Key Points

  • On 1 May 2022 the restrictions in the General Schedule (S85) for clopidogrel and clopidogrel with aspirin changed from Authority Required (Streamlined) with multiple codes to unrestricted listings 
    GPs can prescribe these medicines within their scope of practice, according to clinical evidence and evidence-based guidelines
  • The unrestricted listings will reduce prescribing barriers for antiplatelet therapy in primary care 
    The previous listings required prescribers to select the correct streamlined authority codes for clopidogrel or clopidogrel with aspirin from a list of numerous codes.
  • Evolving evidence encourages individualised consideration of the antiplatelet agents for dual antiplatelet therapy  
    Real-world clinical trials and new analyses of the PLATO trial showed that clinically meaningful differences in efficacy between clopidogrel and ticagrelor or prasugrel depend on risk stratifications and clinical settings.
  • Clopidogrel with aspirin reduces major adverse cardiac events in patients with acute coronary syndrome 
    Dual antiplatelet therapy has been shown to be efficacious in patients with acute coronary syndrome, regardless of the clinical setting (STEMI or NSTEMI) and the management strategy (conservative treatment, percutaneous coronary intervention or coronary artery bypass graft).
  • A patient’s individual risk of bleeding must be considered for optimal pharmacotherapy, weighing therapeutic benefits against bleeding risks 
    Clopidogrel is the first line P2Y12 inhibitor and preferable to prasugrel and ticagrelor in patients at high risk of bleeding.

Abbreviations

ACS  Acute coronary Syndrome

AF  Atrial fibrillation

CVD  Cardiovascular disease

DAPT  Dual antiplatelet therapy

MI  Myocardial infarction

NOAC  Non–vitamin K antagonist oral anticoagulants

NSTEMI  Non-ST segment elevation MI

OAC  Oral anticoagulation

PAD  Peripheral arterial disease

PBAC  Pharmaceutical Benefits Advisory Committee

PBS  Pharmaceutical Benefits Scheme

PCI  Percutaneous coronary intervention

STEMI  ST-segment elevation acute MI

TGA  Therapeutic Goods Administration

TIA  Transient ischaemic attack

 

What’s changed?

On 1 May 2022 the restriction levels of the General Schedule (Section 85) PBS listings for clopidogrel and clopidogrel with aspirin changed from Authority Required (Streamlined) to general listings without restrictions (unrestricted listings).1

Clopidogrel

Prior to 1 May 2022 clopidogrel was listed as four items that included a large group of Authority Required (Streamlined) codes for the following conditions.2

  • prevention of recurrence of myocardial infarction (MI) or unstable angina
  • prevention of recurrence of ischaemic stroke or transient cerebral ischaemic events
  • acute coronary syndrome (MI or unstable angina)
  • cardiac stent insertion

On 1 May 2022 two items were deleted (2275R and 9317J) and made supply onlya.1

The remaining two items (8358X and 9354H)b were changed to be unrestricted. Each item still includes multiple brands of clopidogrel that are ‘a’ flagged as equivalent for substitution.1,2

Clopidogrel with aspirin

Prior to 1 May 2022 clopidogrel with aspirin was listed as a single item, with multiple Authority Required (Streamlined) codes for the following conditions.2

  • acute coronary syndrome (MI or unstable angina)
  • cardiac stent insertion
  • prevention of recurrence of MI or unstable angina

On 1 May 2022 the single item (9296G)b was changed to an unrestricted listing. It still includes multiple brands of clopidogrel with aspirin that are ‘a’ flagged as equivalent for substitution.1,2

a Supply only medicines are available on the Schedule for dispensing but not for prescribing, usually for a period of up to 12 months.1

b Can be prescribed by nurse practitioners.1

 

What are these medicines?

