Section 1 – Rashmi

Rashmi is a 51-year-old lady of Indian ethnic origin with type 2 diabetes diagnosed 4 years previously. She attends the surgery for a routine diabetes review.

Rashmi has background retinopathy but is otherwise free from diabetes complications. Past medical history is unremarkable other than a laparoscopic cholecystectomy 10 years previously. She has no history of cardiovascular disease (CVD) and nor is there a strong family history. She is a non-smoker.

Glycaemic control, blood pressure and lipid profile are all satisfactorily controlled, and Rashmi’s current medication comprises metformin 1000 mg twice daily, dapagliflozin 10 mg once daily, atorvastatin 20 mg once daily and aspirin 75 mg once daily.

Aspirin is on Rashmi’s repeat medication list. How does antiplatelet medication work to provide cardiovascular protection?

Section 2

Arterial thrombus is largely composed of platelets. Antiplatelet medication inhibits the aggregation of platelets and, thus, reduces the possibility of thrombus formation in the arterial circulation that could lead to myocardial infarction, stroke or peripheral artery occlusion.

Aspirin is a cyclo-oygenase inhibitor inhibiting the production of thromboxane A2, which is a potent mediator of platelet aggregation.

Clopidogrel, prasugrel and ticagrelor are antiplatelet treatments that work by a different mechanism – inhibition of the platelet P2Y12 receptor – but again this leads to reduced platelet aggregation (NICE, 2023).

What are your thoughts about Rashmi’s use of aspirin?

Section 3

Rashmi has no history of CVD and her other cardiovascular risk factors are well controlled, so the question is whether or not aspirin can provide significant cardiovascular protection for her (i.e. primary prevention of CVD) and, if this is the case, whether these benefits outweigh the potential risks of aspirin therapy.

Aspirin offers clear benefits for cardiovascular protection in those with established CVD (i.e. secondary prevention) (Antithrombotic Trialists’ Collaboration, 2009). Because of the association of diabetes with increased cardiovascular morbidity and mortality, there has in the past been an assumption that aspirin would also be helpful in people with diabetes for primary prevention of CVD. However, this is more controversial, and there is data showing that people with type 2 diabetes who keep their cardiovascular risk factors within target range have little excess risk of death, myocardial infarction or stroke compared to those without diabetes (Rawshani et al, 2018).

Smoking cessation, control of hypertension and dyslipidaemia, and optimisation of glycaemic control all play an important role in cardiovascular protection (see Sections 5 and 6 for more detail).

What are the side effects of aspirin that cause most concern?

Section 4

The principal concerns with use of aspirin are gastrointestinal bleeding, intracranial bleeding and sight-threatening bleeding in the eye (ADA Professional Practice Committee, 2024).

Bear in mind that aspirin may bring other benefits (e.g. protection against bowel cancer) or cause other harms (e.g. aggravation of asthma) that might further impact on the decision whether to use aspirin or not.

So what evidence is available regarding the benefit–risk ratio of aspirin for primary prevention of CVD in people with type 2 diabetes?

Section 5

To summarise briefly, the evidence that has now accumulated indicates that the benefits of aspirin in primary prevention of CVD in people with type 2 diabetes are small and largely counterbalanced by an increased risk of major bleeding (Timmons et al, 2019). Some of the key supporting evidence for this is described in Section 6. If you wish to skip this detail then move on to Section 7.

Section 6 – Evidence over use of aspirin for primary prevention of CVD in type 2 diabetes

The Antithrombotic Trialists’ Collaboration’s (2009) meta-analysis of trials using aspirin for primary prevention, which included a small proportion of individuals with diabetes, found a small reduced risk of cardiovascular events versus placebo (a 12% relative risk reduction, predominantly due to reduced incidence of non-fatal myocardial infarction) but also a higher risk of bleeding that countered this benefit. Similar benefits and risk were seen between populations with and without diabetes.

