Anti-platelet Drugs

Antiplatelet drug is a generic term, describing agents which decrease platelet aggregation and inhibit thrombus formation. Antiplatelet drugs are most effective for arterial clots that are composed largely of platelets in contrast to anticoagulant drugs which are more effective for venous thrombosis.

Platelets are critical in haemostasis and the development of arterial thrombi. Damaged endothelium activates platelets which respond by adhering and aggregating. Their release of thromboxane A2 and ADP amplifies and propagates the process by stimulating surrounding platelets. The production of thrombin via the coagulation cascade is also accelerated, stabilising the thrombus by the conversion of fibrinogen to fibrin. Different classes of antiplatelet drugs act at different junctures in this process:¹

• Non-selective, irreversible inhibitor of cyclo-oxygenase which catalyzes the production of thromboxane and prostaglandins.
• Antithrombotic action derives from reduction in thromboxane A2.
• Aspirin also has analgesic, anti-inflammatory and anti-oxidant properties. Some of the beneficial actions of aspirin in patients with cardiovascular disease (CVD) may be related to these as well as its antithrombotic effect.¹

• An adenosine diphosphate (ADP) receptor antagonist that competitively inhibits ADP from binding to platelet receptors, preventing ADP mediated up-regulation of glycoprotein (Gp) IIb/IIIa receptor, again blocking amplification of platelet aggregation.
• Clopidogrel may be a slightly more effective antiplatelet drug than aspirin - when compared head to head in the CAPRIE trial⁴, a high NNT (200) to prevent one additional event and high incremental cost (given aspirin's low cost) has meant that clopidogrel is still only recommended for those who cannot tolerate aspirin prophylaxis.⁵

• Mechanism not fully understood but thought to act by inhibiting adenosine uptake into platelets and reducing ADP-induced aggregation.
• Dipyridamole also has vasodilating properties that can make it unsuitable for use in those with severe coronary artery disease, unstable angina, recent MI or left ventricular outflow obstruction.

• Abciximab was the original Gp IIb/IIIa antagonist and is a monoclonal antibody with a much prolonged duration compared to newer agents, eptifibatide and tirofiban, which are non-peptide antagonists.
• These drugs inhibit the final common pathway of platelet aggregation where fibrinogen binds to Gp IIb/IIIa receptor.
• All require intravenous administration under specialist supervision. Patients receiving these drugs require very close monitoring, usually on coronary care units (CCUs).
• Thromboxane A2 and ADP are just 2 of over 90 known platelet agonists. Blockade by aspirin and clopidogrel will not affect the platelet's ability to be stimulated by other agonists whilst use of a Gp IIb/IIIa antagonist should inhibit aggregate formation whatever agonist influences the platelet.¹
• Neutralising antibodies form to abciximib so it can only be used once.
• Gp IIb/IIIa antagonists can cause severe bleeding, most often from the site of femoral puncture for percutaneous transluminal coronary angioplasty (PTCA). It can take over 12 hours for platelet function to be restored after stopping an infusion.

