P2Y12 inhibitors

ACRONYMS AND DEFINITIONS

ACC - American College of Cardiology

A fib - Atrial fibrillation

AHA - American Heart Association

Angina - Chest pain caused by coronary artery disease

CABG - Coronary artery bypass graft

CAD - Coronary artery disease

CVD - Cardiovascular disease (heart attack and stroke)

DAPT - Dual antiplatelet therapy (aspirin + P2Y12 inhibitor)

MI - Myocardial infarction

NSTEMI - Non-ST-Elevation Myocardial Infarction

PAD - Peripheral artery disease

PPI - Proton pump inhibitor (ex. Prilosec®, Protonix®, Nexium®, Prevacid®, etc.)

PCI - Percutaneous coronary intervention. Heart cath and associated procedures - stents, angioplasty, etc.

STEMI - ST-elevation myocardial infarction for more)

TIA - Transient ischemic attack

Triple therapy - anticoagulation + P2Y12 inhibitor + aspirin (see triple therapy for more)

DRUGS IN CLASS

Thienopyridines

Clopidogrel (Plavix®)
Prasugrel (Effient®)
Ticlopidine (Ticlid®)

Other

Ticagrelor (Brilinta™)

MECHANISM OF ACTION

Mechanism of action

Platelets form blood clots when activated
ADP (adenosine diphosphate) is a chemical released by activated platelets in response to inflammation
ADP stimulates "P2Y12 receptors" on the surface of other platelets which causes them to become activated and join in the clotting process
P2Y12 inhibitors block P2Y12 stimulation by ADP and inhibit platelet activation

Illustration of platelet activation

FDA-APPROVED INDICATIONS

Clopidogrel (Plavix®)

Acute Coronary Syndrome (ACS)

Plavix is indicated to reduce the rate of myocardial infarction and stroke (MI) in patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization. Plavix should be administered in conjunction with aspirin.
Plavix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Plavix should be administered in conjunction with aspirin.

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease - In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke, Plavix is indicated to reduce the rate of MI and stroke.

Prasugrel (Effient®)

Acute Coronary Syndrome (ACS) - to reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention

Ticagrelor (Brilinta®)

Acute coronary syndrome or a history of myocardial infarction - to reduce the rate of cardiovascular death, myocardial infarction, and stroke. Ticagrelor also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

Ticlopidine (Ticlid®)

Stroke and TIA - 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
Acute coronary syndrome - as adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation

EFFECTIVENESS

ACUTE HEART ATTACK

Patients who present to the ER with an acute heart attack will typically undergo one of four therapies:

Percutaneous Coronary Intervention (PCI) with possible angioplasty and stent placement
Fibrinolytic therapy (tPA, urokinase, streptokinase)
Coronary Artery Bypass Grafting
Medical therapy

A number of large studies, substudies, and post-hoc analyses have looked at the use of P2Y12 inhibitors in patients who have suffered a heart attack
The studies have a dizzying array of designs and outcome measures
In general, studies have found P2Y12 inhibitors to be beneficial in the treatment of an acute heart attack
There have been two recent head-to-head trials that have compared the newer drugs (prasugrel and ticagrelor) to clopidogrel
Those two studies are detailed below followed by the AHA recommendations for P2Y12 inhibitor use in acute heart attack

TRITON TIMI 38 Trial - Clopidogrel vs Prasugrel, NEJM (2007) [PubMed abstract]

The TRITON TIMI 38 trial enrolled 13,608 patients with an acute coronary syndrome who were scheduled for PCI
Main inclusion criteria: acute coronary syndrome (unstable angina or myocardial infarction); scheduled for PCI
Main exclusion criteria: increased risk of bleeding; anemia; thrombocytopenia; history of pathologic intracranial findings
Baseline characteristics: median age 61 years; unstable angina or NSTEMI - 74%, STEMI - 26%; index procedure, PCI - 99%, CABG - 1%; BMS only - 48%, DES - 47%

Patients were randomized to 1 of 2 groups:

Group 1 (6813 patients) - Prasugrel 60 mg loading dose followed by 10 mg once daily
Group 2 (6795 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
All patients also received aspirin 75 - 162 mg once daily throughout the trial
Clopidogrel or prasugrel were given for 6 - 15 months
Loading dose was given anytime between randomization and 1 hour after PCI

PRIMARY OUTCOME: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke
After 15 months, the following was seen:

Primary outcome: Group 1 - 9.9%, Group 2 - 12.1% (HR 0.81, 95%CI [0.73 - 0.90], p<0.001)
Death from cardiovascular causes: Group 1 - 2.1%, Group 2 - 2.4% (HR 0.89, 95%CI [0.70 - 1.12], p=0.31)
Nonfatal MI: Group 1 - 7.3%, Group 2 - 9.5% (HR 0.76, 95%CI [0.67 - 0.85], p<0.001)
Nonfatal stroke: Group 1 - 1.0%, Group 2 - 1.0% (HR 1.02, 95%CI [0.71 - 1.45], p=0.93)
Overall mortality: Group 1 - 3.0%, Group 2 - 3.2% (HR 0.95, 95%CI [0.78 - 1.16], p=0.64)
Non-CABG TIMI major bleeding: Group 1 - 2.4%, Group 2 - 1.8% (HR 1.32, 95%CI [1.03 - 1.68], p=0.03)
Bleeding requiring transfusion: Group 1 - 4.0%, Group 2 - 3.0% (HR 1.34, 95%CI [1.11 - 1.63], p<0.001)
The median duration of study drug treatment was 14.5 months
In a post-hoc analysis, three subgroups of patients were identified that did not have a net clinical benefit with prasugrel - patients with a history of stroke or TIA, patients ≥ 75 years old, and patients weighing < 60 kg [14]

PLATO Trial - Clopidogrel vs Ticagrelor, NEJM (2009) [PubMed abstract]

The PLATO trial enrolled 18,624 patients with an acute coronary syndrome
Main inclusion criteria: acute coronary syndrome (myocardial infarction or unstable angina) starting within past 24 hours
Main exclusion criteria: fibrinolytic therapy within past 24 hours; need for anticoagulation; increased risk of bradycardia; taking CYP3A4 strong inducer or inhibitor
Baseline characteristics: median age 62 years; qualifying event, STEMI - 38%, NSTEMI - 42%, unstable angina - 17%; index procedure, PCI - 64%, CABG - 10%; stent type, BMS only - 42%, DES - 18%

Patients were randomized to 1 of 2 groups:

Group 1 (9333 patients) - Ticagrelor 180 mg loading dose followed by 90 mg twice a day
Group 2 (9291 patients) - Clopidogrel 300 mg loading dose followed by 75 mg once daily
All patients also received aspirin 75 - 100 mg once daily throughout the study

PRIMARY OUTCOME: Composite of death from cardiovascular causes, heart attack, or stroke
After 12 months, the following was seen:

Primary outcome: Group 1 - 9.8%, Group 2 - 11.7% (HR 0.84, 95%CI [0.77 - 0.92], p<0.001)
Death from cardiovascular causes: Group 1 - 4.0%, Group 2 - 5.1% (HR 0.79, 95%CI [0.69 - 0.91], p=0.001)
Myocardial infarction: Group 1 - 5.8%, Group 2 - 6.9% (HR 0.84, 95%CI [0.75 - 0.95], p=0.005)
Stroke: Group 1 - 1.5%, Group 2 - 1.3% (HR 1.17, 95%CI [0.91 - 1.52], p=0.22)
Overall mortality: Group 1 - 4.5%, Group 2 - 5.9% (HR 0.78, 95%CI [0.69 - 0.89], p<0.001)
Major bleeding: Group 1 - 11.6%, Group 2 - 11.2% (HR 1.04, 95%CI [0.95 - 1.13], p=0.43)
Bleeding requiring transfusion: Group 1 - 8.9%, Group 2 - 8.9% (HR 1.00, 95%CI [0.91 - 1.11], p=0.96)
Dyspnea: Group 1 - 13.8%, Group 2 - 7.8% (HR 1.84, 95%CI [1.68 - 2.02], p<0.001)
The median duration of study drug treatment was 277 days [16]

Professional Guidelines:

The AHA guidelines for dual antiplatelet therapy (DAPT) in coronary artery disease are available at the links below

SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE

Aspirin have been proven to be beneficial in the secondary prevention of CVD. The effects of P2Y12 inhibitors on the secondary prevention of CVD have been compared to aspirin in several studies.
In the CAPRIE study, aspirin was compared to clopidogrel. In the CHARISMA trial, aspirin was compared to the combination of clopidogrel and aspirin. In the PEGASUS-TIMI 54 trial, aspirin was compared to the combination of ticagrelor and aspirin. These studies are detailed below.

CAPRIE Trial - Clopidogrel vs Aspirin, Lancet (1996) [PubMed abstract]

The CAPRIE trial enrolled 19,185 patients with a history of stroke, heart attack, or peripheral artery disease
Main inclusion criteria: one of the following - recent ischemic stroke (onset ≥ 1 week and ≤ 6 months), recent heart attack (onset ≤ 35 days), history of intermittent claudication (with ABI ≤ 0.85 or history of leg surgery for vascular disease)
Main exclusion criteria: uncontrolled hypertension; history of bleeding or bleeding disorder; carotid endarterectomy after qualifying stroke
Baseline characteristics: average age ∼ 62 years; patients with diabetes - 20%; qualifying criteria, stroke - 33.5%, heart attack - 33%, intermittent claudication - 33.5%

Patients were randomized to 1 of 2 groups:

Group 1 (9599 patients) - Clopidogrel 75 mg once daily
Group 2 (9586 patients) - Aspirin 325 mg once daily

PRIMARY OUTCOME: Composite of stroke, heart attack, or vascular death
After an average follow-up of 1.91 years, the following was seen:

Primary outcome (event rate per year): Group 1 - 5.32%/year, Group 2 - 5.83%/year (p=0.043)
Overall mortality (event rate per year): Group 1 - 3.05%/year, Group 2 - 3.11%/year (p=0.71)
GI bleeding: Group 1 - 1.99%, Group 2 - 2.66% (p<0.05)
Any bleeding disorder: Group 1 - 9.27%, Group 2 - 9.28% (p>0.05) [4]

CHARISMA trial - Clopidogrel + Aspirin vs Aspirin, NEJM (2006) [PubMed abstract]

The CHARISMA trial enrolled 15,603 patients with documented CVD or multiple risk factors for CVD
Main inclusion criteria: age ≥ 45 years; documented CVD (CAD, Stroke, TIA, PAD) or multiple risk factors for CVD (diabetes, dyslipidemia, hypertension, etc.)
Main exclusion criteria: taking oral antithrombotics or NSAIDs on a long-term basis
Baseline characteristics: median age 64 years; documented CVD - 78%, multiple risk factors - 21%; documented CAD - 37%, history of stroke/TIA - 28%, documented PAD - 18%

Patients were randomized to one of two groups:

Group 1 (7802 patients) - Clopidogrel 75 mg once daily + Aspirin 75 - 162 mg once daily
Group 2 (7801 patients) - Placebo + Aspirin 75 - 162 mg once daily

PRIMARY OUTCOME: Composite of myocardial infarction, stroke, or death from cardiovascular causes
After a median follow-up of 28 months, the following was seen:

Primary outcome: Group 1 - 6.8%, Group 2 - 7.3% (HR 0.93, 95%CI [0.83 - 1.05], p=0.22)
Myocardial infarction (nonfatal): Group 1 - 1.9%, Group 2 - 2.0% (HR 0.94, 95%CI [0.75 - 1.18], p=0.59)
Stroke (nonfatal): Group 1 - 1.9%, Group 2 - 2.4% (HR 0.79, 95%CI [0.64 - 0.98], p=0.03)
Overall mortality: Group 1 - 4.8%, Group 2 - 4.8% (HR 0.99, 95%CI [0.86 - 1.14], p=0.90)
Severe bleeding: Group 1 - 1.7%, Group 2 - 1.3% (HR 1.25, 95%CI [0.97 - 1.61], p=0.09)
Moderate bleeding: Group 1 - 2.1%, Group 2 - 1.3% (HR 1.62, 95%CI [1.27 - 2.08], p<0.001)
Treatment discontinuation: Group 1 - 20.4%, Group 2 - 18.2% (p<0.001)

PEGASUS-TIMI 54 Trial - Ticagrelor + Aspirin vs Aspirin alone, NEJM (2015) [PubMed abstract]

The PEGASUS-TIMI 54 trial enrolled 21,162 patients with a history of myocardial infarction 1 - 3 years earlier
Main inclusion criteria: myocardial infarction 1 - 3 years before enrollment; one of the following - age ≥ 65 years, diabetes requiring medication, a second prior heart attack, multivessel CAD, or chronic renal failure (CrCl < 60 ml/min)
Main exclusion criteria: planned use of other antiplatelet agent or anticoagulant; history of ischemic stroke or intracranial bleeding; GI bleed within previous 6 months
Baseline characteristics: average age 65 years; qualifying event, STEMI - 53%, NSTEMI - 40%; history of PCI - 83%; multivessel disease - 60%; median time since qualifying event - 1.7 years

Patients were randomized to one of three groups:

Group 1 (7050 patients) - Ticagrelor 90 mg twice a day + Aspirin 75 - 150 mg once daily
Group 2 (7045 patients) - Ticagrelor 60 mg twice a day + Aspirin 75 - 150 mg once daily
Group 3 (7067 patients) - Placebo + Aspirin 75 - 150 mg once daily

PRIMARY OUTCOME: Composite of cardiovascular death, myocardial infarction, or stroke
Patients were followed for a median of 33 months. Kaplan-Meier estimated rates at 3 years of follow-up were as follows:

Primary outcome: Group 1 - 7.85%, Group 2 - 7.77%, Group 3 - 9.04% (HR for 1 vs 3 - 0.85, 95%CI [0.75 - 0.96], p=0.008; HR for 2 vs 3 - 0.84, 95% CI [0.74 - 0.95], p=0.004)
Any stroke: Group 1 - 1.61%, Group 2 - 1.47%, Group 3 - 1.94% (HR for 1 vs 3 - 0.82, 95%CI [0.63 - 1.07], p=0.14; HR for 2 vs 3 - 0.75, 95% CI [0.57 - 0.98], p=0.03)
Myocardial infarction: Group 1 - 4.40%, Group 2 - 4.53%, Group 3 - 5.25% (HR for 1 vs 3 - 0.81, 95%CI [0.69 - 0.95], p=0.01; HR for 2 vs 3 - 0.84, 95% CI [0.72 to 0.98], p=0.03)
Overall mortality: Group 1 - 5.15%, Group 2 - 4.69%, Group 3 - 5.16% (HR for 1 vs 3 - 1.0, 95%CI [0.86 - 1.16], p=0.99; HR for 2 vs 3 - 0.89, 95% CI [0.76 - 1.04], p=0.14)
Major TIMI bleeding events: Group 1 - 2.6%, Group 2 - 2.3%, Group 3 - 1.06% (p<0.001 for Group 1 or Group 2 vs Group 3)
Bleeding requiring transfusion: Group 1 - 2.43%, Group 2 - 2.09%, Group 3 - 0.72% (p<0.001 for Group 1 or Group 2 vs Group 3)
Significantly more patients in Group 1 and Group 2 discontinued treatment because of side effects than in Group 3 (Group 1 - 32%, Group 2 - 29%, Group 3 - 21%, p=<0.001 for each dose compared to placebo) [31]