The more recent ASCEND (A Study of Cardiovascular Events in Diabetes) randomised controlled trial also looked at primary prevention of CVD in people with diabetes. Over 15 000 people with diabetes (without previous CVD) were randomly assigned to aspirin 100 mg daily or placebo, and were followed for an average of 7.4 years. The primary efficacy endpoint was a first serious vascular event, a composite of non-fatal myocardial infarction, non-fatal stroke (not haemorrhagic), transient ischaemic attack and cardiovascular death. The primary safety outcome was occurrence of a major bleed (from gut, brain or elsewhere) that led to hospitalisation or death (ASCEND Study Collaborative Group, 2018).

A first cardiovascular event was less common with aspirin than placebo (8.5% vs 9.6%; relative risk reduction 12%). However, a first major bleed occurred in 4.1% of those taking aspirin versus 3.2% taking placebo, a 29% relative risk increase). These figures translate into a number needed to treat with aspirin to prevent a cardiovascular event of 91 over 7.4 years, compared with a number needed to harm with a major bleed of 115.

Gastrointestinal bleeding accounted for 41% of the haemorrhagic events (despite 25% of participants receiving proton pump inhibitors for gastroprotection), followed by ophthalmological haemorrhage (21%) and intracranial haemorrhage (17%). No subset of participants was identified in whom the benefits of aspirin clearly outweighed the risks.

Thus, the ASCEND study conclusion was that, although aspirin did reduce first cardiovascular events in people with diabetes and no previous CVD, these benefits were largely counteracted by an increase in major bleeding events.

What guidance is provided by NICE on use of aspirin for primary prevention of CVD?

Section 7

The NICE (2022a) NG28 guideline advises against routinely using antiplatelet therapy (aspirin or clopidogrel) in adults with type 2 diabetes who do not have CVD (i.e. not for primary prevention). Nor is aspirin advised for the primary prevention of CVD in the NICE (2022b) NG17 guideline on type 1 diabetes management.

Where people are at a particularly high risk of stroke or myocardial infarction, the benefit/risk balance may favour treatment with antiplatelet therapy. This should be decided on an individual basis (NICE, 2023).

American Diabetes Association guidance does advise consideration of aspirin for primary prevention in those with type 1 or type 2 diabetes who are aged 50 years or older and are at increased cardiovascular risk due to additional major risk factors (strong family history of CVD, hypertension, dyslipidaemia, smoking or albuminuria) and who are not at increased risk of bleeding (ADA Professional Practice Committee, 2024).

Case conclusion – Rashmi
After discussion with Rashmi, where it is agreed that the aspirin use is unlikely to produce a significantly positive benefit/risk profile, her aspirin is discontinued.

Section 8 – Kwame

Kwame, a 76-year-old man of African origin with longstanding type 2 diabetes, attends his diabetes review. He is known to have diabetic retinopathy, neuropathy (with a previous neuropathic ulcer) and nephropathy (eGFR 49 mL/min/1.73 m², ACR 28 mg/mmol).

One year ago, Kwame had a brief episode of unilateral weakness, which was subsequently diagnosed as a transient ischaemic attack (TIA).

Kwame’s current medication is: metformin 500 mg twice daily, gliclazide 80 mg twice daily, alogliptin 25 mg once daily, atorvastatin 20 mg once daily, indapamide 2.5 mg once daily, lisinopril 20 mg once daily, citalopram 20 mg once daily.

Would you recommend antiplatelet treatment for Kwame?

Section 9

There is strong evidence that, for individuals with (and without) diabetes who have had a previous myocardial infarction or stroke, antiplatelet therapy is helpful in preventing further cardiovascular events and mortality. For example, a 25% relative risk reduction of further cardiovascular events has been identified using aspirin for secondary prevention (Antithrombotic Trialists’ Collaboration, 2009).

In this case, Kwame has a history of TIA and so, in the absence of contraindications, antiplatelet therapy would be strongly recommended.

