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.

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 adenosine diphosphate (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.

Aspirin

Non-selective, irreversible inhibitor of cyclo-oxygenase which catalyses 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, although some of these effects are only apparent at much higher doses.

Clopidogrel

An 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.

Direct comparison of clopidogrel may indicate that it is a slightly more effective antiplatelet drug than aspirin - for example, when compared head-to-head in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial.But a high NNT (200) to prevent one additional event and high incremental cost (given aspirin's low cost) have meant that use of clopidogrel alone is limited to those who cannot tolerate aspirin prophylaxis.[4] More importantly, clopidogrel is routinely used in the treatment of acute coronary system (ACS) and post-percutaneous coronary intervention (PCI) stenting in conjunction with aspirin.

Prasugrel

Prasugrel is a novel prodrug from the same family as clopidogrel, with more efficient platelet inhibition.

Current National Institute for Health and Clinical Excellence (NICE) guidance recommends prasugrel in combination with aspirin in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) when:

immediate PCI is necessary for ST segment elevation myocardial infarction (STEMI); or

stent thrombosis occurred during treatment with clopidogrel; or the patient has diabetes mellitus

Dipyridamole

The mechanism is not fully understood but it is 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 myocardial infarction (MI) or left ventricular outflow obstruction.

Glycoprotein IIb/IIIa antagonists

Abciximab was the original GP IIb/IIIa antagonist and is a monoclonal antibody with a much prolonged duration compared to newer agents, eg eptifibatide which is a non-peptide antagonist.

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 two 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.

Neutralising antibodies to abciximab form, 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.

Other agents

Ticagrelor - licensed for use with aspirin in preventing atherothrombotic events in acute coronary syndrome (ACS) for 12 months, and can be used for both medical management or where further coronary intervention is planned. If it needs to be continued beyond this then the diagnosis should be confirmed by a cardiology specialist.

Indications

Primary prevention of cardiovascular disease (CVD):

Previously, aspirin was recommended for those without apparent CVD in whom the total CVD risk over 10 years is >20%, and for almost all diabetic patients over the age of 50 years. The evidence to support this unlicensed indication is not robust and thus current

guidance is that aspirin should not be used in primary prevention (including in those with diabetes mellitus or hypertension).[12] But note: aspirin is increasingly being used in the primary prevention of some cancers - particularly bowel cancer.

Clopidogrel and dipyridamole are neither indicated nor licensed for primary prevention of cardiovascular (CV) events.

Secondary prevention of CVD:

In those with established atherosclerotic disease, low-dose aspirin (75 mg daily) is recommended indefinitely for long-term secondary prevention. Antithrombotic Trialists' Collaboration (ATTC) 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 two years from the most recent event, based on the second European Stroke Prevention (EPS-2) trial. EPS-2's findings have been replicated by the more recent European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) study. Evidence of long-term benefit was not established by EPS-2, so NICE guidance limited treatment duration to two years with preventative treatment reverting to standard treatment (eg low-dose aspirin) but it should probably continue with no time limit.

Where aspirin is contra-indicated 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).

There may be a role for triple antiplatelet therapy in the secondary prevention of CVD but this is as yet unlicensed.

Acute ischaemic events:

Myocardial ischaemia

A single dose of aspirin 300 mg and clopidogrel 300 mg (600 mg - unlicensed in some centres prior to urgent percutaneous coronary intervention (PCI)) should be given as soon as possible after an ischaemic event (both non-ST segment elevation myocardial infarction (NSTEMI) and STEMI), preferably dispersed in water or chewed.

Clopidogrel 75 mg daily is licensed for the treatment of acute coronary syndrome (ACS) ± ST elevation, in combination with aspirin (usually following loading doses).

Post-PCI clopidogrel 75 mg should continue for one month if a bare metal stent is inserted and 12 months if a drug-eluting stent is inserted. Thereafter, treatment should revert to low-dose aspirin alone.

Eptifibatide and tirofiban are licensed for use with heparin and aspirin to prevent early MI in patients with unstable angina or NSTEMI where early percutaneous transluminal coronary angioplasty (PTCA) is desirable but delay is likely.

PCI: abciximab is licensed as an adjunct to heparin and aspirin for the prevention of ischaemic complications in high-risk patients undergoing PCI, 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.

