Should all diabetic patients be on aspirin for primary prevention?

KEYWORDS:

• Aspirin
• diabetes
• prevention

Not all patients with diabetes mellitus (DM) should be routinely prescribed daily aspirin (acetylsalicylic acid) for prevention regardless of their cardiovascular disease (CVD) risk. Aspirin is routinely prescribed for prevention of cardiovascular events that include nonfatal myocardial infarction (MI), unstable angina, ischemic stroke, transient ischemic attack (TIA) or cardiovascular death [1]. In general, the benefit of aspirin as primary prevention in patients who have a low-risk profile for cardiovascular events is questionable, particularly due to high risk of intracranial and gastrointestinal bleeding associated with aspirin use [2]. Given the increased risk for a cardiovascular event, the diabetic patient could benefit from aspirin therapy for primary prevention. However, the routine practice of aspirin for all diabetic patients has been controversial [2]. Nevertheless, administration of daily low-dose aspirin (81 mg) is well recognized in diabetics for secondary prevention [2,3].

In 2015 thirty million Americans; 9.4% of the US population; with more than 1.5 million Americans are diagnosed with diabetes every year [4]. The incidence of diabetes is highest among American Indians/Alaskan Natives (15.1%) followed by African Americans (12.7%). Diabetes is associated with high cardiovascular morbidity and mortality that drives the cost of healthcare for diabetic patients to be 2.3 times higher than what cost would be for non-diabetic patients [4]. This lead to the emphasis on preventing cardiovascular events in diabetic patients by slowing atherosclerosis process using statin therapy, a healthy lifestyle and good glucose control.

1. Pathophysiology of cardiovascular disease in diabetics

Diabetes increases the rate of first and recurrent atherothrombotic events. This is mainly due to the effect of diabetes on enhancing platelets adhesion (expression of p-selectin), activation (activates protein kinase C), and aggregation [5]. Similarly, diabetes causes higher intracellular calcium levels inside platelets, which further promotes platelet degranulation, and aggregation [6]. Additionally, high blood glucose leads to osmotic effect and oxidative stress, which ultimately accelerate the atherosclerosis process [5]. Insulin resistance also decreases the response to antithrombotic stimuli (nitric oxide and PGI2) and causes endothelial dysfunction [7].

Furthermore, diabetics have less platelet lifespan, causing increased bone marrow platelet production [7]. Finally, platelets upregulate both glycoproteins IIb/IIIa and P2Y12 signaling, which ultimately, increase platelet aggregation and adhesion [7]. This makes aspirin therapy of potential value in these patients to diminish platelet activation and aggregation [2]. However, diabetic patients have multiple prothrombotic mechanisms that can also render the response to aspirin use including inhibition of aspirin effect on the anti-aggregating pathway (ae.g. nitric oxide) which is seen with high glucose level [8].

2. Mechanism of aspirin

Aspirin blocks irreversibly cyclooxygenase (COX) (COX-1 and COX-2) activity, resulting in the inhibition of thromboxane A2 (TXA2) and prostacyclin (PGI2) generation. Low-dose aspirin (75 and 100 mg) inhibits TXA2 pathway, which inhibits platelet activation and aggregation, two major mechanisms in the pathophysiology of thrombosis and MI [9]. Also, inhibition of platelet activation, especially at vascular injury sites, is associated with lower production of inflammatory cytokines, oxygen radicals, and growth factors [10]. On the other hand, low-dose aspirin has minimum interference with COX-2 and PGI2-mediated vascular functions, which has antiatherogenic effects, and vascular thrombus resistance [11]. Also, it does not compromise blood pressure, renal function, or interfere with the effects of diuretics or angiotensin-converting enzyme inhibitors [11].

The optimal aspirin dosing was studied through CURRENTOASIS 7 trail, which compared the efficacy and safety of 75–100 mg vs. 300–325 mg of aspirin daily on 17 000 patients undergoing coronary angioplasty. The result of this study showed that low dose aspirin (75–100 mg) had similar efficacy to high doses in death and cardiovascular events prevention. However, in terms of safety, the low dose aspirin had a superior safety profile due to a lower incidence of hemorrhagic events (two events) [9]. In the U.S., the most common low-dose tablet is 81 mg [12].

