Curr Cardiol Rep (2015) 17:13 DOI 10.1007/s11886-015-0566-z


Preventing Cardiovascular Disease in Patients with Diabetes: Use of Aspirin for Primary Prevention Dhaval Desai & Haitham M. Ahmed & Erin D. Michos

# Springer Science+Business Media New York 2015

Abstract Diabetics are at high risk for atherosclerotic cardiovascular disease (ASCVD) and are considered a coronary heart disease risk equivalent. The utility of aspirin in primary prevention of ASCVD in diabetic patients has been widely studied and is still debated. Overall, the current evidence suggests a modest benefit for reduction in ASCVD events with the greatest benefit among those with higher baseline risk, but at the cost of increased risk of gastrointestinal bleeding. Diabetic patients at higher risk (with 10-year ASCVD risk >10 %) are generally recommended for aspirin therapy if bleeding risk is felt to be low. A patient-provider discussion is recommended before prescribing aspirin therapy. Novel markers such as coronary artery calcium scores and high-sensitivity C-reactive protein may help refine ASCVD risk prediction and guide utility for aspirin therapy. This article will review the literature for the most up-to-date studies evaluating aspirin therapy for primary prevention of ASCVD in patients with diabetes. Keywords Aspirin . Diabetes . Cardiovascular disease . Primary prevention

the USA, up to 11.3 % of adults now have diabetes per recent estimates from 2011 [2]. Despite advances in medical therapies, the incidence and prevalence of diabetes have continued to increase at an alarming rate over the past several decades [3, 4]. In this large and rapidly growing patient population, risk for ASCVD is significantly increased. Early data from the Framingham Heart Study showed that diabetes at least doubles the risk for ASCVD in men and women [5]. Later data by Haffner et al. showed that risk for myocardial infarction (MI) and cardiovascular death was comparable in diabetic patients without a history of MI as compared to nondiabetic patients with prior MI [6]. Based on this and other studies, the US National Cholesterol Education Program and European guidelines both considered diabetes to be a coronary heart disease (CHD) risk equivalent in 2002 and 2003, respectively [7, 8]. Since the US and European guidelines in 2002–2003, the utility of aspirin in primary prevention of ASCVD in diabetic patients has been widely studied and debated. In this paper, we will review the literature for the most up-to-date studies evaluating aspirin therapy for primary prevention of ASCVD in patients with diabetes.

Introduction Diabetes mellitus continues to increase in prevalence and is estimated to affect over 380 million people worldwide [1]. In This article is part of the Topical Collection on Diabetes and Cardiovascular Disease D. Desai Department of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, USA H. M. Ahmed : E. D. Michos (*) Division of Cardiology, Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins Hospital, Carnegie 568, 600 N. Wolfe Street, Baltimore, MD 21287, USA e-mail: [email protected]

Methods We reviewed the literature for studies evaluating aspirin therapy for primary prevention of ASCVD in diabetic patients using MEDLINE and PubMed databases to identify Englishlanguage, full-text articles in peer-reviewed journals, published from January 1, 1980 to December 1, 2014. The keywords utilized for the search in all text fields were Baspirin and diabetes^ alone or in combination with Bcardiovascular disease,^ Bcoronary heart disease,^ Bprimary prevention,^ Bprevention,^ Brisk,^ Bdeath,^ and Bmortality.^ We further identified articles not found during the initial electronic search that


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would be useful for this review through reference lists from these articles and our personal records.

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Aspirin for Prevention of Cardiovascular Disease Mechanism of Action

Cardiovascular Disease in Diabetics Increased risk of ASCVD in diabetic patients may be explained by a number of mechanisms that work in concert, including but not limited to endothelial dysfunction, increased platelet activation and thrombosis, and changes in plaque characteristics (Fig. 1). Diabetic patients without CHD have been shown to have endothelial dysfunction with a degree of impairment that is proportional to diabetes duration [9–13]. Conversely, therapy with metformin and thiazolidinediones in insulin-resistant patients was shown to improve coronary vasomotor and endothelial function [14–16]. In addition to endothelial function, elevated blood glucose may also have various effects on platelet function and coagulation. Diabetes has been shown to increase platelet activation, as well as increase primary and secondary platelet aggregation [17–20]. Furthermore, diabetes has been shown to be associated with increased plasma fibrinogen (an ASCVD risk factor) [21–23] and decreased fibrinolytic activity due to impaired tissue-type plasminogen activator (tPA) activity [24, 25]. Coronary plaque composition has been shown to vary between patients with and without diabetes. Moreno et al. found that coronary tissue from diabetic patients contained a greater amount of lipid-rich atheroma and macrophage infiltration on histologic evaluation, compared to patients without diabetes [26]. Such characteristics are thought to comprise Bvulnerable plaque^ at higher risk for rupture. Fig. 1 Pathophysiology of cardiovascular disease in diabetes

Aspirin is among the oldest, cheapest, and most widely available medicines used to prevent ASCVD worldwide. Aspirin irreversibly inhibits cyclooxygenase (COX-1 and COX-2), which in turn halts production of thromboxane A2 and platelet aggregation [27]. In addition to its well-documented antiplatelet effects, aspirin has been shown to increase nitric oxide formation and possibly modulate other inflammatory markers including C-reactive protein (CRP) and thereby decreasing risk of ASCVD [28]. In the next section, we will present clinical and populationbased studies to date evaluating the benefits of aspirin in prevention of ASCVD in diabetic patients.