Eptifibatide: this is also used in NSTEMI where the last episode of chest pain was within 24 hours.

Rarely, GP IIb/IIIa inhibitors are used in complex patients with unstable angina or an acute coronary syndrome (ACS) which is not responding to conventional therapy (under specialist supervision).

Cerebral ischaemia

Acute ischaemic stroke - thrombolyse if appropriate and follow with aspirin 300 mg once daily for 14 days. If not able to be thrombolysed then aspirin alone should be given. Aspirin caused an excess of about two intracranial and four extracranial haemorrhages per 1,000 people treated, but these small risks were more than offset by the reductions in death and disability from other causes.

Long-term management of both TIA or ischaemic stroke - dipyridamole 200 mg bd with aspirin 75 mg once daily.

If aspirin cannot be used then modified-release dipyridamole is the choice.

If there are reasons why both aspirin and dipyridamole cannot be used - clopidogrel 75 mg would be the alternative, although this is currently unlicensed.

Atrial fibrillation (AF) carries a high risk of stroke and other thromboembolic events. Warfarin is more efficacious than aspirin at preventing stroke (particularly in those at highest risk) 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 comorbidities than research patients and thus at higher risk of side-effects.

New oral anticoagulant drugs, eg dabigatran, are likely to become an option for moderate- to high-risk groups in the future and may replace warfarin.

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 is over 75 years.

There is concurrent treatment with non-steroidal anti-inflammatory drugs (NSAIDs).

There is a 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.

Recent research in AF suggests that patients who are unsuitable for anticoagulants may get additional benefit if aspirin and clopidogrel are combined rather than using aspirin alone.

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 review[28] 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.

Cautions and contra-indications

See individual drug 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.

Hypersensitivity and allergy. NICE guidance suggests that true hypersensitivity to aspirin (characterised by rash, urticaria and angio-oedema) is rare.

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.

Hypertension should be controlled (blood pressure (BP) <150/90 mm Hg) before commencing treatment.

Side-effects

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 GP IIb/IIIa antagonists.

Interactions

Check the individual drug. 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.

Treatment issues

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 there is a family history of premature cardiovascular disease (CVD)) should receive opportunistic comprehensive CV risk assessment using Joint British Societies' (JBS) risk prediction charts.

The Scottish Intercollegiate Guidelines Network (SIGN) suggests five-yearly reviews of the same groups.

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'.

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.

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.

The new General Medical Services (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 contra-indications or side-effects to meet targets.

Medicine 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.[35] Seek expert advice.

What dose of aspirin? Antithrombotic Trialists' Collaboration (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 report any abdominal pain, melaena or rectal bleeding urgently.

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 protein pump inhibitor (PPI) - should be used prior to switching to clopidogrel where similar side-effects may occur.

Good communication between primary and secondary care is important. For example:

Ensuring that where aspirin is given for acute coronary syndrome (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 to the patient, what the long-term plan for medication is and, in particular, when to stop clopidogrel or dipyridamole.

Ensure mechanisms for stopping clopidogrel and dipyridamole at the correct times through regular medication reviews.

Auditing prescribing of clopidogrel and dipyridamole will help to ensure that their use falls within the limited indications.

Elective surgery - stopping antiplatelet drugs

The usual advice is that aspirin should be stopped 5-9 days prior to surgery[36] and clopidogrel stopped seven days before 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 postoperative bleeding is high (eg during major surgery) or where the consequences of even minor bleeding are significant (eg retinal and intracranial surgery).

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abciximab (Reopro ®):Platelet aggregation inhibition: (PCI): 0.25 mg/kg IV 10–60 minute prior to PCI, then 0.125 mcg/kg/minute (Maximum 10 mcg/min) IV Infusion x 12 hours.

The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in CLINICAL STUDIES.  In patients with failed PCls, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting.  In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately.

Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 m m filter (Millipore SLGV025LS or equivalent).

Aggrenox ® (dipyridamole/ASA):  INDICATIONS:  AGGRENOX (aspirin/extended-release dipyridamole) is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

DOSAGE AND ADMINISTRATION:  The recommended dose of AGGRENOX (aspirin/extended-release dipyridamole) is one capsule given orally twice daily, one in the morning and one in the evening. The capsules should be swallowed whole without chewing. AGGRENOX capsules may be administered with or without food.