• Primary Prevention of CVD
  • In those without clinically apparent CVD, the benefits of taking aspirin must outweigh the potential risks including bleeding. The current consensus for this threshold is where a total CVD risk over 10 years >20%.^12,13
  • Aspirin 75 mg daily is also recommended for all people with type 2 diabetes who are over 50 years old and for younger diabetics who are considered to be at higher risk.¹²
  • Hypertension should be controlled (BP <150/90) before commencing treatment.¹²
  • Clopidogrel and dipyridamole are not indicated or licensed for primary prevention of cardiovascular events.
• Secondary Prevention of CVD¹⁴
  • In those with established atherosclerotic disease, low dose aspirin (75 mg daily) is recommended indefinitely for long-term secondary prevention. Antithrombotic Trialists' Collaboration (ATTC)¹⁵ provided evidence that this reduces the risk of any serious vascular event by 25 % and vascular mortality by a sixth.
  • Modified release dipyridamole 200 mg bd plus low-dose aspirin (50 mg or 75 mg daily) is recommended for secondary prevention following an ischaemic stroke or a transient ischaemic attack (TIA) for a period of 2 years from the most recent event⁵ based on the second European stroke prevention (EPS-2) trial¹⁶. EPS-2's findings have been replicated by the more recent European/Australasian stroke prevention in reversible ischaemia trial (ESPIRIT) study¹⁷. Evidence of long term benefit was not established by EPS-2 so NICE guidance⁵ limited treatment duration to 2 years with preventative treatment reverting to standard treatment (eg low dose aspirin) at this time. However,ESPIRIT showed benefit beyond this time so 2007 SIGN guidance¹³ also recommends this drug combination but without a time limit.
  • Where aspirin is contraindicated or genuinely not tolerated (ie proven hypersensitivity or history of severe low dose aspirin-induced dyspepsia), clopidogrel 75 mg daily is a suitable alternative to aspirin (or aspirin plus dipyridamole post-stroke)¹⁵
• Acute Ischaemic Events (acute MI, ischaemic stroke)
  • A single dose of aspirin 150-300 mg should be given as soon as possible after an ischaemic event, preferably dispersed in water or chewed.
  • Early treatment with aspirin within 48 hours of an acute ischaemic stroke will save lives and help prevent dependency.¹⁸ Most centres wait to treat until after the brain has been imaged to give aspirin. Aspirin caused an excess of about two intracranial and four extracranial haemorrhages per 1000 people treated, but these small risks were more than offset by the reductions in death and disability from other causes.¹⁹
  • Clopidogrel 75 mg daily is licensed for the treatment of acute coronary syndrome ±ST elevation, in combination with aspirin.²⁰ Such patients do better on clopidogrel 75 mg daily in combined with low-dose aspirin for at least one month after MI than on aspirin alone (CLARITY study²¹, COMMITstudy²²) and for 9-12 months following non-ST elevation ACS (based on the CURE study²³). Thereafter, treatment should revert to low-dose aspirin alone. This is the only indication for which a combination of aspirin and clopidogrel is currently licensed in the UK.
  • CHARISMA²⁴ showed no benefit and possible harm (increased rate of bleeding) to dual therapy (aspirin and clopidogrel) compared to placebo in patients with multiple CV risk factors.
  • Eptifibatide and tirofiban are licensed for use with heparin and aspirin to prevent early MI in patients with unstable angina or non-ST segment elevation MI where early PTCA is desirable but delay is likely.¹¹

