The Role of Aspirin in the primary prevention of cardiovascular disease in patients with diabetes, especially T2DM - current knowledge and recommendations -

1. Aspirin as Prevention Therapy for Cardiovascular Events
Stefania Dumitrescu
in patients with Diabetes

2. Prevalence of CHD rises from 2% to 4% in the general population to as
high as 55% among adult diabetic patients (Berry et al. 2007)
Diabetes mellitus is an independent risk factor for CVD (acute MI, stroke,
heart failure, PAD, arrhythmias) in both men and women.
About one-quarter of patients with an acute MI have DM (Grundy et al., 2002)
Excess risk for CVD can be found in patients with type 1 and type 2 DM,
prediabetes, obesity or metabolic syndrome (Lteif et al., 2003)
Overall mortality from CHD is twice as great in men and 4 to 5 times
higher in women with than without DM (Hammoud et al., 2000)
Berry et al. 2007 Coronary Heart Disease in Patients with Diabetes Am Coll Cardiol. 2007;49(6):631-642.
Grundy et al., 2002 Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive Summary Conference
Proceeding for Healthcare Professionals From a Special Writing Group of the American Heart Association. Circulation.
2002;105:2231-2239.
Lteif et al.,.; Diabetes and heart disease an evidence-driven guide to risk factors management in diabetes. Cardiol Rev. 11
2003:262-274.
Hammoud et al., 2000; Management of coronary artery disease: therapeutic options in patients with diabetes. J Am Coll
Cardiol. 36 2000:355-365.

3. Compared with non-diabetics, diabetic subjects
• have more severe coronary disease,
• more extensive coronary/ vessels calcifications,
• higher prevalence of left main stem disease,
• reduced coronary collateral artery recruitment (Natali et al., 2000; Cariou et
al., 2000; Werner et al.,2003) .
Diabetes mellitus is considered a CHD risk factor equivalent, especially in
patients with coexisting cardiovascular risk factors (Grundy SM 2006)
CHD risk equivalent defines the risk of developing a major acute coronary
event (MACE) over 10 years of more than 20% (Grundy SM 2006).
Natali et al.,2000 Coronary atherosclerosis in Type II diabetes: angiographic findings and clinical outcome. Diabetologia. 43 2000:632-641.
Cariou et al., 2000 Angiographic characteristics of coronary artery disease in diabetic patients compared with matched non-diabetic
subjects. Diabetes Nutr Metab. 13 2000:134-141.
Werner et al., 2003 Impaired acute collateral recruitment as a possible mechanism for increased cardiac adverse events in patients with
diabetes mellitus. Eur Heart J. 24 2003:1134-1142.
Grundy SM 2006 Diabetes and coronary risk equivalency, Diabetes care, 2006; 29(2): 457-460

4. Reasons for increased vascular risk in DM
• Accelerated/ premature atherosclerosis due to increased prevalence of risk factors:
long term diabetes (especially T2DM) favoring long term hyperinsulinemia and hyperglycemia,
autonomic dysfunction, blood hypertension, dyslipidemia, obesity, smoking, chronic kidney disease
(albuminuria, hyperhomocysteinemia), autoimmune diseases (Grundy et al., 2007)( Anavekar et al.,2004) (Berry
et al., 2007) .
• Altered cardiac metabolism
• Undiagnosed DM
• Underutilized evidence based therapies
• Increased restenosis post-PCI
Grundy et al., 2002 Prevention Conference VI: Diabetes and Cardiovascular Disease: Executive Summary Conference Proceeding for
Healthcare Professionals From a Special Writing Group of the American Heart Association. Circulation. 2002;105:2231-2239.
Anavekar et al., 2004 Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for
albuminuria. Kidney Internat. 2004;66:S50-S55.
Berry et al. 2007 Coronary Heart Disease in Patients with Diabetes Am Coll Cardiol. 2007;49(6):631-642.

5. Pathophysiologic mechanisms of accelerated
atherosclerosis and thrombosis in DM (Berry et al. 2007):
• systemic inflammation,
• oxidative stress systemic
• endothelial dysfunction
• increased coagulation factors synthesis and activation
• platelet function abnormalities
• impaired fibrinolysis
• Increased glycation and oxidation of coagulation factors
Berry et al. 2007 Coronary Heart Disease in Patients with Diabetes Am Coll Cardiol. 2007;49(6):631-642.