Professional Guidelines:

The AHA/ACC recommend aspirin 75 - 162 mg once daily as first-line therapy in all patients with CAD who do not have a contraindication
Treatment with clopidogrel 75 mg once daily is reasonable in patients who have a contraindication to aspirin
Clopidogrel 75 mg once daily + aspirin 75 - 162 mg once daily "might" be reasonable in certain high-risk patients with CAD [3]

StraightHealthcare analysis:

Clopidogrel (Plavix®) and aspirin appear to have similar efficacy in the secondary prevention of CAD
Patients with a contraindication to aspirin will benefit from clopidogrel
The combination of clopidogrel and aspirin does not appear to be superior to either drug alone, and it may increase the risk of bleeding events
In the PEGASUS-TIMI 54 study, the combination of ticagrelor and aspirin decreased cardiovascular events at the expense of more major bleeding events

PRIMARY PREVENTION OF STROKE

Primary prevention is measures taken to prevent a disease before it is present or has been diagnosed in an individual (see primary prevention for more information)
Patients with a heart arrhythmia known as atrial fibrillation are at increased risk for stroke
Clopidogrel has been studied for the primary prevention of stroke in patients with atrial fibrillation (see atrial fibrillation below)
There is no indication to use P2Y12 inhibitors for primary prevention of stroke in patients without atrial fibrillation

SECONDARY PREVENTION OF STROKE

Clopidogrel, ticagrelor, aspirin, and Aggrenox® (aspirin + dipyridamole) have all been studied in the secondary prevention of stroke
Some of the larger studies are presented below

CAPRIE Trial - Clopidogrel vs Aspirin, Lancet (1996) [PubMed abstract]

In the CAPRIE trial that compared clopidogrel to aspirin in patients with a history of CVD, there was no significant difference in the primary outcome between clopidogrel and aspirin in the subgroup of patients who had a stroke as their qualifying event (clopidogrel - 7.15%, aspirin - 7.71%, p=0.26)
See CAPRIE trial above for more details on the study

SOCRATES trial - Ticagrelor vs Aspirin, NEJM (2016) [PubMed abstract]

The SOCRATES study enrolled 13,199 patients with a recent stroke or high-risk TIA
Main Inclusion criteria: acute ischemic stroke (NIHSS score ≤ 5) or high-risk TIA (ABCD² stroke risk score ≥ 4); patient able to be randomized within 24 hours of event
Main exclusion criteria: A fib or other cardioembolic risk factors; fibrinolytic therapy within 24 hours before randomization; taking CYP3A4 strong inhibitor; bleeding disorder; history of intracerebral hemorrhage
Baseline characteristics: average age 66 years; qualifying event, TIA - 27%, ischemic stroke - 73%; taking aspirin before randomization - 32%; taking clopidogrel before randomization - 3.4%

Patients were randomized to one of two groups:

Group 1 (6589 patients) - Ticagrelor 180 mg loading dose followed by 90 mg twice a day
Group 2 (6610 patients) - Aspirin 300 mg loading dose followed by 100 mg once daily
Placebo doses of opposing therapy were also given to all patients

PRIMARY OUTCOME: Composite of stroke (ischemic or hemorrhagic), myocardial infarction, or death within 90 days
After 90 days, the following was seen:

Primary outcome: Group 1 - 6.7%, Group 2 - 7.5% (HR 0.89, 95%CI [0.78 - 1.01], p=0.07)
All stroke: Group 1 - 5.9%, Group 2 - 6.8% (HR 0.86, 95%CI [0.75 - 0.99], p=0.03)
Myocardial infarction: Group 1 - 0.4%, Group 2 - 0.3% (HR 1.20, 95%CI [0.67 - 2.14], p=0.55)
Overall mortality: Group 1 - 1.0%, Group 2 - 0.9% (HR 1.18, 95%CI [0.83 - 1.67], p=0.36)
Major bleeding: Group 1 - 0.5%, Group 2 - 0.6% (HR 0.83, 95%CI [0.52 - 1.34], p=0.45)
Premature treatment discontinuation: Group 1 - 17.5%, Group 2 - 14.7%
Dyspnea: Group 1 - 6.2%, Group 2 - 1.4%

PROFESS study - Aspirin + dipyridamole vs Clopidogrel, NEJM (2008) [PubMed abstract]

The PROFESS study enrolled 20,332 patients with a recent stroke
Main Inclusion criteria: age ≥ 50 years; stroke within 90 days or stroke within 90 - 120 days with at least 2 vascular risk factors
Main exclusion criteria: contraindication to antiplatelet therapy
Baseline characteristics: average age 66 years; median time from qualifying event to randomization - 15 days; prior stroke or TIA (before qualifying event) - 24%

Patients were randomized to one of two groups:

Group 1 (10,181 patients) - Aspirin 25 mg + dipyridamole 200 mg twice a day
Group 2 (10,151 patients) - Clopidogrel 75 mg once daily

PRIMARY OUTCOME: Recurrent stroke of any type
After an average follow-up of 2.5 years, the following was seen:

Primary outcome: Group 1 - 9%, Group 2 - 8.8% (HR 1.01, 95%CI [0.92 - 1.11])
Myocardial infarction: Group 1 - 1.7%, Group 2 - 1.9% (HR 0.90, 95%CI [0.73 - 1.10])
Overall mortality: Group 1 - 7.3%, Group 2 - 7.4% (HR 0.97, 95%CI [0.87 - 1.07])
Major bleeding event: Group 1 - 4.1%, Group 2 - 3.6% (HR 1.15, 95%CI [1.0 - 1.32])
Intracranial hemorrhage: Group 1 - 1.4%, Group 2 - 1.0% (HR 1.42, 95%CI [1.11 - 1.83])
Premature treatment discontinuation: Group 1 - 29.1%, Group 2 - 22.6% (p<0.001) [7]

MATCH Trial - Clopidogrel + Aspirin vs Clopidogrel, Lancet (2004) [PubMed abstract]

The MATCH trial enrolled 7599 patients with recent TIA or stroke who were at high risk for a recurrent event
Main inclusion criteria: stroke or TIA in previous 3 months + 1 or more of the following (within 3 years) - previous ischemic stroke, previous myocardial infarction, angina, diabetes, symptomatic peripheral artery disease
Main exclusion criteria: age younger than 40 years; increased risk of bleeding; severe comorbid condition
Baseline characteristics: average age 66 years; qualifying event, TIA - 21%, stroke - 79%; prior history of TIA or stroke (before qualifying event) - 46%; previous MI - 5%; symptomatic PAD - 10%

Patients were randomized to 1 of 2 groups:

Group 1 (3797 patients) - Aspirin 75 mg once daily + clopidogrel 75 mg once daily
Group 2 (3802 patients) - Placebo + clopidogrel 75 mg once daily