3. Aspirin for primary prevention in diabetic patients

The current guidelines and risk assessment tools (e.g., ASCVD risk calculators) help clinicians identify diabetic patients who have a high risk for CV events and will draw the best benefit from aspirin therapy to reduce CV events [12]. High cardiovascular risk factors in diabetics include both men and women patients aged ≥50 years who have at least one additional major risk factor (Family history of premature atherosclerosis cardiovascular disease before 55 years of age in a first-degree male relative or before 65 years of age in a first-degree female relative, hypertension, dyslipidemia, smoking or chronic kidney disease/albuminuria) and do not possess any bleeding vulnerability (eg anemia, renal disease) [12]. The 2019 American Diabetes Association (ADA) guidelines recommends a CVD risk-based approach to guide aspirin therapy for diabetic patients [12].

The ADA guidelines recommend low-dose aspirin for diabetic patients with 10-year CVD risk ≥10%. Patients who are at intermediate (5% to 10%) 10-year CVD risk, aspirin can be prescribed based on the clinician’s clinical judgment (Table 1) [12]. This is similar to the recommendations by the American Heart Association (AHA), and the American College of Cardiology (ACC) published in 2015 [13]. However, the American College of Chest Physicians and the US Preventive Services Task Force (USPSTF) support initiating low-dose aspirin based on age (≥50 years) [14]. The USPSTF recommends aspirin for adults 50 to 59 years of age who have a 10-year cardiovascular risk of ≥10%, not at increased risk for bleeding, with a life expectancy of ≥10 years, and willing to receive low-dose aspirin daily for at least ten years [14]. Secondary prevention in diabetic patients with a history of atherosclerotic CVD could be started on aspirin therapy [12].

Table 1. 2015 AHA/ACC Scientific Statement & 2019 ADA guidelines. Aspirin therapy recommendation based on 10-year ASCVD risk^12,13.

DM with ASCVD Risk (%)	Age (Years)	Risk Factors*	Recommended low dose Aspirin
<5%	<50 or ≥70	None	No
5–10%	≥50 to <70	At least one	Clinical Judgment^δ
≥10%	≥50 to <70	At least one	Yes

DM – diabetes mellitus; ASCVD – atherosclerosis cardiovascular disease; ADA- American diabetic Association; AHA- American Heart Association.

*Risk Factors: family history of premature ASCVD, hypertension, smoking, dyslipidemia, chronic kidney disease, or albuminuria.

^δClinical Judgment: depends on the individual patient assessment for risk of aspirin therapy vs. its benefit for primary prevention of ASCVD as well as patient’s preference and acceptance to comply with aspirin therapy for at least the upcoming 10 years.

4. Recent aspirin studies for primary prevention in diabetic and non-diabetic patients

A study of cardiovascular events in diabetes (ASCEND) trial evaluated the daily aspirin (100 mg) use in diabetic patients who are ≥40 years of age without known CVD [15]. ASCEND was a multicenter, double-blinded, placebo-controlled trial that involved 15,480 diabetics with a median of 7.4 years follow up period. This study showed that the use of aspirin was associated with a 12% relative reduction in major adverse cardiovascular events (absolute risk reduction 1.1%) and 29% relative increase in major bleeding events (absolute risk increase for major bleeding was 0.9%) mainly gastrointestinal bleeding compared with placebo [15]. In ASCEND, the number of patients needed to treat to avoid a major CVD event and to suffer a major bleeding incident were 91 and 112, respectively [16]. Based on these findings, although low-dose aspirin use in diabetics showed a reduction in CVD events, it was counterbalanced with a higher risk of major bleeding [15].