Clopidogrel and aspirin are antiplatelet medicines.3

Clopidogrel is a specific and potent inhibitor of platelet aggregation, exerting its action via the P2Y12 receptor. It is commonly known as a P2Y12 inhibitor.3,4

Aspirin stops platelet activation by inhibiting the enzyme cyclo-oxygenase-1. This prevents the synthesis of thromboxane A2, which is responsible for platelet aggregation.3

When administered together, the aspirin and clopidogrel combination (100mg/75mg) is known as dual antiplatelet therapy (DAPT).5

TGA-approved indications

Clopidogrel is registered in the Australian Register of Therapeutic Goods (ARTG) for the following indications:4

  • Prevention of vascular ischaemia associated with atherothrombotic events (MI, stroke and vascular death) in patients with a history of symptomatic atherosclerotic disease.
  • Acute coronary syndrome (ACS). Clopidogrel is indicated in combination with aspirin for:
    • Unstable angina or non-ST-elevation MI (NSTEMI) in order to prevent early and long-term atherothrombotic events (MI, stroke, vascular death or refractory ischaemia). Clopidogrel is indicated for the treatment of ACS whether or not patients undergo cardiac revascularisation (surgical or percutaneous coronary intervention, with or without stent)
    • ST-segment elevation acute MI (STEMI) in order to prevent atherothrombotic events.

Clopidogrel 75mg/Aspirin 100mg is registered in the ARTG for the following indication:3

  • Continuation of therapy in patients with ACS already initiated with separate clopidogrel and aspirin products.

See the TGA website for each product information for the multiple brands of clopidogrel and clopidogrel with aspirin

 

Why were the changes made?

At the December 2021 meeting, the Pharmaceutical Benefits Advisory Committee (PBAC) noted that clinicians regarded the (then current) Authority Required (Streamlined) listings as barriers to prescribing.6 

The PBAC considered the change to unrestricted listings reflected the evolving place in therapy of clopidogrel in recent years.6 Unrestricted listings would better enable prescribing according to current clinical evidence and evidence-based recommendations. 

The PBAC also considered that unrestricted listings would reduce administrative burden for prescribers and enable better access for patients in need of antiplatelet therapy.6

 

Current guidance on clopidogrel

It is important for GPs to have an understanding of the evidence base supporting the use of clopidogrel. It is the most commonly prescribed P2Y12 inhibitor in Australia,7 meaning there are many people in the community that will need to be managed while taking this medicine.

Acute coronary syndrome

Australian guidelines recommend that DAPT should be administered for a duration of up to 12 months after an ACS episode, followed by indefinite use of aspirin, or clopidogrel where aspirin is contraindicated.8,9 The duration of DAPT may be reduced or increased depending on clinical settings and risk stratifications (ie, patients at higher bleeding risk, or at higher risk of recurrent events). Any decision to vary the duration of DAPT should be determined in consultation with the cardiologist.8,9

DAPT has been consistently shown to be efficacious in patients with ACS, regardless of the clinical setting (ie, STEMI or NSTEMI) and the management strategy (eg, conservative treatment, percutaneous coronary intervention or coronary artery bypass graft).7,9-11

For more information on ACS management read this Australian Prescriber article Diagnosis and management of acute coronary syndromes.

Atrial fibrillation and stroke prevention

Australian guidelines for atrial fibrillation (AF) state that secondary stroke prevention in patients with AF should be managed with oral anticoagulation (OAC), using warfarin or non–vitamin K antagonist oral anticoagulants (NOAC).12,13

Antiplatelet therapy for secondary stroke prevention in patients with AF is not recommended.13 Health professionals should liaise with their patient’s cardiologist/specialist with a view to stopping antiplatelet therapy unless triple therapy (clopidogrel with low-dose aspirin combined with OAC) is required for ACS or stent implantation (or both).13,14 Guidelines recommend using triple therapy for the shortest duration possible, then reverting to OAC alone.13 Ticagrelor and prasugrel are contraindicated in triple therapy due to bleeding risks.13

For more information on AF management read this Australian Prescriber article Balancing the benefits and harms of oral anticoagulation in non-valvular atrial fibrillation.