AGGRENOX is not interchangeable with the individual components of aspirin and Persantine® Tablets.

Supplied:  Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release sugar-coated tablet.   [200 mg /25 mg]

anagrelide (Agrylin ®): INDICATIONS:   AGRYLIN Capsules are indicated for the treatment of patients with thrombocythemia, secondary to myeloproliferative disorders, to reduce the elevated platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombo-hemorrhagic events.

DOSAGE AND ADMINISTRATION:  Treatment with AGRYLIN Capsules should be initiated under close medical supervision. The recommended starting dosage of AGRYLIN is 0. 5 mg orally four times daily or 1 mg orally twice daily which should be maintained for at least one week. Dosage should then be adjusted to the lowest effective dosage required to reduce and maintain platelet count below 600,000/L, and ideally to the normal range. The dosage should be increased by not more than 0.5 mg/day in any one week. Dosage should not exceed 10 mg/day or 2.5 mg in a single dose.

Supplied: [ 0.5 mg , 1 mg  capsule]

cilostazol (Pletal ®)

Mechanism of Action: The mechanism of the effects of cilostazol tablets on the symptoms of intermittent claudication is not fully understood. Cilostazol tablets and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.

Cilostazol tablets reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking cilostazol tablets.

INDICATIONS AND USAGECilostazol is indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance.

CONTRAINDICATIONSCilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV congestive heart failure. Cilostazol is contraindicated in patients with congestive heart failure of any severity.

Cilostazol is contraindicated in patients with haemostatic disorders or active pathologic bleeding, such as bleeding peptic ulcer and intracranial bleeding. Cilostazol inhibits platelet aggregation in a reversible manner.

Cilostazol is contraindicated in patients with known or suspected hypersensitivity to any of its components.

Dosing (Adults): Peripheral vascular disease: 100 mg orally twice daily taken at least 30 minutes before or 2 hours after breakfast and dinner. Dosage should be reduced to 50 mg twice daily during concurrent therapy with inhibitors of CYP3A4 or CYP2C19.

Supplied: 50 mg, 100 mg tablet.

clopidogrel (Plavix ® ):INDICATIONS:  Plavix (clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events as follows:

* Recent MI, Recent Stroke or Established Peripheral Arterial Disease:  For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, Plavix has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.* Acute Coronary Syndrome:   For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, Plavix has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.

For patients with ST-segment elevation acute myocardial infarction, Plavix has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke. This benefit is not known to pertain to patients who receive primary angioplasty.

DOSAGE AND ADMINISTRATION:Recent MI, Recent Stroke, or Established Peripheral Arterial DiseaseThe recommended daily dose of Plavix is 75 mg once daily.

Acute Coronary SyndromeFor patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), Plavix should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Aspirin (75 mg-325 mg once daily) should be initiated and continued in combination with Plavix. In CURE, most patients with Acute Coronary Syndrome also received heparin acutely.

For patients with ST-segment elevation acute myocardial infarction, the recommended dose of Plavix is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. Plavix may be initiated with or without a loading dose (300 mg was used in CLARITY --  Review CLINICAL STUDIES).

Plavix can be administered with or without food.No dosage adjustment is necessary for elderly patients or patients with renal disease.

Supplied:  75 mg,  300 mg tablet.

dipyridamole (Persantine ®):INDICATIONS:  Dipyridamole is indicated as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement.DOSAGE AND ADMINISTRATION:Adjunctive Use in Prophylaxis of Thromboembolism after Cardiac Valve Replacement

The recommended dose is 75-100 mg four times daily as an adjunct to the usual warfarin therapy. Please note that aspirin is not to be administered concomitantly with coumarin anticoagulants.

Supplied:  25 mg, 50 mg and 75 mg tablets.

eptifabatide (Integrilin ®):ADMINISTRATION:

Administration: Bolus: withdraw dose from 10ml vial and give by IV push over 1-2 minutes. Continuous infusion: administer calculated rate directly from 100ml vial.

Properties: Onset: within 1 hr. T1/2 = 2.5 hours. Platelet fcn restored in @ 4hours after discontinuation. [Supplied: 0.75 mg/ml (100ml) vial. 20 mg/10 ml vial.]