PRIMARY OUTCOME: Composite of ischemic stroke, myocardial infarction, vascular death (including haemorrhagic death of any origin), or rehospitalization for an acute ischemic event (including unstable angina pectoris, worsening of peripheral arterial disease requiring therapeutic intervention or urgent revascularization, or transient ischaemic attack)
After 18 months of follow-up, the following was seen:

Primary outcome: Group 1 - 16%, Group 2 - 17% (diff 1%, 95%CI [-0.6% to 2.7%], p=0.24)
Ischemic stroke: Group 1 - 8%, Group 2 - 9% (diff 0.62%, 95%CI [-0.6% to 1.9%], p=0.35)
Myocardial infarction: Group 1 - 2%, Group 2 - 2% (diff -0.13%, 95%CI [-0.7% to 0.5%], p=0.66)
Overall mortality: Group 1 - 5%, Group 2 - 5% (diff -0.01%, 95%CI [-1.0% to 1.0%], p=0.99)
Life-threatening bleeding: Group 1 - 3%, Group 2 - 1% (diff 1.26%, 95%CI [0.64% to 1.88%], p=<0.0001)
Major bleeding: Group 1 - 2%, Group 2 - 1% (diff 1.36%, 95%CI [0.86% to 1.86%], p=<0.0001) [6]

CHANCE trial - Aspirin + Clopidogrel vs Aspirin, NEJM (2013) [PubMed abstract]

The CHANCE study enrolled 5170 patients with a TIA or minor ischemic stroke within the past 24 hours
Main inclusion criteria: ischemic stroke (NIHSS score ≤ 3) or high-risk TIA (ABCD² score ≥ 4) within last 24 hours
Main exclusion criteria: cardiac source of stroke or TIA (A fib or heart valve disease); history of intracranial hemorrhage; procedure-related TIA or stroke
Baseline characteristics: median age 62 years; qualifying event, minor stroke - 72%, TIA - 28%; prior history of ischemic stroke (before qualifying event) - 20%; taking aspirin prior to presentation - 11%

Patients were randomized to 1 of 2 groups:

Group 1 (2584 patients) - Aspirin 75 - 300 mg on Day 1 followed by 75 mg once daily for 20 days + clopidogrel 300 mg loading dose followed by 75 mg once daily for 90 days
Group 2 (2586 patients) - Aspirin 75 - 300 mg on Day 1 followed by 75 mg once daily for 90 days + placebo

PRIMARY OUTCOME: Recurrent stroke (ischemic or hemorrhagic) within 90 days
After 90 days, the following was seen:

Primary outcome: Group 1 - 8.2%, Group 2 - 11.7%, (HR 0.68, 95%CI [0.57 - 0.81], p<0.001)
Stroke, MI, or cardiovascular death: Group 1 - 8.4%, Group 2 - 11.9%, (HR 0.69, 95%CI [0.58 - 0.82], p<0.001)
Overall mortality: Group 1 - 0.4%, Group 2 - 0.4%, (HR 0.97, 95%CI [0.40 - 2.33], p=0.94)
Severe bleeding: Group 1 - 0.2%, Group 2 - 0.2%, (HR 0.94, 95%CI [0.24 - 3.79], p=0.94)
Any bleeding: Group 1 - 2.3%, Group 2 - 1.6%, (HR 1.41, 95%CI [0.95 - 2.10], p=0.09)

Professional Guidelines:

The AHA states that aspirin 50 mg - 325 mg once daily, clopidogrel 75 mg once daily, or aspirin 25 mg + dipyridamole 200 mg (Aggrenox®) twice a day are all acceptable options for first-line therapy in the secondary prevention of stroke
Aspirin + clopidogrel is not recommended because of an increased risk of bleeding
For patients who have a stroke while taking aspirin, there is no evidence that increasing the aspirin dose or changing agents is beneficial [8]

StraightHealthcare analysis:

Aspirin, clopidogrel, and aspirin + dipyridamole (Aggrenox®) all appear to be equally effective for the secondary prevention of stroke
There is no proven benefit of combining aspirin with clopidogrel, and the combination may be harmful
In the SOCRATES trial, ticagrelor was not significantly better than aspirin for the primary outcome (p=0.07), but it was superior for preventing all strokes (p=0.03). The study was short, lasting only 90 days.
The CHANCE trial is interesting because it found a benefit with short-term (20 days) dual antiplatelet therapy in patients with minor stroke or high-risk TIA. The study was performed in China where risk factor control (ex. hypertension, diabetes) is often suboptimal compared to developed nations. Also, Asians tend to be poor CYP2C19 metabolizers which means clopidogrel is not as active in this population. It's unclear how this may or may not affect outcomes (good and bad) in other patient populations.

ATRIAL FIBRILLATION

Atrial fibrillation is a common heart arrhythmia that increases a person's risk for stroke
To prevent strokes in atrial fibrillation, anticoagulants (e.g. warfarin, Factor Xa inhibitors, direct thrombin inhibitors) are prescribed
Not all patients are good candidates for anticoagulants, so researchers have looked at using aspirin and clopidogrel to prevent strokes in atrial fibrillation

ACTIVE W trial - Vitamin K antagonist vs Clopidogrel + Aspirin, Lancet (2006) [PubMed abstract]

The ACTIVE W trial enrolled 6706 patients with A fib
Main inclusion criteria: A fib + one of the following - age ≥ 75 years, treatment for hypertension, previous TIA/stroke, previous systemic embolism, EF < 45%, PAD, (patients 55 - 74 years with diabetes or CAD were also eligible)
Main exclusion criteria: peptic ulcer disease within previous 6 months; previous intracerebral hemorrhage; thrombocytopenia (< 50,000/mm³)
Baseline characteristics: average age 70 years; average CHADS₂ score - 2; A fib type, permanent - 69%, persistent - 13%, paroxysmal - 18%; duration of A fib > 2 years - 60%; history of stroke/TIA - 15%

Patients were randomized to one of two groups:

Group 1 (3335 patients) - Aspirin 75 - 100 mg once daily + Clopidogrel 75 mg once daily
Group 2 (3371 patients) - Vitamin K antagonist - target INR of 2-3
Treatment was open-label

PRIMARY OUTCOME: composite of stroke, non-CNS systemic embolism, myocardial infarction, or vascular death
After a median follow-up of 1.28 years, the study was stopped early because of clear warfarin superiority:

Primary outcome: Group 1 - 5.6%/year, Group 2 - 3.93%/year, (HR 1.44, 95%CI [1.18 - 1.76], p=0.0003)
Stroke: Group 1 - 2.39%/year, Group 2 - 1.4%/year, (HR 1.72, 95%CI [1.24 - 2.37], p=0.001)
Non-CNS systemic embolism: Group 1 - 0.43%/year, Group 2 - 0.10%/year, (HR 4.66, 95%CI [1.58 - 13.8], p=0.005)
Myocardial infarction: Group 1 - 0.86%/year, Group 2 - 0.55%/year, (HR 1.58, 95%CI [0.94 - 2.67], p=0.09)
Overall mortality: Group 1 - 3.8%/year, Group 2 - 3.76%/year, (HR 1.01, 95%CI [0.81 - 1.26], p=0.91)
Severe and fatal hemorrhage: Group 1 - 2.42%/year, Group 2 - 2.21%/year, (HR 1.10, 95%CI [0.83 - 1.45], p=0.53)
Primary outcome + major bleed: Group 1 - 7.56%/year, Group 2 - 5.45%/year, (HR 1.41, 95%CI [1.19 - 1.67], p<0.0001)
Permanent drug discontinuation Group 1 - 13.8%, Group 2 - 7.8%
INR was in therapeutic range 64% of the time [9]