Percutaneous coronary intervention

Adjuvant drug therapy protocols for percutaneous coronary intervention (PCI) can vary with specialist centres. Among patients with ACS who require PCI, Australian and international guidelines recommend DAPT with ticagrelor or prasugrel over clopidogrel except in cases where the patient cannot use ticagrelor or prasugrel or there is a need for OAC.9,11 Concerns about patient adherence with ticagrelor’s twice daily dosing may also influence antiplatelet choice.15

Peripheral artery disease

Patients with peripheral artery disease (PAD) (asymptomatic or experiencing intermittent claudication) are at high absolute cardiovascular disease (CVD) risk. It is recommended that they receive aspirin or clopidogrel to help reduce that risk.16 Australian guidelines on the management of PAD in people with diabetes and foot ulcers also recommends intensive CVD risk management that includes antiplatelet therapy with aspirin or clopidogrel.16,17

Clinical trial evidence does not support DAPT in patients with stable PAD, as it does not confer an advantage over monotherapy and is associated with increased bleeding.16 Evidence from the CHARISMA trial found that in a subgroup of patients with PAD, DAPT did not produce a statistically significant reduction of major adverse cardiovascular events when compared with aspirin alone.16,18-20

Secondary prevention of cardiovascular disease

The Therapeutic Guidelines and international guidance recommend the indefinite use of low dose aspirin for secondary prevention in established atherosclerotic CVD.11,16 In patients where aspirin is contraindicated, evidence from the CAPRIE trial showed that clopidogrel is a suitable substitute.11,16,19

Stroke / Transient ischaemic attack

National guidelines for the management of stroke recommend initiating DAPT (with clopidogrel) within 24 hours of a minor ischaemic stroke or high-risk transient ischaemic attack (TIA), and continuing with this treatment for three weeks before switching to monotherapy.21

Long term monotherapy with aspirin, clopidogrel or dual therapy aspirin with dipyridamole is recommended for all patients with ischaemic stroke or TIA who are not taking anticoagulation therapy.21

The evidence for this recommendation is based on results from the CHANCE and POINT clinical trials.21 CHANCE showed that DAPT, administered for the first 21 days after a high-risk TIA or minor stroke, reduced recurrence compared to aspirin alone.22 The POINT trial demonstrated the same result at 90 days.23 A meta-analysis which included the CHANCE and POINT trials found that DAPT appears to be most beneficial in the first three weeks following minor stroke.21-24

For more information on medicines for secondary stroke prevention read this Australian Prescriber article Drugs in secondary stroke prevention.

 

Evolving place in therapy for clopidogrel

The place for clopidogrel and aspirin in secondary prevention continues to evolve.

Current use of these medicines has been established based on a number of key trials. The CAPRIE trial demonstrated that clopidogrel is a suitable substitute for aspirin in patients with atherosclerotic disease. When compared to aspirin, clopidogrel significantly reduced the primary outcome of vascular death, MI or ischemic stroke by 8.7% (p = 0.045).19

The CURE, CLARITY and COMMIT clinical trials established the place of DAPT in several CVD settings, including ACS. These trials demonstrated that adding clopidogrel as a second antiplatelet provided further suppression of platelet function through complementary mechanisms of action.25-28

The TRITON-TIMI38 and PLATO trials found that the newer P2Y12 inhibitors, prasugrel and ticagrelor, were superior to clopidogrel in ACS for reducing the composite endpoint of cardiovascular death, myocardial infarction, and stroke.11,29-31 As a result, several guidelines recommended ticagrelor or prasugrel as first line ahead of clopidogrel in ACS, especially after stenting or in patients without high bleeding risks.29

However, evidence from recent real-world clinical trials (CHANGE-DAPT, SCAAR, PROMETHEUS) and new analyses of PLATO have presented data that favour clopidogrel over the other P2Y12 inhibitors in ACS.25,29,32-34

In the PLATO analyses for example, the authors noted that results could not be generalised to current improved clinical practices, which treat older patients and use better drug eluting stents.25,29,31 These results suggest that clinically meaningful differences in efficacy between clopidogrel and the newer P2Y12 inhibitors depend on risk stratifications and clinical settings.