DOSAGEAcute Coronary Syndrome: The recommended adult dosage of eptifibatide in patients with

acute coronary syndrome and normal renal function is an intravenous bolus of 180 µg/kg (maximum: 22.6 mg) over 1-2 minutes as soon as possible following diagnosis, followed by a continuous infusion of 2.0 µg/kg/min (maximum: 15 mg/hour) until hospital discharge or initiation of CABG surgery, up to 72 hours. If a patient is to undergo a percutaneous coronary intervention (PCI) while receiving eptifibatide, the infusion should be continued up to hospital discharge, or for up to 18-24 hours after the procedure, whichever comes first, allowing for up to 96 hours of therapy. Concurrent aspirin (160-325 mg initially and daily thereafter) and heparin therapy (target aPTT 50-70 seconds) are recommended.

Dosing adjustment in renal impairment: Patients with CRCL less than 50 ml/min: The recommended adult dosage of eptifibatide in patients with acute coronary syndrome with an estimated CRCL <50 ml/min (using the Cockcroft-Gault equation) is an IV bolus of 180 µg/kg (maximum: 22.6 mg) as soon as possible following diagnosis, immediately followed by a continuous infusion of 1.0 µg/kg/min (maximum: 7.5 mg/hour).

Percutaneous Coronary Intervention (PCI): The recommended adult dosage of eptifibatide in patients with normal renal function is an intravenous bolus of 180 µg/kg (maximum: 22.6 mg) over 1-2 minutes administered immediately before the initiation of PCI followed by a continuous infusion of 2.0 µg/kg/min (maximum: 15 mg/hour) and a second 180 µg/kg bolus (maximum: 22.6 mg) 10 minutes after the first bolus. Infusion should be continued until hospital discharge, or for up to 18 to 24 hours, whichever comes first. A minimum of 12 hours of infusion is recommended. Concurrent aspirin (160-325 mg 1-24 hours before PCI and daily thereafter) and heparin therapy (ACT 200-300 seconds during PCI) are recommended. Heparin infusion after PCI is discouraged.Dosing adjustment in renal impairment: Patients with CRCL less than 50 mL/min: The recommended adult dose of eptifibatide in patients with an estimated CRCL < 50 ml/min (using the Cockcroft-Gault equation) is an IV bolus of 180 µg/kg (maximum: 22.6 mg) administered immediately before the initiation of the procedure, immediately followed by a continuous infusion of 1.0 µg/kg/min (maximum: 7.5 mg/hour) and a second 180 µg/kg bolus (maximum: 22.6 mg) administered 10 minutes after the first. In patients who undergo coronary artery bypass graft surgery, eptifibatide infusion should be discontinued prior to surgery.

Use the Cockcroft-Gault equation with actual body weight to calculate CRCL:

Males: [(140 – age) x (actual body wt in kg) ]----------------------------------------72 x (serum creatinine)

Females: [(140 – age) x (actual body wt in kg) x (0.85)] ---------------------------------------------- 72 x (serum creatinine)

prasugrel - EFFIENT™INDICATIONS AND USAGE Acute Coronary Syndrome

Effient™ is indicated to reduce the rate of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) as follows:

--Patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).--Patients with ST-elevation myocardial infarction (STEMI) when managed with primary or delayed PCI.

Effient has been shown to reduce the rate of a combined endpoint of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke compared to clopidogrel. The difference between treatments was driven predominantly by MI, with no difference on strokes and little difference on CV death [see Clinical Studies (14) - package insert].

It is generally recommended that antiplatelet therapy be administered promptly in the management of ACS because many cardiovascular events occur within hours of initial presentation. In the clinical trial that established the efficacy of Effient, Effient and the control drug were not administered to UA/NSTEMI patients until coronary anatomy was established. For the small fraction of patients that required urgent CABG after treatment with Effient, the risk of significant bleeding was substantial [see Warnings and Precautions (5.2)]. Because the large majority of patients are managed without CABG, however, treatment can be considered before determining coronary anatomy if need for CABG is considered unlikely. The advantages of earlier treatment with Effient must then be balanced against the increased rate of bleeding in patients who do need to undergo urgent CABG.

