Doncaster & Bassetlaw Medicines Formulary Section 2.9: Antiplatelet Drugs Aspirin 75mg Dispersible Tablets Aspirin 300mg Dispersible Tablets Aspirin 300mg Suppositories Clopidogrel 75mg Tablets Dipyridamole 200mg MR capsules Prasugrel 5mg and 10mg Tablets Ticagrelor 90mg Tablets Tirofiban 12.5mg in 250ml Infusion Approved by Drug and Therapeutics Committee: May 2017 Review Date: May 2020 Prescribing Guidance: Aspirin Acute ischaemic stroke 300mg once daily via the oral or rectal route for 14 days or until discharge whichever is sooner followed by clopidogrel 75mg daily thereafter. Secondary prevention of cardiovascular disease 75mg orally daily Following coronary artery bypass surgery 300mg orally daily for 1 year then usually reduced to 75mg daily thereafter Management of ACS (Acute coronary syndrome) 300mg chewed orally/rectally immediately followed by 75mg daily thereafter for life. In ACS, DAPT (Dual antiplatelet therapy) is recommended for 1 year for most patients. However, based on individual risk parameters this may be shortened to 3 to 6 months in those at high risk of bleeding and low risk of events, and extended up to 30 months in selected patients at high risk of events and low risk of bleeding. Decisions on shortening or increasing the length of DAPT should always be made on the advice of a Consultant Cardiologist. The duration of DAPT should always be detailed on the discharge letter. Unless stated otherwise this will always be assumed to be the recommended 1 year.
Aspirin EC should generally not be used as this may affect the absorption and bioavailability which could lead to patients not receiving an appropriate dose. Aspirin should not routinely be used in primary prevention of CVS disease Clopidogrel (75mg daily) Ischaemic Stroke. Aspirin 300mg daily is given acutely (either orally, or by the rectal route, if the oral route is not available). The clopidogrel is started after 14 days (or upon discharge if this occurs sooner). For full details of stroke management see trust guidance via the intranet site (clinical guidelines) and also National Guidance. TIA Loading dose 300mg stat followed by 75mg daily (unlicensed) Prevention of atherothrombotic events in peripheral artery disease and multivessel disease 75mg daily Acute coronary syndrome The dose for both aspirin and clopidogrel for this indication is 300mg as a single dose followed by 75mg daily. In most patients with NSTEMI/STEMI clopidogrel is changed to ticagrelor on confirmation of diagnosis unless the patient is at a higher risk of bleeding. This is a clinical decision made by a senior member of the cardiology team. (clopidogrel is the P2Y12 agent recommended for patients who cannot receive ticagrelor or prasugrel or in those patients who require concomitant anticoagulation.) In ACS, DAPT (Dual antiplatelet therapy) is recommended for 1 year for most patients. However, based on individual risk parameters this may be shortened to 3 to 6 months in those at high risk of bleeding and low risk of events, and extended up to 30 months in selected patients at high risk of events and low risk of bleeding. Decisions on shortening or increasing the length of DAPT should always be made on the advice of a Consultant Cardiologist. The duration of DAPT should always be detailed on the discharge letter. Unless stated otherwise this will always be assumed to be the recommended 1 year. A full blood count should be taken during the first week of treatment in cases of co-administration of clopidogrel with aspirin, NSAIDS, heparin, glycoprotein iib/iiia inhibitors or thrombolytics and in patients at high risk of bleeding from trauma, surgery or other pathological conditions. Elective coronary/carotid stent procedures should also receive clopidogrel in combination with aspirin. The duration of therapy will depend on the stenting strategy. In coronary stent procedures ticagrelor or prasugrel may be used as an alternative to clopidogrel, as indicated by the Interventionist.