Benefits of Aspirin for Secondary ASCVD Prevention in Patients with Diabetes There is ample evidence to support the use of aspirin in secondary prevention of ASCVD in patients, regardless of diabetes status. The Antithrombotic Trialists’ Collaboration showed in their meta-analysis that aspirin significantly decreases the risk of future ASCVD events in patients with previous MI, stroke, or transient ischemic attack [29]. The meta-analysis included 212,000 patients from 287 studies and found that antiplatelet treatment reduced the incidence of vascular events in high-risk groups by 23 %. The greatest benefit was seen in patients with acute or previous MI, other high-risk patients (which included patients on hemodialysis or with fistula or

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shunt placement, diabetes mellitus, and carotid disease), and previous stroke or transient ischemic attack. Current Recommendations for Aspirin Use in Primary Prevention for Diabetics The American Diabetes Association (ADA), American Heart Association (AHA), and American College of Cardiology Foundation (ACCF) synthesized an expert consensus document in 2010 to address the use of aspirin in primary prevention in patients with diabetes. Their recommendations were as follows [30•]: –

– –

Low-dose aspirin is generally recommended for adults with diabetes with an increased ASCVD risk score (10year risk >10 %), who are not at increased risk for bleeding (e.g. previous gastrointestinal bleeding, peptic ulcer disease, or concurrent NSAID or warfarin use). This group comprises men over age 50 years and women over 60 years with one or more ASCVD risk factors (e.g. smoking, hypertension, dyslipidemia, family history of premature ASCVD). Low-dose aspirin is not recommended for adults with diabetes with low ASCVD risk score (10-year risk 10 deaths per 1000 person years. This could aid in identifying diabetics at elevated risk for aspirin therapy. Conversely, younger diabetes 10 deaths per 1000 person years; thus, CAC testing to guide aspirin therapy would likely not be useful in this group. However, further research is needed to explore the utility of CAC scoring to guide aspirin therapy among diabetics. Concurrent treatment with statins in diabetics should also be considered when discussing aspirin therapy for primary prevention. Similarly to aspirin therapy, statin therapy for prevention of ASCVD in diabetics is well established from the

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meta-analysis performed by Cholesterol Treatment Trialists’ (CTT) Collaboration [54]. This statin meta-analysis also showed a statistically significant decrease in ASCVD events in high-risk diabetics (individuals with FRS >10 %), regardless of baseline lipid levels. Concurrent treatment with aspirin and statin provides additional benefit in secondary prevention compared to aspirin alone or statin alone. [55]. However, there are no randomized studies published thus far in diabetics that have looked at incremental benefit of aspirin therapy to patients already on statin therapy. Macchia et al. looked at thrombin generation as a marker of thrombotic risk in diabetics without previous ASCVD events treated with aspirin, atorvastatin, both, or none [56]. The group found that statins reduce thrombin generation compared to placebo, whereas aspirin had no effect on thrombin generation compared to placebo. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) is an ongoing trial in Italy that is investigating this question [57]. Results of this study will provide valuable insight on incremental benefit of aspirin for primary prevention in diabetics already on statin therapy. Who Should Receive Aspirin Therapy? In summary, based on currently available trials and guidelines [2010 ADA/AHA/ACC Consensus Document [30•] and 2014 European Society of Cardiology Position Paper on Aspirin Therapy in Primary Prevention [58]], we recommend the following (Clinical Flow Diagram, Fig. 2):

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cancer (notably colorectal cancer), a family history of colon cancer might also be factored into the shared decision-making [58].

Conclusions The use of aspirin for primary prevention of ASCVD in patients with diabetes is still debated. However, given the morbidity and mortality associated with ASCVD, diabetics at high-risk for developing ASCVD should be prescribed aspirin. For those at low-risk for developing ASCVD, the bleeding complications associated with aspirin outweigh benefits and lifestyle modifications should be recommended. For individuals at intermediate risk, more studies need to be conducted to risk-stratify patients who may benefit from aspirin therapy. Coronary artery calcium scoring can serve as one of these risk-stratification tools. Compliance with Ethics Guidelines Conflict of Interest Dhaval Desai, Haitham M. Ahmed, and Erin D. Michos declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References –

In asymptomatic patients with diabetes with low ASCVD risk score (10-year risk score 10 %) above the age of 50 for men and 60 for women with at least one other ASCVD risk factor, aspirin therapy should generally be recommended if there is no increased risk of bleeding. However, a patient-provider discussion about benefits vs. risk should be conducted before prescribing aspirin. In asymptomatic patients with diabetes with intermediate ASCVD risk score (10-year risk score 5–10 %) or for men younger than 50 and women younger than 60 with ASCVD risk score >10 %, or older patients with no risk factors, an individualized approach that involves provider-patient discussion should be used. This may involve further risk stratification using modalities such as CAC testing or biomarkers such as high-sensitivity CRP, while incorporating risk of bleeding, to make decision about whether aspirin therapy should be recommended. Given emerging data on aspirin for the prevention of

Papers of particular interest, published recently, have been highlighted as: • Of importance


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Preventing cardiovascular disease in patients with diabetes: use of aspirin for primary prevention.

Diabetics are at high risk for atherosclerotic cardiovascular disease (ASCVD) and are considered a coronary heart disease risk equivalent. The utility...
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