NICE recommends that antiplatelet treatment be used for secondary prevention of CVD (i.e. in people with angina, previous myocardial infarction, stroke, TIA or peripheral arterial disease) (NICE, 2023).

Which antiplatelet treatment would you choose for secondary prevention of CVD depending on whether the primary event occurred in the coronary, cerebral or peripheral arterial system?

Section 10

The choice of specific antiplatelet agent will vary according to the arterial bed that has been affected. NICE (2023) recommends the following first-choice long-term antiplatelet therapies:

• Aspirin 75 mg once daily for stable angina.
• Clopidogrel 75 mg once daily for stable cerebrovascular disease.
• Clopidogrel 75 mg once daily for symptomatic peripheral vascular disease.

 
Where aspirin is contraindicated or not tolerated, clopidogrel is an alternative. In the case of cerebrovascular disease, if clopidogrel is contraindicated or not tolerated then a combination of aspirin and modified-release dipyridamole (200 mg twice daily) can be offered (or if either of these agents is problematic then use the other agent singly). For peripheral arterial disease, if clopidogrel cannot be used then aspirin is an alternative.

Dual antiplatelet therapy is typically used following acute coronary syndrome (unstable angina, non-ST segment elevated myocardial infarction and ST segment elevated myocardial infarction). This usually comprises aspirin with clopidogrel (or prasugrel or ticagrelor), typically for 12 months.

Aspirin plus clopidogrel is usually instigated for 6 months following percutaneous coronary intervention.

Finally, there is evidence that adding a low dose of the anticoagulant rivaroxaban to aspirin provides additional benefit in preventing cardiovascular and adverse limb events in those with stable CVD or peripheral artery disease (Connolly et al, 2018; Bonaca et al, 2020). These benefits are maintained in people with diabetes, and absolute benefits are greater in this cohort because of the greater baseline risk (Bhatt et al, 2020). However, the combined rivaroxaban/aspirin treatment does carry a higher risk of major bleeding, so it should be restricted to those at low risk of bleeding (ADA Professional Practice Committee, 2022).

So what would you choose as antiplatelet therapy for Kwame?

Section 11

Clopidogrel 75 mg once daily would be the first-choice antiplatelet treatment for Kwame given his history of a cerebrovascular event (NICE, 2023).

Kwame is prescribed clopidogrel for secondary CVD prevention.

Should Kwame receive gastroprotection alongside his antiplatelet therapy?

Section 12

Kwame is at relatively high risk of gastrointestinal bleeding because of his age and also because he is taking citalopram. On balance, he ought to be offered gastroprotective prophylaxis.

What gastroprotection medication would you choose for Kwame?

Section 13

A proton pump inhibitor (PPI) would be the most effective treatment. In this case, there is the added subtlety that the antiplatelet effect of clopidogrel is reduced with concomitant use of omeprazole or esomeprazole because the enzyme which activates clopidogrel (CYP2C19) is inhibited by these two PPIs (Juurlink et al, 2009). An alternative PPI should be selected in this case, as other PPIs do not significantly interact in this way (NICE, 2023).

Kwame was prescribed lansoprazole 30 mg once daily for gastroprotection, for use alongside his aspirin.

More generally, when would you consider using PPIs for gastroprotection in people using antiplatelet medication?

Section 14

People taking antiplatelet therapy who are at high risk of upper gastrointestinal bleeding, and thus might require a PPI, include (NICE, 2023):

• Older people, especially those >75 years of age.
• History of gastroduodenal ulceration or perforation, or gastrointestinal bleeding.
• Helicobacter pylori infection
  
• Concomitant use of medication known to increase the risk of gastrointestinal bleeding, such as SSRI antidepressants, anticoagulants (warfarin or newer oral anticoagulants such as apixaban), corticosteroids, NSAIDs, nicorandil and other antiplatelet agents.