  Antiplatelet drugs for CVD prevention: the studies and their acronyms11
  Aspirin Second International study of Infarct Survival (ISIS II) Collaborative Group (1988)25 Provided evidence of benefit of aspirin for secondary prevention following MI. ISIS II randomly assigned patients presenting within 24 hours of onset of acute MI to streptokinase, aspirin (162.5mg daily for 30days), both or neither. Significant survival benefits of aspirin seen at end of 5 weeks and remain evident even after 10 years. Anti-thrombotic Trialist's Collaboration (ATTC) (2003)15 Important meta-analysis providing conclusive evidence for the benefits of antiplatelet drugs (primarily aspirin) in preventing serious CV events in high-risk patients (those with established IHD, heart failure, PAD, AF, diabetes). RRR of 19% overall (ARR of 2.5%) with NNT of 40 and NNH of 238.
  Clopidogrel alone Clopidogrel versus Aspirin in patients at risk of ischaemic events (CAPRIE) study (1996)4 CAPRIE was a double-blind RCT comparing clopidogrel (75mg daily) with aspirin (325mg daily) in patients with a recent ischaemic stroke, MI or with symptomatic PAD on risk of serious ischaemic event. The two drugs were equally effective at preventing major vascular complications in those with recent MI or stroke, but clopidogrel was more effective in those with PAD. The drugs were equally well tolerated (despite the high dose of aspirin) but there was a higher incidence of GI bleeding with those on aspirin (NNH 455). Clopidogrel may be slightly more effective than aspirin in preventing CV events (absolute risk reduction of 0.5 % in serious vascular events, including death) and slightly less likely to cause a GI bleed but, on the basis of cost considerations, solo clopidogrel therapy is still only recommended for those who cannot tolerate aspirin prophylaxis.
  Asprin and clopidogrel Clopidogret in unstable angina to prevent recurrent events (CURE) study23(2001) Double-blind RCT looking at patients with symptoms suggestive of ACS and non-ST segment elevation on ECG and comparing their treatment with clopidogrel (loading dose of 300mg, followed by 75mg daily) or placebo in addition to standard aspirin therapy. Combination therapy was associated with far fewer primary out come events (CV death, non-fatal stroke or MI) but a significantly increased risk of major bleeding than on aspirin alone. Benefits of clopidogrel appeared within 30 days and were maintained up to 12 months, with most of the benefit in the first three months. Clopidogrel and metoprolol in MI trial (COMMIT) 22(2005) RCT looking at use of clopidogrel+/-aspirin +/- metoprolol following MI. 86% trial patients had ST elevation on ECG. Mean duration of treatment was 15 days. Small decreace in incidence of major CV events where aspirin and clopidogrel used in combination (9/1000 fewer deaths, reinfarctions or stroke) Management of Atherothrombosis with Clopidogrel in high risk patients (MATCH) study (2004).26 Double-blind RCT where Aspirin and clopidogrel (both 75mg daily) was compared to clopidogrel (75mg daily) alone in preventing serious vascular events in those with a recent ischaemic stroke or TIA and at least one additional CV risk factor over 18 months' duration. There was no significant beneficial effect of the combination treatment over clopidogrel alone as regards the end points. Those on combination treatment were more likely to experience life-threatening bleeds than those on clopidogrel alone (NNH 77). Clopidogrel versus placebo in vascular disease and high risk factors (CHARISMA) (2006)24 Large, 3 year trial looking at the effectiveness of aspirin with or without clopidogrel preventing CV events in those already diagnosed with CVD or in those with multiple risk factors for developing it. There was no difference in primary outcomes (MI, CVA and cardiovascular death) on dual therapy in those with risk factors only and a small, non-significant decrease in those with evident disease. There was an increased risk of bleeding on dual therapy.
  Dipyridamole alone European Stroke Prevention Study (ESPS-2) (1996)16 provided some evidence that MR dipyridamole alone may be effective for secondary prevention of stroke. A recent Cochrane Review27 however questioned evidence of any benefit, particularly in protection against cardiac events.
  Aspirin and dipyridamole European Stroke Prevention Study (ESPS-2) (1996)16 Large double blind RCT that found MR-dipyridamole (200mg bd) in combination with aspirin (25mg bd) to be more effective than either drug alone for prevention of stroke in those with a previous stroke or TIA. NNT of 34 over 2 years' treatment (compared to aspirin alone). No significant benefit on mortality but significantly increased risk of bleeding with combination treatment. European/Australasian stroke prevention in reversible ischaemia trial (ESPIRIT) (2007)17 'Pragmatic' open and non-blinded, randomised trial looking at endpoints of vascular death, strokes, MIs and major bleeds. Randomised patients within 6 months of minor stroke or TIA to low dose aspirin or low dose aspirin plus dipyridamole 200 mg bd. At 3.5 years follow-up, absolute risk reduction of 3% and NNT=33. No significant differences in mortality or bleeding rates but more drop-outs on dual therapy, primarily due to headache. At the end of the study, rate of events between the two groups was continuing to widen, suggesting prolonged treatment does continue to have benefit. Prevention regimen for effectively avoiding second stroke (PROFESS) trial Large randomised double-blind trial looking at use of clopidogrel versus aspirin and dipyridamole in secondary prevention of stroke in patients with a previous ishcaemic stroke. Due to report in 2008 and will hopefully provide more evidence to guide use of dipyridamole and aspirin.

• Percutaneous Transluminal Coronary Intervention.
  • Abciximab is licensed as an adjunct to heparin and aspirin for the prevention of ischaemic complications in high-risk patients undergoing percutaneous transluminal coronary intervention and NICE suggests that Gp IIb/IIIa inhibitors be used as adjuncts where the procedure is complex or is delayed and in patients with diabetes.²⁸
  • Clopidogrel reduces the risk of stent thrombosis following implantation, and should be used together with aspirin for 3 months (6-12 months if drug eluting stent).²⁹
• Atrial Fibrillation (AF) carries a high risk of stroke and other thromboembolic events.

  Annual risk of stroke in patients with atrial fibrillation30
  Risk group	No treatment	Aspirin	Warfarin
  Very High(previous CVA or TIA)	12 %	10 %	5 %
  High(>65 years and other risk factor eg diabetes, hypertension, left ventricular failure)	5-8 %	4-6 %	2-3 %
  Moderate(>65 years with no other risk factor or <65 years with other risk factor)	3-5 %	2-4 %	1-2 %
  Low(<65 years with no other risk factor)	1.2 %	1 %	0.5 %

  A recent study³¹ looked at data from 18,000 patients with non-rheumatic AF (from 19 trials) comparing warfarin and aspirin in the prevention of ischaemic stroke. Results indicate that warfarin is more efficacious at preventing stroke (particularly in those at highest risk) than aspirin but carries a greater risk of major haemorrhage:

  • Overall baseline risk is 51 strokes per 1,000 patient years.
  • Warfarin will prevent 28 strokes at the cost of 11 major bleeds.
  • Aspirin will prevent 16 strokes at the cost of 6 major bleeds.
  Primary care doctors worry that their patients tend to be older, sicker and with more co-morbidities than research patients and thus at higher risk of side-effects.
  Individual decisions to take aspirin or warfarin for thromboprophylaxis with AF remain difficult. Most recent guidance from NICE³² suggests that we should be advising on the basis of stratifying background stroke risk:

  Thromboprophylaxis on basis of background stroke risk32
  Stroke risk	High	Medium	Low
  Determined by	Previous ischaemic stroke, TIA or thromboembolic event 75 years or older with hypertension, diabetes or other vascular disease Clinical evidence of valve disease, heart failure or impaired left ventricular function.	65 years or older with no high risk factors. Less than 75 years with hypertension, diabetes or vascular disease.	Less than 65 with no medium or high risk factors.
  Suitable thromboprophylaxis	Anticoagulation with warfarin if no contraindications. Aim for target INR 2.5 (range 2-3). If contraindications, use aspirin 75-300 mg/day.	Consider aspirin or warfarin on an individual basis.	Aspirin 75-300 mg/day if no contraindications.

  Decisions for those with moderate risk are obviously hardest - lack of clear-cut evidence means that the decision to use warfarin or aspirin in this group should be individual, based on risk of bleeding and personal preference. Bleeding risk with warfarin is higher where:

  • Age over 75 years
  • Concurrent treatment with NSAIDs
  • Past history of bleeding
  • Polypharmacy
  • Uncontrolled hypertension
  NICE also recommends:
  • Start antithrombotic treatment where indicated as soon as possible following diagnosis of AF.
  • Treatment decisions should be made in the same way for paroxysmal AF.
• Pre-Eclampsia is associated with excessive production of thromboxane so antiplatelet agents have been proposed as possible therapy to prevent or delay the development of pre-eclampsia. A Cochrane Review³³ found that antiplatelet agents (primarily low-dose aspirin) did indeed have small to moderate benefits in the prevention of pre-eclampsia but research evidence is still required as to which women are most likely to benefit, when to start treatment, suitable dose etc. Antiplatelet drugs are not licensed for this use.

See individual drugs' profiles, but some general or important points:

• All antiplatelet drugs can cause bleeding. Avoid in patients who are at a high risk of bleeding or where the consequences of bleeding would be severe - for example:
  • Active peptic ulcer disease
  • Uncontrolled hypertension
  • Severe hepatic insufficiency
  • Pregnancy
  • Haemophilia
  • Other bleeding disorders
• Severe renal and hepatic impairment.
• Hypersensitivity and allergy. NICE guidance suggests that true hypersensitivity to aspirin (characterised by rash, urticaria and angio-oedema) is rare.²⁰
• Aspirin can cause bronchospasm and worsen pre-existing asthma. A systematic review estimated the prevalence of aspirin-exacerbated asthma in adults with pre-existing asthma as 21 % (from oral provocation testing). From this, it suggests that approximately 80 % of asthmatics can take aspirin safely but caution should be exercised. Always check about previous experiences with aspirin and other NSAIDs and warn to stop aspirin if their asthma deteriorates. High-risk features for developing aspirin-induced asthma include severe asthma, nasal polyps, urticaria and rhinitis.³⁴
• Pregnancy and breastfeeding - aspirin increases the risk of intrauterine and intrapartum bleeds and risk of closure of patent ductus arteriosus in utero. Aspirin whilst breast feeding may risk Reye's syndrome and increase the risk of neonatal bleeding if vitamin K stores are low.
• Children - aspirin is contraindicated in those under 16 years due to the risk of Reye's syndrome.

See individual drugs. All antiplatelet drugs can cause gastrointestinal (GI) disturbance and bleeding - dipyridamole is the least risky (but is rarely used alone) to the high risk associated with the GpIIb/IIIa antagonists.

Check individual drug. Important interactions include:

• Be wary of co-prescribing with other drugs that increase risk of bleeding (ie warfarin and heparin, other antiplatelet drugs, corticosteroids, iloprost). Adding clopidogrel to aspirin increases the antiplatelet effect but also increases the risk of bleeding so is only justified where the risk is outweighed by the potential benefit.
• Some NSAIDs (ibuprofen in particular) are thought to inhibit the antiplatelet action of these drugs.³⁵ It is wise to avoid these especially if the patient has unstable cardiac disease.
• Aspirin can antagonise the action of diuretics and cause fluid retention.
• There is an increased risk of renal impairment when taken with high dose aspirin and ACEIs are taken concomitantly. Their hypotensive effect is also antagonised.
• Aspirin reduces methotrexate's excretion so there is a higher risk of toxicity
• Dipyridamole enhances and extends the effects of adenosine.

