To provide practical information on the optimal utilization of prasugrel in clinical practice.Prasugrel is an irreversible inhibitor of platelet activation and aggregation through the binding of its active metabolite to the P2Y12 adenosine diphosphate (ADP) receptor on platelets.# INDICATION:
Prasugrel, co-administered with acetylsalicylic acid (ASA), is indicated for the secondary prevention of ischemic cardiac events in patients with an acute coronary syndrome (ACS) (i.e. unstable angina, ST elevation myocardial infarction  or non-ST elevation MI) who are managed with percutaneous coronary intervention (PCI). This indication is based on the findings of a large phase 3 randomized controlled trial that demonstrated a statistically significant 2.2% absolute risk reduction (ARR) with prasugrel on the combined outcome rate of cardiovascular death, non-fatal MI, and non-fatal stroke (driven mostly by non-fatal MI) compared with clopidogrel, in patients presenting with ACS managed by PCI (number needed to treat  = 46). MI and stent thrombosis were also significantly reduced (ARR 2.3%; NNT = 43 and ARR 1.3%; NNT = 77, respectively). The benefit of prasugrel has been demonstrated only in patients with ACS undergoing PCI. There was no benefit for prasugrel over clopidogrel in ASA-treated patients who were managed medically following non-ST elevation ACS.
Evidence directly comparing the efficacy and safety of ticagrelor and prasugrel in patients undergoing PCI is mixed. Smaller studies have reported similar outcomes, but a moderately sized (n= 4018), randomized, open-label comparison between prasugrel and ticagrelor in patients hospitalized with ACS intended to receive a planned invasive evaluation suggested improved outcomes with prasugrel. The ARR at one year for the composite of MI, stroke and CV death was 2.4% in patients treated with prasugrel, and there was no difference in the risk of major bleeding compared to ticagrelor.

# DOSING:
In patients with ACS, a loading dose of 60 mg should be administered at the time of PCI followed by a maintenance dose of 10 mg daily. Prasugrel is not recommended in patients weighing 75 years due to increased risk of bleeding. Prasugrel 5mg daily, however, was evaluated in patients >75 years in a secondary analysis of a study in medically managed ACS patients and was shown to have similar bleeding rates to that seen with clopidogrel. However, there is currently no approved indication for a 5 mg daily dosing in Canada and the available 10 mg pill is not scored to permit accurate dose reduction.
Patients taking prasugrel should also take ASA 81 mg daily, unless specifically contraindicated. Absorption is not affected by food intake and no dosing adjustment is required for patients with chronic renal disease or patients with mild to moderate hepatic impairment. There do not appear to be any significant pharmacokinetic drug interactions with prasugrel. Duration of therapy is typically one year, but this may vary by clinical factors.

# ADVERSE EFFECTS:
As with all antiplatelet agents, prasugrel increases the risk of major bleeding including intracerebral hemorrhage. In a 1-year randomized trial of 13,608 ACS patients undergoing PCI, major bleeding unrelated to coronary artery bypass graft (CABG) surgery occurred in 2.4% of subjects randomized to prasugrel, a significant absolute increase of 0.6% compared with clopidogrel (number needed to harm  = 167). Major bleeding related to CABG occurred in 13.4% of prasugrel patients, a significant absolute increase of 10.2% (NNH=10) versus clopidogrel. Fatal bleeding, although rare, was also significantly increased compared with clopidogrel (0.4% vs 0.1%; NNH = 333). Although intracranial hemorrhage was not increased overall, patients with a history of stroke or transient ischemic attack (TIA) were at a significantly greater risk. Major bleeding was also increased, and the net clinical benefit to prasugrel therapy was lost in patients age >75 years or with a body weight <60 kg.

# PERIPROCEDURAL MANAGEMENT:
The periprocedural use of antiplatelet agents may increase the risk of bleeding and transfusion requirements associated with surgery and other invasive procedures. However, discontinuation of dual antiplatelet therapy within 12 months of stent implantation is associated with an increased risk of major adverse cardiovascular events and stent thrombosis. For this reason, procedures associated with significant bleeding risk should be delayed beyond 1 year if possible, and, if not possible, done with consideration of the patient remaining on therapy. If prasugrel can be stopped safely, it should be discontinued 7 days prior to surgery. In general, consultation with a specialist is advised before discontinuing prasugrel in patients with a coronary stent. In patients undergoing a minor procedure (e.g. dental, skin, cataract, arthrocentesis), discontinuation is not necessary. See Clinical Guide Perioperative Management of Antiplatelet Therapy.

# SPECIAL CONSIDERATIONS:
Due to increased risk of fatal and intracranial bleeding, prasugrel should be avoided in patients with a previous history of stroke or TIA. Prasugrel should not be prescribed to patients with severe liver disease. There are no adequate and well-controlled studies of this drug in pregnant women; therefore, prasugrel should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. A study in rats showed that prasugrel metabolites are excreted in the animals' milk. There are no clinical studies in lactating women and it is not known whether this drug is excreted in human milk. Prasugrel use while breastfeeding is generally not recommended.

# OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:
- Acetylsalicylic Acid (ASA) - Clopidogrel (Plavix) - Perioperative Management of Antiplatelet Therapy - Ticagrelor (Brilinta)

# Date of Version: 29November2021
Please note that the information contained herein is not to be interpreted as an alternative to medical advice from your doctor or other professional healthcare provider. If you have any specific questions about any medical matter, you should consult your doctor or other professional healthcare providers, and as such you should never delay seeking medical advice, disregard medical advice or discontinue medical treatment because of the information contained herein.