ACTIVE A trial - Clopidogrel + Aspirin vs Aspirin alone, NEJM (2009) [PubMed abstract]

The ACTIVE A trial enrolled 7554 patients with atrial fibrillation who were unsuited for vitamin K antagonists
Main inclusion criteria: A fib + one of the following - age ≥ 75 years, hypertension, previous TIA/stroke, previous systemic embolism, EF < 45%, PAD, (patients 55 - 74 years with diabetes or CAD were also eligible)
Main exclusion criteria: peptic ulcer disease within previous 6 months; previous intracerebral hemorrhage; thrombocytopenia (< 50,000/mm³)
Baseline characteristics: average age 71 years; average CHADS₂ score - 2; A fib type, permanent - 64%, persistent - 14%, paroxysmal - 22%; duration of A fib > 2 years - 53%; history of stroke/TIA - 13%; reason for not taking vitamin K antagonist, bleeding risk - 23%, doctor deemed inappropriate - 50%, patient declined - 26%

Patients were randomized to one of two groups:

Group 1 (3772 patients) - Clopidogrel 75 mg once daily + Aspirin 75 - 100 mg once daily
Group 2 (3782 patients) - Placebo + Aspirin 75 - 100 mg once daily

PRIMARY OUTCOME: Composite of stroke, systemic embolism, myocardial infarction, or death from vascular causes
After a median follow-up of 3.6 years, the following was seen:

Primary outcome: Group 1 - 6.8%/year, Group 2 - 7.6%/year (RR 0.89, 95%CI [0.81 - 0.98], p=0.01)
Any stroke: Group 1 - 2.4%/year, Group 2 - 3.3%/year (RR 0.72, 95%CI [0.62 - 0.83], p<0.001)
Myocardial infarction: Group 1 - 0.7%/year, Group 2 - 0.9%/year (RR 0.78, 95%CI [0.59 - 1.03], p=0.08)
Overall mortality: Group 1 - 6.4%/year, Group 2 - 6.6%/year (RR 0.98, 95%CI [0.89 - 1.08], p=0.69)
Major bleeding: Group 1 - 2.0%/year, Group 2 - 1.3%/year (RR 1.57, 95%CI [1.29 - 1.92], p<0.001)
Any bleeding: Group 1 - 9.7%/year, Group 2 - 5.7%/year (RR 1.68, 95%CI [1.52 - 1.85], p<0.001) [10]

Professional Guidelines:

The 2014 AHA A fib guidelines state that patients with a CHA₂DS₂-VASc score ≥ 2 should be anticoagulated with warfarin, dabigatran, apixaban, or rivaroxaban. For patients with a CHA₂DS₂-VASc score of 1, no antithrombotic therapy, anticoagulation, or aspirin may be considered. [32]
The 2010 AHA secondary stroke prevention guidelines state that the combination of aspirin and clopidogrel carries a bleeding risk similar to that of warfarin and therefore should not be taken by patients with a hemorrhagic contraindication to warfarin [8]

StraightHealthcare analysis:

Anticoagulation is clearly superior to antiplatelet therapy in preventing strokes in patients with atrial fibrillation
Warfarin can be cumbersome for some patients because of the frequent lab monitoring and dose adjustments. The newer anticoagulants (Factor Xa inhibitors and direct thrombin inhibitors) are easier to manage but are much more expensive.
Aspirin provides some degree of stroke prevention in A fib and may be appropriate in patients who are unable or unwilling to take anticoagulants
In the ACTIVE A trial, the combination of aspirin and clopidogrel was slightly better at preventing strokes than aspirin alone, but it increased the risk of bleeding events

PERIPHERAL ARTERY DISEASE (PAD)

Peripheral artery disease is atherosclerotic vessel disease that affects the arteries of the legs and pelvis
Antiplatelet therapy with either aspirin or clopidogrel is recommended in patients with PAD to help reduce the risk of MI, stroke and vascular death
The EUCLID trial summarized below compared the effects of ticagrelor to clopidogrel in symptomatic PAD

EUCLID trial - Clopidogrel vs Ticagrelor in Patients with Symptomatic PAD, NEJM (2017) - [PMID 27959717]

DESIGN: Randomized, controlled trial (N=13,885, length= median 30 months)
TREATMENT: Ticagrelor 90 mg twice daily vs Clopidogrel 75 mg once daily. Aspirin was not allowed.
PRIMARY OUTCOME: First occurrence of any event in the composite of cardiovascular death, myocardial infarction, or ischemic stroke (defined as any stroke not shown to be primarily hemorrhagic)
FINDINGS: In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups.

Professional guidelines:

The AHA 2016 Lower Extremity PAD Guidelines state the following:

Antiplatelet therapy with aspirin alone (range 75–325 mg per day) or clopidogrel alone (75 mg per day) is recommended to reduce MI, stroke, and vascular death in patients with symptomatic PAD
In asymptomatic patients with PAD (ABI ≤ 0.90), antiplatelet therapy is reasonable to reduce the risk of MI, stroke, or vascular death
In asymptomatic patients with borderline ABI (0.91 – 0.99), the usefulness of antiplatelet therapy to reduce the risk of MI, stroke, or vascular death is uncertain
The effectiveness of dual-antiplatelet therapy (aspirin and clopidogrel) to reduce the risk of cardiovascular ischemic events in patients with symptomatic PAD is not well established
Dual-antiplatelet therapy (aspirin and clopidogrel) may be reasonable to reduce the risk of limb-related events in patients with symptomatic PAD after lower extremity revascularization [33]

SIDE EFFECTS

Clopidogrel (Plavix®)

Bleeding

The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
By this mechanism, they will also increase the risk of unwanted bleeding
A person's risk of bleeding on clopidogrel will depend on a number of variables including medical problems, medications, medical history, activity level, etc.
In trials, the addition of clopidogrel to aspirin increased major bleeding events by about 1% compared to aspirin alone [12]

Prasugrel (Effient®)

Bleeding

The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
By this mechanism, they will also increase the risk of unwanted bleeding
A person's risk of bleeding on prasugrel will depend on a number of variables including medical problems, medications, medical history, activity level, etc.
In the TRITON TIMI 38 trial, prasugrel had a significantly higher rate of major bleeding (2.4% vs 1.8%) when compared to clopidogrel [13, 14]

Ticagrelor (Brilinta™)

Bleeding

The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
By this mechanism, they will also increase the risk of unwanted bleeding
A person's risk of bleeding on prasugrel will depend on a number of variables including medical problems, medications, medical history, activity level, etc.
In the PLATO trial, there was no significant difference in major bleeding events between ticagrelor and clopidogrel (11.6% vs 11.2%) [16]

Shortness of breath (dyspnea)

Some patients taking ticagrelor will experience shortness of breath
Shortness of breath often resolves with continued treatment
In the PLATO trial, 13.8% of patients on ticagrelor experienced shortness of breath compared to 7.8% taking clopidogrel [16]
In the PEGASUS trial, 19% of patients taking ticagrelor 90 mg complained of shortness of breath compared to 6.4% of patients taking placebo [31]