Screening, risk assessment and communication

• Appropriate identification of patients remains a challenge:
  • Many of the guidelines advocate case-finding of those at high CV risk by screening.
  • Asymptomatic adults aged 40 years and over (younger where family history of premature cardiovascular disease) should receive opportunistic comprehensive cardiovascular risk assessment using Joint British Societies (JBS) risk prediction charts¹².
  • SIGN suggests five yearly reviews of the same groups.¹³
• By the age of 50, 90 % of the UK population are at sufficient CV risk to require treatment according to current guidelines and normal symptom-free individuals become 'patients'³⁶.
• Screening makes sense from a population perspective where lives are undoubtedly saved but on an individual basis, a small reduction in CV risk will lead to very little absolute benefit with all the disadvantages of medicalising lives.
• Communicating balances of risk and benefit to individuals is demanding. Even where figures derived from clinical trials can be applied straightforwardly to a patient's case, it is impossible to predict whether a particular individual will benefit, be harmed or receive no effect either way from a particular treatment. Sharing this uncertainty is very difficult.³⁷
• High risk individuals for primary and secondary prevention should be identifiable from disease registers. CVD prevention (including the use of antiplatelet drugs) within a practice can be audited against JBS standards.¹²
• The nGMS contract uses antiplatelet therapy as a quality indicator in three domains (CHD 9, STROKE 8 and AF 3) so it is particularly important to consider treatment (where appropriate) and record contraindications or side-effects to meet targets.³⁸

Medicines management

• Routine monitoring of antiplatelet treatment for primary and secondary prevention is not usually required.
• It should be remembered that antiplatelet therapy reduces but does not eliminate the risk of CV events. Where patients suffer a CV event whilst on antiplatelet medication, it should not be assumed that they are 'resistant' to the drug's antiplatelet effect or that a switch to another agent would offer any greater protection. True resistance to the antiplatelet action of aspirin or clopidogrel may occur in a small proportion of patients but there are no reliable tests available currently to confirm this.¹⁰ Seek expert advice.
• What dose of aspirin? ATTC provided good evidence that lower doses of aspirin (75-150 mg) were no less effective than higher ones with a reduced rate of bleeding complications.¹⁵ Common practice is to prescribe 75 mg daily for primary and secondary prevention of CVD, although a lot of cardiologists seem to use 150 mg daily.
• GI side-effects are common with aspirin:
  • Advise patients to urgently report any abdominal pain, melaena or rectal bleeding.
  • There is no evidence that enteric-coating or dispersible formulations of aspirin lessen the risk.
  • Ensure that it is taken with food.
  • Co-prescription of symptomatic or preventative medication (for example, maintenance dose PPI) should be used prior to switching to clopidogrel where similar side-effects may occur. The evidence that clopidogrel is a safer drug for GI side effects comes largely from the CAPRIE study where clopidogrel was compared with 325 mg aspirin and so may not translate to usual clinical practice.
  • A RCT showed evidence that esomeprazole (20 mg bd) plus aspirin (80mg od) was superior to clopidogrel (75 mg od) in preventing incidence of recurrent bleeding.³⁹
• Good communication between primary and secondary care is important, for example:
  • Ensuring that where aspirin is given for ACS, it is documented and passed on to paramedics/admitting team
  • Discharge plans from CCU/stroke unit should make it clear to primary care and the patient the long-term plan for medication and, in particular, when to stop clopidogrel or dipyridamole.
• Ensure mechanisms for stopping clopidogrel and dipyridamole at correct times through regular medication reviews
• Auditing prescribing of clopidogrel and dipyridamole will help to ensure that their use falls within the limited indications.⁵

Elective surgery - stopping antiplatelet drugs

• Usual advice is that aspirin should be stopped 5-9 days prior to surgery⁴⁰ and clopidogrel stopped 7 days before³ to reduce the risk of bleeding complications.
• However, it has been suggested that stopping aspirin leads to a rapid loss of protection and even rebound increased risk of ischaemic event.
• There also is the risk that the drug may not be restarted.
• This may make us question the wisdom of stopping antiplatelet agents in high risk individuals for minor surgical procedures such as skin or cataract surgery.
• In general, aspirin should be stopped where the risk of post-operative bleeding is high (eg during major surgery) or where the consequences of even minor bleeding are significant (eg retinal and intracranial surgery).³⁵
• If concerned, discuss with the surgeon or dentist.