Ticagrelor Ticagrelor is indicated in combination with aspirin for the prevention of atherothrombotic events in patients with ACS. It is the formulary first-line P2Y12 agent to be used in combination with aspirin in patients with a confirmed diagnosis of ACS. Initially a single 180 mg loading dose should be prescribed followed by a dose of 90 mg twice daily, continued (in combination with aspirin) for 12 months. Aspirin should be continued indefinitely following the discontinuation of ticagrelor. Co-administration with strong inhbitors of CYP3A4 (e.g. ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir) is contraindicated; (please note if a macrolide is unavoidable azithromycin does not interact discuss choice with microbiology) See SPC for full list of interactions, but also note: o The maximum concomitant dose of simvastatin is 40mg, and digoxin levels may be increased. o Inducers of CYP3A4 (e.g. rifampicin, phenytoin, dexamethasone, carbamazepine, phenobarbital) may reduce the efficacy of ticagrelor. o Carbamazepine is also an inducer of CYP 3A4 and can affect the metabolism of ticagrelor and clopidogrel resulting in a reduction in antiplatelet efficacy. In patients on carbamazepine, prasugrel may be the antiplatelet of choice in patients that need to continue their carbamazepine As with other anti-platelet agents, an increase in bleeding is associated with ticagrelor. Use is contra-indicated in active pathological bleeding, history of intracranial haemorrhage and moderate to severe hepatic impairment. Ticagrelor also causes dyspnoea in a small but significant number of patients. In ACS, DAPT (dual antiplatelet therapy) is recommended for 1 year for most patients. However, based on individual risk parameters this may be shortened to 3 to 6 months in those at high risk of bleeding and low risk of events, and extended up to 30 months in selected patients at high risk of events and low risk of bleeding. Decisions on shortening or increasing the length of DAPT should always be made on the advice of a Consultant Cardiologist. The duration of DAPT should always be detailed on the discharge letter. Unless stated otherwise this will always be assumed to be the recommended 1 year. Where
extended treatment (beyond 1 year) is required, the recommended dose of ticagrelor is generally 60mg twice daily. See also NICE Guidance Prasugrel Prasugrel is indicated in combination with aspirin for the prevention of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. The decision regarding choice of DAPT is made by the specialist performing the procedure. A loading dose of 60mg is given initially followed by prasugrel 10mg daily for one year or 5mg daily for one year if body weight less than 60kg. Use of prasugrel in patients 75 years of age is generally not recommended. See SPC for further details. Prasugrel may be the preferred anti-platelet in combination with aspirin in patients who need to continue carbamazepine therapy as efficacy is not reduced in the presence of carbamazepine unlike ticagrelor and clopidogrel. Dipyridamole Dipyridamole is now rarely used in practice. It is used only in those patients with ischaemic stroke or TIA who are intolerant to clopidogrel where the MR capsule should be used in conjunction with aspirin. In patients intolerant to both clopidogrel and aspirin, dipyridamole m/r can be used as a sole agent. Dose: Dipyridamole 200mg MR capsules one twice daily
DAPT--Further Prescribing Notes Withdrawal of oral anti-platelets therapy may lead to an increased risk of recurrent events particularly when the recommended course of therapy has not been completed. Interruption of DAPT soon after stent implantation increases the risk of stent thrombosis significantly. Any decisions to discontinue any antiplatelet agent earlier than advised should only be made after discussion with a Consultant Cardiologist. Consider stopping clopidogrel/ticagrelor 5 days prior to CABG in patients with a low risk of adverse cardiovascular events. For those at intermediate or high risk the decision on whether to continue the clopidogrel should be discussed with the surgeon concerned. Clopidogrel/ticagrelor should be stopped 7 days prior to epidural anaesthesia. Clearly, the decision as to whether this is an appropriate intervention to be making will depend on the level of cardiac risk against the need for the epidural/surgery. This should be discussed with the cardiologist concerned. The combination of aspirin and clopidogrel is not licensed in secondary prevention of TIA/stroke and should only be prescribed under the guidance of a Consultant Specialist in Stroke Services. A proton pump inhibitor in combination with DAPT is recommended in patients at higher than average risk of GI bleeds (ie history of GI ulcer/haemorrhage, anticoagulant therapy, chronic NSAID/ corticosteroid use or 2 or more of the following; age>65years, dyspepsia, gord, chronic alcohol use, h pylori infection etc). In view of the possibility of an interaction between omeprazole/esomeprazole with clopidogrel resulting in the possibility of a reduced efficacy of clopidogrel it is advised that lansoprazole should be the ppi of choice for these patients.
Managing oral antiplatelet therapy in patients requiring long term anticoagulation in ACS In general, the period of triple therapy should be as short as possible, followed by OAC plus a single antiplatelet therapy (preferably clopidogrel 75 mg/day, or as an alternative, aspirin 75 mg/day). The duration of triple therapy is dependent on a number of considerations: acute vs. elective procedures, bleeding risk (as assessed by the HAS-BLED score), type of stent (with a preference for new generation DES or BMS). In the ESC consensus recommendations for patients with non-valvular AF, where OAC is referred to, this can either be with well-controlled adjusted dose VKA (with TTR 70%) or with a DOAC. The following recommendations are summarised in the table below taken from the ESC 2015 Guidance for the management of acute coronary syndromes in patients presenting without persistent ST elevation. 1. In patients with a firm indication for oral anticoagulation(oac) (eg AF with a CHA 2 DS 2-VAS s score >/= 2, recent venous thromboembolism, LV thrombus or mechanical valve prosthesis anticoagulation OAC is recommended in addition to antiplatelet therapy 2. Following coronary stenting DAPT including the new P2Y12 inhibitors should be considered as an ALTERNATIVE to triple therapy for patients with NSTE-ACS and AF with a CHA 2 DS 2-VAS s score of 1 in males and 2 in females 3. In patients at low risk of bleeding (HASBLED score less than or equal to 2) triple therapy with OAC, aspirin and clopidogrel should be considered for 6 months, followed by OAC and aspirin or clopidogrel continued up to 12 months 4. In patients at high risk of bleeding (HASBLED score greater or equal to 3) triple therapy with OAC, aspirin and clopidogrel should be considered for 1 month followed by OAC and aspirin OR clopidogrel for up to 12 months irrespective of stent type (BMS or new generation DES) 5. Dual antiplatelet therapy with OAC and clopidogrel may be considered as an alternative to triple therapy in selected patients (HASBLED score greater or equal to 3 and a low risk of stent thrombosis) 6. The use of ticagrelor or prasugrel as part of a triple regime IS NOT RECOMMENDED 7. One antiplatelet agent in addition to OAC should be considered in medically managed patients for up to 1 year
Summary Table ESC Guidance on treatment of NSTEMI in patients with NVAF
The Pioneer AF-PCI Trial published in the NEJM was an open labelled, multicentre randomised control trial comparing VKA vs DOAC in patients with NVAF receiving antiplatelet therapy after PCI to assess the relative risk of bleeding. The table below shows the trial design The primary outcome was clinically significant bleeding. The results of the trial show that those who received either low-dose rivaroxaban plus a P2Y 12 inhibitor for 12 months or very low-dose rivaroxaban plus dual antiplatelet therapy (DAPT) for one, six or 12 months had lower rates of significant bleeding compared with the standard therapy group. The three groups had similar rates of death from cardiovascular events, myocardial infarction, or stroke. Whilst the trial results are promising the study was not empowered to test efficacy with respect to reduction in stroke and the doses used of the rivaroxaban in the trial have not been formally tested for the prevention of stroke in previous studies. It should also be noted that the trial did not include many high risk patients for stroke in the study population. Nonetheless following this study the consultant cardiologist may decide to utilise the rivaroxaban combinations in this study in their patients with NVAF following PCI after reviewing the risk vs benefit for their individual patients.