Ventricular pause

Ventricular pause is a condition where there is a longer than normal amount of time between ventricular contractions
Ticagrelor increases the incidence of these pauses. The effect appears to be from an undefined action on the sinoatrial node. [17]
The effect appears to diminish after 30 days
The pauses do not typically cause symptoms [16]
Patients with certain heart conditions (see bradyarrhythmias below) should use caution when taking ticagrelor

Increase in serum uric acid

Ticagrelor causes a slight increase in uric acid levels
In the PLATO study, uric acid levels increased by 0.6 mg/dl from baseline in the ticagrelor group (clopidogrel group increase 0.2 mg/dl)
There was no difference in reports of gout between the two groups [15]

Increase in serum creatinine

Ticagrelor may cause an increase in serum creatinine levels
In the PLATO study, 7.4% of patients had an increase of > 50% in their serum creatinine level compared to 5.9% of patients taking clopidogrel [15]
There was no difference in renal outcomes between the two groups

Ticlopidine (Ticlid®)

Bleeding

The therapeutic effect of all P2Y12 inhibitors is their ability to prevent blood clotting
By this mechanism, they will also increase the risk of unwanted bleeding
A person's risk of bleeding on ticlopidine will depend on a number of variables including medical problems, medications, medical history, activity level, etc.

Neutropenia

One of the main reasons ticlopidine is no longer widely used is because of the risk of neutropenia (decreased neutrophils in blood)
Neutropenia may occur in 2-3% of patients taking ticlopidine
The manufacturer recommends monitoring blood counts every 2 weeks through the first 3 months of therapy [18]

Thrombotic Thrombocytopenic Purpura (TTP)

Ticlopidine has been associated with TTP, a serious condition that causes a decrease in platelets
The incidence of ticlopidine-induced TTP is unknown
The manufacturer recommends monitoring blood counts every 2 weeks through the first 3 months of therapy [18]

Diarrhea

Ticlopidine may cause diarrhea (12.5% of patients on ticlopidine vs 4.5% on placebo) [18]

Stomach upset

Ticlopidine may cause stomach upset (7.0% of patients) [18]

Rash

Ticlopidine may cause a rash (5.1% of patients) [18]

STOPPING BEFORE PROCEDURES

Manufacturer recommendations for stopping P2Y12 inhibitors before surgery or procedures that have a high risk of bleeding:

Clopidogrel (Plavix®) - stop for at least 5 days
Prasugrel (Effient®) - stop for at least 7 days
Ticagrelor (Brilinta™) - stop for at least 5 days
NOTE: stopping therapy may increase the risk of cardiovascular events

Professional guidelines:

REVERSING P2Y12 INHIBITORS

There is no proven agent that has been shown to reverse the antiplatelet effects of P2Y12 inhibitors
Because it is biologically plausible that fresh platelets may overcome the inhibitory effect of P2Y12 inhibitors, platelet transfusions are often given to patients on P2Y12 inhibitors in emergency situations. The efficacy of platelet transfusions in reversing the antiplatelet effects of P2Y12 inhibitors has not been validated in clinical trials.
Clopidogrel and prasugrel irreversibly inhibit platelets, and ticagrelor is a reversible inhibitor
Case studies and in vitro tests have suggested that the antiplatelet effects of ticagrelor may not be reversible with platelet transfusions. The ticagrelor PI states that platelet transfusions did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is unlikely to be of clinical benefit in patients with bleeding. [15,28,29,30]

PLATELET FUNCTION MONITORING

The effects of P2Y12 inhibitors and aspirin on platelet reactivity can vary between individuals
Assays are available that can measure platelet reactivity (e.g. VerifyNow®) in patients taking P2Y12 inhibitors and/or aspirin
Theoretically, monitoring platelet reactivity and adjusting the dosage of P2Y12 inhibitors and aspirin based on the results should improve the effectiveness of antiplatelet therapy
Two large studies have evaluated the effect of platelet function monitoring on outcomes in patients with CAD receiving coronary stents
The ARCTIC study compared platelet function monitoring to no monitoring in patients (n=2440) undergoing coronary stenting. Patients were treated with aspirin + clopidogrel or prasugrel. The study found no benefit of platelet function monitoring for the composite outcome of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization at one year after stent implantation. [PMID 23121439]
The ANTARCTIC study compared platelet function monitoring to no monitoring in patients (n=877) aged ≥ 75 years who underwent coronary stenting for acute coronary syndrome. Patients were treated with aspirin + clopidogrel or prasugrel. The study found no benefit of platelet function monitoring for the composite outcome of cardiovascular death, myocardial infarction, stroke, stent thrombosis, urgent revascularization, and bleeding after one year of follow-up. [PMID 27581531]
SUMMARY: There is no evidence that platelet function monitoring improves outcomes in patients receiving antiplatelet therapy for coronary stents

CONTRAINDICATIONS

Clopidogrel (Plavix®)

Active bleeding
Known hypersensitivity

Prasugrel (Effient®)

Active bleeding
Prior TIA or stroke (see precautions below)
Known hypersensitivity

Ticagrelor (Brilinta™)

History of intracranial hemorrhage
Active bleeding
Known hypersensitivity
Severe liver disease

Ticlopidine (Ticlid®)

Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding)
Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia
Known hypersensitivity
Severe liver disease

PRECAUTIONS

KIDNEY DISEASE

Clopidogrel (Plavix®)

Severe kidney disease (CrCl 5 - 15 ml/min): drug effect is reduced. Manufacturer makes no specific dosage recommendation
Moderate kidney disease (CrCl 30 - 60 ml/min): drug effect is reduced. Manufacturer makes no specific dosage recommendation [12]

Prasugrel (Effient®)

No dose adjustment is necessary in kidney disease [13]

Ticagrelor (Brilinta™)

No dose adjustment is necessary in kidney disease
Has not been studied in dialysis patients [15]

Ticlopidine (Ticlid®)

Mild kidney disease (CrCl 60 - 89 ml/min): No dose adjustment necessary
Moderate-to-severe kidney disease: Ticlopidine has not been studied extensively. Manufacturer makes no specific dosage recommendations [18]

LIVER DISEASE

Clopidogrel (Plavix®)

No dosage adjustment is necessary in patients with liver disease
NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [12]

Prasugrel (Effient®)

No dosage adjustment is necessary in patients with mild-to-moderate liver disease (Child-Pugh Class A and B)
Prasugrel has not been studied in patients with severe liver disease
NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [12]

Ticagrelor (Brilinta™)

No dosage adjustment is necessary in patients with mild liver disease
Ticagrelor has not been studied in patients with moderate-to-severe liver disease
Ticagrelor should not be used in severe liver disease
NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease. [15]

Ticlopidine (Ticlid®)

Ticlopidine should not be used by patients with severe liver disease
In mild-to-moderate liver disease, drug dose may need to be adjusted
The manufacturer makes no specific dosage recommendations [18]
NOTE: Patients with significant liver disease may be at increased risk of bleeding. See coagulopathy of liver disease.