6. 1997- American Diabetes Association (ADA) has
recommended aspirin (ASA) therapy for the primary and
secondary prevention of cardiovascular events

7. Gurbel, P (2009). Aspirin – scope and limitations. The British Journal of Cardiology, 17 (Suppl 1), pp.S8–S9.

8. Major Clinical Trials Using Routine Aspirin to Prevent Major Cardiovascular Events in patients with or
without diabetes (Nguyen et al. 2005)
Nguyen, K.X., Marinac, J.S. & Sun, C., (2005). Aspirin for primary prevention in patients with diabetes mellitus. Family medicine, 37(2),
pp.112–7.

10. Aspirin is recommended in secondary prevention in any patient with
established CVD, being the most cost effective intervention for
reducing the risk of MACE in patients with or without diabetes (Buse et al.
2007).
Platelet inhibition with low-dose aspirin (75–250 mg/day) is indicated
in all patients with T2DM and overt CVD who do not have a
contraindication (Ryden et al. 2007).
Buse JB et al., (2007). Primary Prevention of Cardiovascular Disease in people with Diabetes Mellitus: A Scientific
Statement From the American Heart Association and the American Diabetes Association. Circulation.2007; 115: 114-126
Ryden, L. et al., (2007). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: full text: The Task Force on
Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for
the Study of Diabetes (EASD). European Heart Journal Supplements, 9(Suppl C), pp.C3–C74.

11. Aspirin efficacy and safety in primary prevention of MACE in patients with
diabetes is controversial
The optimal dosage of aspirin for prevention of CHD events is also controversial
(Butalia et al. 2011)
• risk reduction achieved with low dosages (75 to 162 mg per day) similar
to that obtained with higher dosages
• ASPECT study found a stronger dose-dependency of platelet function
among patients with diabetes, suggesting the need for need higher
doses of aspirin (Gurbel et al., 2007).
• Aspirin resistance (1%-27%)(Schrör K. 2010)
• Platelet hyperreactivity (“residual platelet activity”) (i.e. diabetes, atherosclerosis)
• Platelet stimulation by aspirin-insensitive mechanisms (ADP, shear stress)
• COX-2-dependent (platelet-mediated) thromboxane formation (i.e. ,
atherosclerosis)
• Platelet sensitisation by isoprostanes (i.e. diabetes)
• COX-1 gene polymorphisms (A842G / C50T)
• Impaired sensitivity of platelet COX-1 (CABG)
• Insufficient bioavailability (low-dose enteric- coated preparations)
• Prevention of access to binding sites inside the COX-1 channel by NSAIDs
Butalia et al., (2011). Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a
systematic review and meta-analysis. Cardiovascular diabetology, 10(1), p.25.
Gurbel et al., (2007) Evaluation of dose-related effects of aspirin on platelet function: results from the Aspirin-Induced Platelet Effect
(ASPECT) study. Circulation 2007;115:3156–64.
Schrör K. (2010). What is aspirin resistance? The British Journal of Cardiology, 17 (Suppl 1), pp.S8–S9.

12. Evidence from trials conducted in patients with diabetes without CVD suggests that
aspirin therapy in primary prevention is associated at most with a non-significant
decrease in the risk of CHD events and stroke
• Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes study (JPAD 2008)(Ogawa et al.
2008)(diabetes patients only)
• Prevention of Progression of Arterial Disease and Diabetes trial (POPADAD 2008) (Belch et al. 2008)
(diabetes patients only)
• Early Treatment of Diabetic Retinopathy Study (ETDRS 1992) (Butalia et al. 2011)
• Aspirin for Asymptomatic Atherosclerosis (AAA)
• Primary Prevention Project (PPP 2003) (diabetes subgroup) (Sacco et al., 2003)
• Physician Health Study (PHS 1989) (diabetes subgroup) (***, 1989)
• Womens’ Health Study (WHS 2005) (diabetes subgroup )(Ridker et al., 2005)
Ogawa, H. et al., (2008). Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled
trial. JAMA : the journal of the American Medical Association, 300(18), pp.2134–41
Belch, J. et al., (2008). The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of
aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ (Clinical research ed.), 337(oct16_2), p.a1840.
Butalia, S. et al., (2011). Aspirin effect on the incidence of major adverse cardiovascular events in patients with diabetes mellitus: a systematic review
and meta-analysis. Cardiovascular diabetology, 10(1), p.25.
Sacco et al.,( 2003) A Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the
Primary Prevention Project (PPP) trial. Diabetes Care 2003;26:3264-72
***,( 1989) Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research
Group. N Engl J Med 1989;321:129-35
Ridker et al., (2005) NEJM 2005;352:1293-304