DOSAGE AND ADMINISTRATION Initiate Effient treatment as a single 60 mg oral loading dose and then continue at 10 mg orally once daily. Patients taking Effient should also take aspirin (75 mg to 325 mg) daily. Effient may be administered with or without food].

Dosing in Low Weight PatientsCompared to patients weighing 60 kg, patients weighing < 60 kg have an increased exposure to the active metabolite of prasugrel and an increased risk of bleeding on a 10 mg once daily maintenance dose. Consider lowering the maintenance dose to 5 mg in patients < 60 kg. The effectiveness and safety of the 5 mg dose have not been prospectively studied.

HOW SUPPLIEDEffient (prasugrel) 5 mg is supplied as a yellow, elongated hexagonal, film-coated, non-scored tablet debossed with "5 MG" on one side and with "4760" on the other side.

5 mg tablets are supplied as follows: Bottles of 7 - NDC 0002-4760-76 Bottles of 30 - NDC 0002-4760-30

Effient (prasugrel) 10 mg is supplied as a beige, elongated hexagonal, film-coated, non-scored tablet debossed with "10 MG" on one side and "4759" on the other side.

10 mg tablets are supplied as follows: Bottles of 30 – NDC 0002-4759-30 Blisters ID 90* NDC 0002-4759-77

ticagrelor -BRILINTA™DESCRIPTIONHIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use BRILINTA safely and effectively. See full prescribing information for BRILINTA.

BRILINTA™ (ticagrelor) tablets, for oral useInitial U.S. Approval: 2011

BRILINTA contains ticagrelor, a cyclopentyltriazolopyrimidine, inhibitor of platelet activation and aggregation mediated by the P2Y12 ADP-receptor.

INDICATIONS AND USAGE Acute Coronary SyndromesBRILINTA is a P2Y12 platelet inhibitor indicated to reduce the rate of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) (unstable angina, non-ST elevation myocardial infarction, or ST elevation myocardial infarction). BRILINTA has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. In patients treated with PCI, it also reduces the rate of stent thrombosis.

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily

DOSAGE AND ADMINISTRATION Initiate BRILINTA treatment with a 180 mg (two 90 mg tablets) loading dose and continue treatment with 90 mg twice daily.

After the initial loading dose of aspirin (usually 325 mg), use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

ACS patients who have received a loading dose of clopidogrel may be started on BRILINTA.

BRILINTA can be administered with or without food.

A patient who misses a dose of BRILINTA should take one 90 mg tablet (their next dose) at its scheduled time.

HOW SUPPLIEDBRILINTA (ticagrelor) 90 mg is supplied as a round, biconvex, yellow, film-coated tablet marked with a “90” above “T” on one side.

Bottles of 60 – NDC 0186-0777-60Bottles of 180 – NDC 0186-0777-18

100 count Hospital Unit Dose – NDC 0186-0777-39

ticlopidine (Ticlid ®): INDICATIONS: --To reduce the risk of thrombotic stroke (fatal or nonfatal) in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke. Because TICLID is associated with a risk of life-threatening blood dyscrasias including thrombotic thrombocytopenic purpura (TTP), neutropenia/agranulocytosis and aplastic anemia, TICLID should be reserved for patients who are intolerant or allergic to aspirin therapy or who have failed aspirin therapy.

--As adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation.

DOSAGE AND ADMINISTRATION:Stroke: The recommended dose of TICLID is 250 mg bid taken with food. Other doses have not been studied in controlled trials for these indications.

Coronary Artery Stenting: The recommended dose of TICLID is 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.

Supplied:  250 mg tablet.

tirofiban (Aggrastat ®):Dosing: 0.4 mcg/kg/min for 30 minutes, followed by 0.1 mcg/kg/min. Therapy should continue through angiography and for 12-24 hours after angioplasty or atherectomy.

Dosing adjustment in renal impairment:(Note: Reduce dose by 50% if CRCL < 30 ml/min - 0.2 mcg/kg/min x 30 min, followed by 0.05 mcg/kg/min).

Preparation: Add 12.5 mg (50 ml) to 200ml NS or D5W. Total volume= 250ml. Concentration= 50 mcg/ml. Or add 25 mg (100ml) to 400 ml D5W or NS.

Supplied: 250 mcg/ml-50 ml vial (12.5 mg/50ml).