results about their product to prevent backlash or decrease in sales. Additionally, there were not enough events to reach the previous power wanted of 91%, so after receiving the data they had to adjust their protocol to adjust for a power of 80%.³ External validity is not strong with per-protocol population, but this population did show statistical significance regarding myocardial infarctions. The intention-to-treat population has a stronger external validity because patients will not always be compliant, but this population did not show a statistical difference. Which is more important?

Overall, the ARRIVE trial determined aspirin is not an effective therapy in moderate risk patients for primary prevention of cardiovascular disease. Patients treated with aspirin had no reduction in the risk of cardiovascular incidences compared to the placebo. The aspirin treatment group also showed increased rates of gastrointestinal bleeding, 61 patients out of 6270 total, compared to the placebo group, 29 of the 6276 patients.³ Prescribing aspirin for primary prevention would only harm the patient due to bleeding risks with no benefits of reducing the risk of cardiovascular events. The trial’s funding bias and skewed data also further dispute the idea that aspirin should be given to individuals for primary prevention.

The Aspirin Reducing Events in the Elderly (ASPREE) trial was a randomized, double-blind study that studied whether low dose aspirin could extend the life of healthy elderly individuals. Men and women who were 70 years or older and were compliant when taking pills due to a 1 month trial were included in this study.⁴ They could not have cardiovascular disease, dementia, high bleeding risks, anemia, disabilities, or were expected to die within 5 years. Exclusions included use of anticoagulants or antiplatelet therapy and blood pressure higher than 180/105 mmHg.⁴ Once they were eligible, the 19,114 participants were then randomized and received either aspirin 100 mg or placebo.^4,5 The primary outcome for this trial was a composite of death, dementia, or persistent disability.

The National Institute on Aging was the primary financial resource, which strengthens this study’s findings since it is a non-biased source as opposed to Bayer funding the ARRIVE trial. This study also set clear, distinct standards as to what they considered bleeding to be.⁴ This was a major strength and improved the study’s accuracy and results. The sample size in which this study drew results from was vast, which is another strength. Additionally, this study used intention-to-treat and Cox regression to analyze the data.^4,5 The confidence intervals were not adjusted, thus concluding the data is accurate and raw, unlike the ARRIVE trial, furthering increasing the strength of this study.

The National Institute on Aging stopped the trial early because the data already collected and analyzed proved there would be no benefit regarding the primary outcome in continuing treatment.⁵ Concerning major bleeding, the aspirin group showed significantly higher results compared to the placebo group and the risk of major hemorrhaging increased with continued use of aspirin (hazard ratio: 1.38, confidence interval: 1.18 to 1.62, p< 0.001).⁴ The study concluded that individuals who were over 70 years old should not take aspirin due to the high mortality rates and increased bleeding risks. In patients who received aspirin, there were 1.6 excess deaths per 1000 years after 4.7 years compared to the placebo.^4,5 Previous trials have not found results similar to this statistic, thus one should question how accurate the results prove to be. The median age for the participants was 74 years old, which is considered a weakness and limitation. One of the risk factors for cardiovascular disease is age; therefore, only studying individuals who are already at risk of developing the disease could have skewed the data results. Out of the 19,114 participants, 1052 individuals died during the trial.⁵ Did the individuals die of natural causes or was it from the aspirin? To determine this and to eliminate bias, an outside adjudicator with no knowledge of which patient was in which group was responsible for determining the cause of death, which was considered a strength.⁵ Not only was the adjudicator an unbiased source, it also helped reduce limitation from the median age. Adherence was noted to be an issue towards the end of the trial, which could have skewed data results and weakened the trial’s conclusions. Was forgetfulness with age becoming an increasing problem for these individuals who were deemed prior to the study free of dementia or did they begin noticing adverse side effects and stop taking the medication? Despite its few weaknesses, the ASPREE trial proved to be a strong trial that discouraged the use of aspirin in the elderly for primary prevention due to increased bleeding risks and death rates.

The Women’s Health Study was a two-by-two factorial, randomized control trial that compared the combination of aspirin and vitamin E to placebo in the primary prevention of cardiovascular disease in 39,876 healthy women.² This study sought to determine the lowest dose of aspirin one could take to receive cardio-protective effects, while also reducing bleeding risks. Women who were 45 years or older were eligible if they had no history of cancer, cardiovascular disease, or another major illness. They could not be taking more than one dose of aspirin or vitamin supplements (A, E, or beta-carotene) per week. These women also could not be on any anticoagulants or corticosteroids. The women were followed for 10 years to assess for a combination primary endpoint of myocardial infarction, stroke, or death as a result of cardiovascular issues.²

These individuals took aspirin and vitamin E every other day. This could create complications with compliance because the patient has to remember what pills to take on what specific day, which could skew results. The Women’s Health Study not only received a grant from Bayer, but also received their drug supply from them. As with the ARRIVE trial, this causes major flaws and bias within the study data. How can one trust these results when the manufacturer is once again funding the study and supplying the drug?

The greatest strength of this study was the fact they used only women. For example, while there’s no difference in myocardial infarction with aspirin, the big difference is in stroke. This is significant because women have more strokes than men.¹ This can also emphasize how important it is to study different populations like gender when it comes to drug therapy. In addition, their population size was vast. This gave them the ability to have a high power to detect differences in subgroups. Cox regression and intention-to-treat analyses were performed for all primary endpoints, which helped to ensure accurate results.

The Women’s Health Study showed that aspirin had more of an effect on the elderly population seeing as they had one third of the cardiovascular events. Bleeding in the aspirin group was statistically significant when compared to the placebo group (p = 0.02). The transient ischemic attack was also significant, as well as the overall stroke risk. Once again, this study proves aspirin causes more harm than benefit in the treatment of primary prevention of cardiovascular disease.

After reviewing the three trials, it is obvious aspirin should not be used in the primary prevention of cardiovascular disease. Not only does it increase the risk of bleeding, but it also causes increased numbers of mortality. Additionally, it shows no risk in reducing the occurrence of cardiovascular events. Instead of having these patients take aspirin, which causes more harm than benefit, doctors should focus on having these individuals make lifestyle modifications to reduce their risk of developing cardiovascular disease. A healthy and nutritious diet with low salt intake and physical activity can significantly reduce one’s risk. In conclusion, prophylaxis with non-pharmacological treatments will provide the most benefit in patients compared to prophylaxis with aspirin in patients needing primary prevention for cardiovascular disease.

References:

1. Sergio Coccheri. Use and misuse of aspirin in primary cardiovascular prevention. Clinical Medicine Insights: Cardiology. 2017;2017(11):1179546817702149. doi: 10.1177/1179546817702149.
2. Ridker PM, Cook NR, Lee I, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. The New England Journal of Medicine. 2005;352(13):1293-1304. doi: 10.1056/NEJMoa050613.
3. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): A randomised, double-blind, placebo-controlled trial. The Lancet. 2018;392(10152):1036-1046.
4. McNeil JJ, Wolfe R, Woods RL, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. The New England Journal of Medicine. 2018;379(16):1509-1518. doi: 10.1056/NEJMoa1805819.
5. McNeil JJ, Nelson MR, Woods RL, et al. Effect of aspirin on all-cause mortality in the healthy elderly. The New England Journal of Medicine. 2018;379(16):1519-1528. doi: 10.1056/NEJMoa1803955.