The study of the effect of aspirin on cardiovascular events and bleeding in the healthy elderly-ASPREE trial, is a double-blinded, randomized study comparing the benefit of low-dose aspirin (100 mg) versus placebo among healthy elderly who are ≥70 years of age or ≥65 years of age among African Americans and Hispanics in the United States. All included patients had no history of CVD. The study followed patients for 4.7 years. Diabetes was present in 11% of treatment and placebo groups. Even though this study was limited in representing patients with diabetes mellitus, but its outcomes were important to provide an insight into the aspirin use in elderly patients for primary prevention of ASCVD. The rate of cardiovascular disease was 10.7 events per 1,000 person-years in the aspirin group and 11.3 events per 1,000 person-years in the placebo group (hazard ratio, 0.95; 95% confidence interval [CI], 0.83 to 1.08). The rate of major hemorrhage was 8.6 events per 1000 person-years and 6.2 events per 1000 person-years in the aspirin and placebo groups, respectively (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P < 0.001). The authors concluded the use of low-dose aspirin in primary prevention among healthy elderly did not provide a statically significant reduction in risk of CVD events while the risk of major bleeding was significantly higher [17].

Another study looked into the effect of aspirin as primary prevention in patients without diabetes. The aspirin to reduce risk of initial vascular events (ARRIVE) study is a multicenter, double-blinded, randomized trial comparing the administration of once-daily enteric-coated aspirin tablets (100 mg) versus placebo with median 60 months duration of follow-up in seven countries. The study included 12,546 non-diabetic patients who were 55 years (men) or 60 years (women) and older and had a moderate CVD risk (≥3 cardiovascular risk factors: dyslipidemia, current smoking, high blood pressure, positive family history of CVD). The study excluded patients who have diabetes, history of cardiovascular disease, use of antiplatelet or anticoagulation medication, and those who had a history of gastrointestinal bleeding. ARRIVE study showed no statically significant reduction in overall major CV events; 4.3% of the aspirin group compared with 4.5% of the placebo group (p = 0.60). However, aspirin therapy was associated with a lower risk for first MI (1.4%) in patients who were at least 60% compliant with compared with 1.6% in patients who were treated with placebo (p = 0.84). However, the risk of gastrointestinal bleeding was higher, 0.97% of patients in the aspirin group compared with 0.46% in the placebo group (p = 0.0007), but severe GI bleeding was low. Based on these findings, the investigators concluded that among patients at moderate risk of CVD, the use of aspirin was not beneficial, and low-dose aspirin use was not associated with a significant reduction in adverse cardiovascular events [18]. Although ARRIVE study excluded diabetics, it is important to study to cover in this review since it has the same design compared with ASCEND and ASPREE and a similar outcome in the cohort of patients who were treated with aspirin [18].

Based on the recent trials and guidelines, aspirin has CVD prevention in a certain cohort of patients who are at high risk for CV events. Diabetic patients with 10-year CVD risk that is ≥10% will benefit the most from aspirin therapy. For diabetic patients who are at intermediate or low risk for CVD, aspirin therapy showed a slight benefit but more bleeding. Therefore, clinical judgment and individual assessment of diabetic patients for CV risk should be considered before initiation of aspirin therapy. In cases where aspirin is to be used for primary prevention; it should be at the lowest dose possible (between 75–100 mg). Furthermore, uncoated aspirin with co-administration of a proton-pump inhibitor for patients at high risk for bleeding and avoid management with non-steroidal anti-inflammatory drugs [2]. Shared decision‐making taking into account the patient’s age, bleeding history and risk, cardiovascular risk factors, quality of life, preferences, and willingness to undergo long‐term aspirin therapy; is necessary [16,19].

A Japanese trail studied the effect of Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes. It was a randomized controlled trial, Multicenter, prospective, open-label, blinded, an end-point trial conducted from December 2002 through April 2008 at 163 institutions throughout Japan, which enrolled 2539 patients with type 2 diabetes without a history of atherosclerotic disease and had a median follow-up of 4.37 years. A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the nonaspirin group (17.0 per 1000 person-years) (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.58–1.10; log-rank test, P = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and ten patients (five fatal myocardial infarctions and five fatal strokes) in the nonaspirin group (HR, 0.10; 95% CI, 0.01–0.79; P = .0037). A total of 34 patients in the aspirin group and 38 patients in the nonaspirin group died from any cause (HR, 0.90; 95% CI, 0.57–1.14; log-rank test, P = 0.67). The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and nonaspirin groups. The study concluded that for patients with type 2 diabetes, low-dose aspirin as primary prevention did not result in decrement the risk of CVD events [20].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.