Prescribers should be aware that the doses used for this indication are lower than the licensed doses for stroke prevention.
Peri-operative management of antiplatelets It is essential when patients are on antiplatelet therapy and being considered for surgery that the risk of the patient having a thrombotic event is balanced against the risk of haemorrhage from the procedure and decisions on whether antiplatelet therapy should be continued should always be made on an individual patient basis. Thus for each patient you must know the indication for the antiplatelet therapy the risk of bleeding for the surgical procedure In general 1. For patients on aspirin alone (<300mg) this doesn t appear to add significant risk of bleeding so may be continued for the majority of surgery (except those at very high risk of bleeding, eg. neurosurgery, prostatectomy) unless the surgeon specifically requests cessation. In situations where there is a very high risk of bleeding aspirin is generally stopped 7 days pre-operatively 2. For patients on clopidogrel alone. If the patient is at moderate or high risk of thrombosis the clopidogrel will usually be stopped 7 days preoperatively and changed to aspirin 75mg daily again considering the risks and benefits of this for the individual patient 3. For patients on DAPT any decisions to discontinue any antiplatelet agent earlier than advised should only be made after discussion with a Consultant Cardiologist/Vascular surgeon as appropriate. It may be appropriate to defer surgery/intervention. If this cannot be deferred: In patients with a recent acute coronary syndrome or coronary artery stent on dual antiplatelet therapy, low bleeding risk procedures should proceed without interruption of antiplatelet therapy. In patients with a recent acute coronary syndrome or coronary artery stent on dual antiplatelet therapy elective high bleeding risk procedures should, if possible, be postponed in patients still requiring dual antiplatelet therapy and if surgery cannot be deferred aspirin should be continued and clopidogrel or ticagrelor interrupted from 5 days pre-op or prasugrel from 7 days pre-op. Clopidogrel/ticagrelor should be stopped 7 days prior to epidural anaesthesia.
Use of GPIIb/IIIa receptor antagonists Glycoprotein IIb/IIIa receptor antagonists (GPIIb/IIIa antagonists) prevent platelet aggregation by blocking the binding of fibrinogen to receptors on platelets. Tirofiban is the GPIIb/IIIa antagonist of choice within the trust. In the light of new P2y12 inhibitor and direct thrombin inhibitors GPIIb/IIa receptor antagonists have little role to play in the routine management of ACS. They should be reserved for those patients with the highest thrombotic burden only on the advice of the Consultant Cardiologist or specialist Registrar on call from Sheffield after consideration of bleeding risk against ischaemic risk for the patient concerned. Tirofiban infusion Dosage: initial infusion rate 0.4microgram/kg/min for 30 minutes followed by a maintenance infusion of 0.1microgram/kg/min. Give concurrently with fondaparinux 2.5mg s/c daily (unfractionated heparin can be used if fondaparinux therapy unsuitable) Ensure aspirin and clopidogrel co-prescribed Reduce dose of tirofiban by 50% in severe renal impairment (creatinine clearance less than 30ml/min). Duration of treatment with tirofiban should not exceed 108 hours. Patients should be monitored for bleeding during treatment. FBC should be determined before starting treatment, within 2 to 6 hours after the start of treatment and at least daily whilst on therapy. Contra-indications include (see product literature for complete list) pregnancy, thrombocytopenia, history of haemorrhagic stroke, clinically relevant bleeding, stroke in the last 30 days, malignant hypertension, clotting disturbances, severe liver failure. Start within 12 hours of last angina attack. See also Guidance for Nurses on the Administration of Tirofiban Infusion