HISTORY OF STROKE OR TIA (PRASUGREL)

Prasugrel (Effient®)

Prasugrel is contraindicated in patients with a prior history of stroke or TIA
In the TRITON TIMI 38 trial, patients with a history of stroke or TIA had a higher rate of stroke on prasugrel when compared to clopidogrel (6.5% vs 1.2%) [13]

GERIATRIC (PRASUGREL)

Prasugrel (Effient®)

Prasugrel is not recommended in patients ≥ 75 years old
In the TRITON TIMI 38 trial, patients ≥ 75 years old had a higher risk of bleeding compared to those taking clopidogrel [13]

LOW BODY WEIGHT (PRASUGREL)

Prasugrel (Effient®)

For patients weighing ≤ 60 kg (132 pounds), exposure to prasugrel's active metabolite is increased
In the TRITON TIMI 38 trial, patients weighing ≤ 60 kg had an increased risk of bleeding
Consider lowering the maintenance dose to 5 mg a day
The efficacy and safety of the 5 mg dose has not been studied [13]

BRADYARRHYTHMIAS (TICAGRELOR)

Ticagrelor (Brilinta®)

Ticagrelor can cause ventricular pauses (see side effects above)
Patients with sick sinus syndrome, second or third degree AV block, or bradycardia-related syncope may be at increased risk of bradyarrhythmias when taking ticagrelor. Use caution. [18]

DRUG INTERACTIONS

NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.

HIGH ALERT INTERACTIONS

NOTE: High alert interactions are interactions that are known to be significant and occur between two medications that are likely to be prescribed together

All P2Y12 Inhibitors

Drugs that increase the risk of bleeding

Other medications that inhibit coagulation may increase the risk of bleeding when taken with P2Y12 inhibitors
In some conditions (ex. after stent placement), it may be appropriate to take P2Y12 inhibitors with these drugs

Drugs that may increase the risk of bleeding include:

Warfarin (Coumadin®)
Direct thrombin inhibitors (dabigatran, Pradaxa®)
Aspirin
Factor Xa inhibitors (rivaroxaban, Xarelto®, apixaban, Eliquis®)
NSAIDS (ibuprofen, naproxen, Aleve®, Celebrex®, Motrin®, etc.)
SSRIs and SNRIs (Prozac®, Cymbalta®, Paxil®, Effexor®, Zoloft®, etc.)
Vorapaxar (Zontivity®)

Clopidogrel (Plavix®)

CYP2C19 Inhibitors

See CYP2C19 and clopidogrel below

CYP2C8 substrates

The acyl-β-glucuronide metabolite of clopidogrel is a CYP2C8 strong inhibitor
Clopidogrel may increase exposure to CYP2C8 substrates

Bupropion (Wellbutrin®)

Clopidogrel inhibits CYP2B6 which can lead to elevated bupropion levels (Wellbutrin®, Contrave®)
When taken together, doses of bupropion may need to be decreased

PPIs (Prilosec®, omeprazole, Nexium®, etc.)

See CYP2C19 and clopidogrel below

Repaglinide (Prandin®)

Repaglinide is a sensitive CYP2C8 substrate. Clopidogrel increases repaglinide exposure by 4 - 5 fold.
Repaglinide should not be given with clopidogrel
If concomitant use cannot be avoided, initiate repaglinide at a dose of 0.5 mg before each meal and titrate based on blood sugars. Do not exceed 4 mg/day.
When clopidogrel is added to repaglinide, repaglinide doses should be reduced to no more than 4 mg/day

Ticagrelor (Brilinta™)

Strong CYP3A Inhibitors and Inducers

Ticagrelor should not be taken with strong CYP3A4 inhibitors or inducers

Simvastatin (Zocor®)

Ticagrelor may cause higher blood levels of simvastatin
The manufacturer recommends the simvastatin dose not exceed 40 mg when taken with Ticagrelor

Lovastatin (Mevacor®)

Ticagrelor may cause higher blood levels of lovastatin
The manufacturer recommends the lovastatin dose not exceed 40 mg when taken with Ticagrelor

Ticlopidine (Ticlid®)

Bupropion (Wellbutrin®)

Ticlopidine inhibits CYP2B6 which can lead to elevated bupropion levels (Wellbutrin®, Contrave®)
When taken together, doses of bupropion may need to be decreased

METABOLISM AND ELIMINATION

NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are taking medications together and are concerned about a possible interaction.

Clopidogrel (Plavix®)

CYP2C19 - substrate (primary)
CYP2C8 - strong inhibitor
CYP3A4 - substrate
CYP2B6 - substrate, weak inhibitor
CYP1A2 - substrate [12]
CYP2C9 - substrate [23]

Prasugrel (Effient®)

CYP3A4 - substrate (primary)
CYP2B6 - substrate (primary), weak inhibitor
CYP2C19 - substrate
CYP2C9 - substrate [13]

Ticagrelor (Brilinta™)

CYP3A4 - substrate (primary)
P-glycoprotein - weak substrate and inhibitor [15]

Ticlopidine (Ticlid®)

CYP2C19 - strong inhibitor
CYP2B6 - weak inhibitor
CYP1A2 - weak inhibitor
CYP2D6 - inhibitor

OTHER

Opiate medications - opiate agonists may slow gastric emptying and delay the absorption of P2Y12 inhibitors. Consider parenteral antiplatelet agents in acute coronary syndrome.
Phenytoin (Dilantin®) - Ticlopidine may raise phenytoin levels. Monitor levels when starting concurrent therapy.
Digoxin - Ticagrelor may increase digoxin levels. Monitor levels when starting concurrent therapy.

P2Y12 INHIBITORS + ANTICOAGULATION

In some cases, anticoagulation and antiplatelet therapy are both indicated in the same patient. An example of this would be a patient with atrial fibrillation who has heart stents placed. In this scenario, anticoagulation, aspirin, and a P2Y12 inhibitor are all indicated.
Recommendations for combining anticoagulation and antiplatelet therapy are reviewed at the link below

Combining anticoagulation and antiplatelet therapy

CLOPIDOGREL AND CYP2C19

OVERVIEW

Clopidogrel (Plavix®) is a prodrug which means it must be metabolized by the body before it becomes active (active metabolite)
The enzyme that converts clopidogrel to its active metabolite is CYP2C19
If CYP2C19 is inhibited by another drug, or if a person has weak CYP2C19 enzymes (poor metabolizer), then clopidogrel may not be metabolized extensively, and its effectiveness may diminish

CLOPIDOGREL AND PPIs

A handful of widely prescribed medications, namely proton pump inhibitors (PPIs, Prilosec®, Nexium®, etc.), inhibit CYP2C19
PPIs are often prescribed with clopidogrel because they decrease the risk of bleeding from aspirin and/or clopidogrel
The COGENT trial detailed below looked at the effect of taking omeprazole (Prilosec®) with clopidogrel on clinical outcomes. Omeprazole is a moderate CYP2C19 inhibitor that is widely prescribed.

COGENT trial - Clopidogrel + Omeprazole vs Clopidogrel alone NEJM (2010) [PubMed abstract]

The COGENT trial enrolled 3873 patients who had an indication for 12 months of clopidogrel therapy
Main inclusion criteria: anticipated therapy with aspirin and clopidogrel for 12 months including patients with acute coronary syndrome and/or stent placement
Main exclusion criteria: medical need for PPI, H₂ antagonist, sucralfate, or misoprostol; erosive esophagitis; previous gastric surgery; recent fibrinolysis
Baseline characteristics: median age 68 years; positive for H. Pylori - 48%; using NSAIDs - 8.6%; cardiovascular history, PCI - 71%, ACS - 42%, MI - 29%, PAD - 12%, stroke - 7.8%; history of GI bleed or ulcer - 4.1%

Patients were randomized to one of two groups:

Group 1 (1876 patients) - Omeprazole 20 mg once daily + clopidogrel 75 mg once daily
Group 2 (1885 patients) - Placebo + clopidogrel 75 mg once daily
All patients also received enteric coated aspirin 75 - 325 mg once daily