Prasugrel removed from PBS

Prasugrel (brand name Effient) was removed from the PBS on 1 July 202035 following a request from the sponsor. Effient was the only brand available at that time and was discontinued in Australia and other countries due to a business decision.7,36 

There is evidence to suggest that prasugrel experienced lower uptake in clinical practice than other available P2Y12 inhibitors7,36 potentially due to factors such as higher bleeding risk (compared with clopidogrel) and limited use outside patients receiving PCI.36

 

What else should health professionals know?

Bleeding risks

Guidelines place emphasis on evidence-based clinical decision making for timely interventions to decrease morbidity and mortality, weighing therapeutic benefits against the patient’s bleeding risk.5,9,13,21 For example, the National Heart Foundation guidelines on ACS recommends optimising pharmacotherapy based on clinical settings and bleeding risk scoring tools. A short duration (3 to 6 months) of DAPT in ACS may be optimal if the bleeding risk is high. If a patient’s bleeding risk is low, prolonged DAPT could be considered although the optimal duration beyond 12 months is not well established.5,9

Several patient factors such as advanced age (>75 years), low body weight (<60kg), diabetes or chronic kidney disease can increase bleeding risks.5,9,37,38

For patients at high risk of bleeding clopidogrel remains the first line P2Y12 inhibitor.5,9,39

Proton pump inhibitors (PPIs) and gastrointestinal (GI) bleeding

Patients on antiplatelet therapy who are at high risk of GI bleeding could benefit from the concomitant use of a PPI.9,11 However, prescribers should be aware that not all PPIs are suitable - omeprazole or esomeprazole may reduce the therapeutic response to clopidogrel because they inhibit CYP2C19. The interaction has not demonstrated clinical significance, but co-administration of these medicines with clopidogrel is not recommended.9,11

Interaction with other medicines

Optimised therapy for the management of CV risk should consider potential drug interactions that could increase bleeding risk, including interactions with short term use of nonsteroidal anti-inflammatory drugs (NSAIDS).3,4,37,40

The antiplatelet efficacy of aspirin could be reduced by NSAIDS (especially ibuprofen) due to their cyclooxygenase-1 inhibition, and the concomitant use of these medicines should be avoided.3,5

Ceasing for surgery

The decision to cease antiplatelet therapy should weigh the risk of ischaemic events or stent thrombosis against bleeding risks. For patients undergoing minor dental surgery, it may be an option to continue antiplatelet therapy as the risk of a subsequent bleed is low.41 Most hospitals will contact patients with advice for discontinuing DAPT or antiplatelet therapy prior to surgery.

In general, aspirin or ticagrelor should be stopped for five days, and clopidogrel or prasugrel for seven days prior to surgery, and then antiplatelet therapy should be recommenced as soon as possible.41

Pre- and post-hospital clinical management

Patients with a suspected stroke or TIA require urgent management in a specialist facility.20 The Stroke Foundation has recommended that GPs educate their reception staff to redirect calls about suspected stroke to 000 (triple zero), according to the FAST stroke recognition message. Early intervention will have a significant impact on favourable outcomes.20

Secondary prevention pharmacotherapies for patients recovering from ACS should start before the patient leaves the hospital, and the discharge process must include a comprehensive patient care plan for primary care health professionals. These strategies are vital for minimising the risk of further atherosclerotic cardiovascular events.42

 

What else should patients know?

Talk with patients and carers about these points:3,4,37,40,43

  • Do not drink grapefruit juice as it may stop clopidogrel from working.
  • While taking clopidogrel try not to take NSAIDs, commonly known as anti-inflammatory medicines, as it can cause bleeding.
  • Clopidogrel may not be suitable if you are pregnant, breastfeeding or intend to become pregnant.
  • Tell your doctor if you have had recent surgery or are about to have surgery in the next 2 weeks.
  • If you are taking clopidogrel, tell a health professional at once if you notice:
    • Bleeding or bruising
    • Nose bleeds 
    • Bloody or black bowel motions
    • Red or purple patches on your skin
    • Swelling of the face, lips, mouth, tongue, or throat
  • If you have had a stomach ulcer or bleeds in the past, check with your doctor before taking this medicine.
 

More information

 

References

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