14. Belch J et al.,2008; for Prevention of Progression of Arterial Disease and Diabetes Study Group. BMJ.337;

15. 2 major ongoing trials collectively enrolling over 15,000 participants are evaluating the role of aspirin (100mg daily)
in patients with diabetes without cardiovascular disease:
• Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes
(ACCEPT-D) (De Berardis et al.2007 )
• A Study of Cardiovascular Events in Diabetes (ASCEND)
De Berardis G, Sacco M, Evangelista V, the ACCEPT-D Study Group, et al: Aspirin and simvastatin combination for cardiovascular
events prevention trial in diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of
cardiovascular events in subject with diabetes mellitus treated with statins. Trials 2007, 8:21-29.

16. Current recommendations regarding aspirin therapy in primary
prevention of CVD in patients with diabetes:
The International Diabetes Federation (IDF) 2012 recommends the use of
low dose aspirin along with lifestyle modification only in diabetes patients who
have had a previous CVD event (IDF 2012). No recommendations for primary
prevention.
The European Society of Cardiology (ESC) and the European Association
for the Study of Diabetes (EASD) do not recommend primary prevention with
aspirin in patients with diabetes, considering the evidence supporting the safety,
efficacy and net benefits of aspirin inconclusive (Rydén et al. 2013).
NICE type 2 diabetes guidelines recommend primary prevention with
75 mg/day aspirin in patients aged 50 years or older if their blood pressure is
below 145/90 mm/Hg and in patients younger than 50 who have another
significant cardiovascular risk factor (NICE-CG87 2009).

17. The JBS2 guidelines recommend daily 75 mg aspirin in selected people with
diabetes (> 50 years, or who are younger but have had the disease for more than 10
years, or who are already receiving treatment for hypertension), once the blood
pressure has been controlled to at least the audit standard of <150mm Hg systolic
and <90 mm Hg diastolic (JBS 2 2005).
The American Diabetes Association (ADA) 2014 guidelines for the management of
diabetes recommend the use of a statin in combination with aspirin in diabetes
patients with overt CVD to reduce the risk of a CV event (ADA 2014). No
recommendations for primary prevention.
The Standards of Medical Care in diabetes (2014) recommend aspirin therapy
(75–162 mg/ day) as primary prevention strategy in diabetes patients at increased
cardiovascular risk (10-year risk >10%). This includes most men aged >50 years or
women aged >60 years who have at least one additional major risk factor (family
history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) (American Diabetes
Association 2014)

18. The American Heart Association (AHA), American Stroke Association (ASA) and an
expert consensus document of the American College of Cardiology Foundation
recommend
1. Low-dose (75–162 mg/day) aspirin for primary prevention in adults with diabetes
and no previous history of vascular disease who are at high CVD risk (10 year risk of
CVD events over 10%) and who are not at increased risk for bleeding. This include
most men over age 50 years and women over age 60 years who have one or more of
the following additional major risk factors: smoking, hypertension, dyslipidemia,
family history of premature CVD, and albuminuria.
2. Aspirin should not be recommended for CVD prevention for adults with diabetes at
low CVD risk (men under age 50 years and women under 60 years with no major
additional CVD risk factors; 10-year CVD risk under 5%).
3. Low-dose (75–162 mg/day) aspirin use for prevention might be considered for
those with diabetes at intermediate CVD risk (younger patients with one or more risk
factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5–
10%) until further research is available (Pignone et al. 2010) (Goldstein et al. 2011) .

19. Conclusions
Cardiovascular disease is a major cause of morbidity and mortality in individuals with
diabetes
Periodic assessment of cardiovascular risk is a key step in the clinical judgment process
for recommending aspirin therapy
The benefits of aspirin in the secondary prevention of MACE in patients with diabetes
are well established
Aspirin use in primary prevention of MACE in patients with diabetes is still controversial
but ongoing trial results are awaited
In selected individuals with diabetes and high risk for CV events assessed by
cardiovascular risk calculators low dose aspirin can be effective in preventing CV
events, especially nonfatal ones. Because the potential benefits of aspirin therapy are
offset by clinically relevant bleeding events, routine use of aspirin for primary prevention
is not warranted and treatment decisions should be considered on an individual case
Future longer-term studies should aim to assess the impact of low- dose, alternate-day
aspirin treatment on both vascular and nonvascular outcomes, especially in specific sub-groups
of individuals and within diverse populations

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