COPRIMARY OUTCOMES: The primary cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary revascularization (PCI or CABG), or ischemic stroke. The primary gastrointestinal outcome was a composite of upper GI clinical events (defined as bleeding, ulcer, pain with erosions, obstruction, or perforation)
After a median follow-up of 106 days, the following was seen:

Primary outcome (cardiovascular events at 180 days): Group 1 - 4.9%, Group 2 - 5.7% (HR 0.99, 95%CI [0.68 - 1.44], p=0.96)
Primary outcome (gastrointestinal events at 180 days): Group 1 - 1.1%, Group 2 - 2.9% (HR 0.34, 95%CI [0.18 - 0.63], p<0.001)
The trial was truncated because of loss of funding [19]

StraightHealthcare analysis:

All PPIs may inhibit CYP2C19 to some degree [22]
The most widely studied PPI for this interaction is omeprazole (Prilosec®)
The COGENT trial was a randomized, controlled trial designed specifically to look at the effect of taking omeprazole (Prilosec®) with clopidogrel
The trial found no effect of omeprazole on cardiovascular outcomes, and a benefit in bleeding outcomes
The main weakness of the trial is its short follow-up (median 106 days) because of loss of funding
CONCLUSION: Based on the available evidence, there is no reason to avoid PPI use with clopidogrel. There is no evidence that one PPI is less likely to interact than any other.

CLOPIDOGREL AND POOR METABOLIZERS

OVERVIEW

Different forms of a gene are called alleles. Individuals and populations can vary in the alleles they carry for a gene.
Variations in alleles that code for CYP enzymes can affect the performance of these enzymes. Some alleles may decrease the activity of the enzyme (loss-of-function alleles), while other alleles may increase the activity.
Studies have shown that the prevalence of CYP2C19 alleles varies by ethnicity (see below), and these variations affect the metabolic activity of the CYP2C19 enzyme. The most common CYP2C19 loss-of-function alleles are the *2 and *3 variants. The *17 variant is a common gain-of-function allele that increases CYP2C19 activity.
One loss-of-function allele leads to a 47% reduction in CYP2C19 activity, and two loss-of-function alleles leads to a 65% reduction
People with one loss-of-function allele are considered "intermediate metabolizers," and people with two loss-of-function alleles are considered "poor metabolizers"

Prevalence of at least one loss-of-function allele by ethnicity:

Asians: 51 - 55%
African-Americans: 33 - 40%
Caucasians: 24 - 30%
Mexican-Americans: 18% [22]

Prevalence of two loss-of-function alleles by ethnicity (poor metabolizers):

Chinese: 14%
African-Americans: 4%
Caucasians: 2% [12]

STUDIES

Post-hoc analyses from 4 trials have looked at the effect of CYP2C19 metabolizer status and its effect on outcomes in patients treated with clopidogrel

TRITON TIMI 38 Post-hoc Analysis (2009)

In TRITON TIMI 38 trial, patients with acute coronary syndrome who were to undergo PCI were randomized to clopidogrel or prasugrel
In the post-hoc analysis, investigators took 1477 patients treated with clopidogrel and tested their blood to see if they were normal CYP2C19 metabolizers or poor CYP2C19 metabolizers
Differences in the study outcomes were then compared between the two groups

Results:

The primary outcome in the TRITON TIMI 38 trial was a composite of death from cardiovascular causes, heart attack, or stroke
CYP2C19 Poor metabolizers had an absolute increase in the primary outcome of 4.1% when compared to normal metabolizers (p=0.01)
CYP2C19 Poor metabolizers had an absolute increase in stent thrombosis of 1.8% when compared to normal metabolizers (p=0.02) [20]

CURE and ACTIVE A Post-hoc Analysis (2010)

In the CURE trial, patients with acute coronary syndrome were randomized to clopidogrel or placebo
In the ACTIVE A trial, patients with atrial fibrillation were randomized to clopidogrel or placebo in addition to aspirin
In the post-hoc analysis, investigators took a total of 5059 patients from CURE and 1156 patients from ACTIVE-A who were treated with clopidogrel and tested their blood to see if they were normal CYP2C19 metabolizers or poor CYP2C19 metabolizers
The study also compared patients who were "strong metabolizers" of CYP2C19 to normal and poor metabolizers
Differences in the study outcomes were then compared between the two groups

Results from CURE trial:

The primary outcome in the CURE trial was a composite of death from cardiovascular causes, heart attack, or stroke
The effect of clopidogrel in reducing the primary outcome was the same for poor metabolizers and normal metabolizers when compared to placebo
CYP2C19 strong metabolizers derived more benefit from clopidogrel than patients who were not strong metabolizers [21]

Results from ACTIVE A trial:

The primary outcome in the ACTIVE-A trial was a composite of stroke, blood clot, heart attack, or vascular death
The effect of clopidogrel in reducing the primary outcome was the same for poor metabolizers and normal metabolizers when compared to placebo
CYP2C19 strong metabolizers did not derive more benefit from clopidogrel than patients who were not strong metabolizers [21]

CHANCE Trial Post-hoc Analysis, JAMA (2016) [PubMed abstract]

In the CHANCE trial, patients with a TIA or minor stroke were randomized to aspirin + clopidogrel or aspirin only for 90 days. The primary outcome was recurrent stroke within 90 days. The study was performed in China where CYP2C19 loss-of-function alleles are more prevalent.
In the post-hoc analysis, researchers compared outcomes between carriers (n=1726) of loss-of-function alleles and noncarriers (n=1207). Patients were considered carriers if they had ≥ 1 loss-of-function allele.

Results:

Primary outcome in carriers: Aspirin - 10.8%, Aspirin + clopidogrel - 9.4% (HR 0.93, 95%CI [0.69 - 1.26], p=0.64)
Primary outcome in noncarriers: Aspirin - 12.4%, Aspirin + clopidogrel - 6.7% (HR 0.51, 95%CI [0.35 - 0.75], p<0.01)
A significant interaction (p=0.02) was found between carrier status and the primary outcome

Professional Guidelines:

AHA/ACC

The AHA/ACC issued a statement in 2010 in regards to clopidogrel and CYP2C19 metabolism (PPI use and poor metabolizers)
The statement is mostly a review of the available evidence (much of which is contradictory), and offers no real guidance [22]

FDA

The FDA placed a "boxed warning" on clopidogrel stating that the effectiveness of clopidogrel is diminished in poor metabolizers. It recommends that patients be tested to determine if they are poor metabolizers. Poor metabolizers should have their therapy adjusted. [12]

StraightHealthcare analysis:

Results from the studies above are conflicting. The trials differed by indication for clopidogrel along with outcome measures and duration. This makes it difficult to draw conclusions about the effect of metabolizer status on outcomes.
To date, no randomized controlled trial has been performed to specifically address the effect of metabolizer status on outcomes with clopidogrel
Based on the available evidence, it is unclear if CYP2C19 metabolizer status affects outcomes with clopidogrel. Patients at high risk for loss of function alleles (e.g. Asians, African-Americans) may want to undergo testing before taking clopidogrel.

LONG TERM SAFETY

Clopidogrel has been available in the US since 1997. Its safety and side effects are well known.
Prasugrel has been available in the US since 2009. Its long term effects are not well known.
Ticagrelor has been available in the US since 2011. Its long term effects are not well known.

DOSING

P2Y12 inhibitor dosing chart

GENERIC AVAILABILITY

Generic:

Clopidogrel (Plavix®)
Ticlopidine (Ticlid®)

Possible generic:

DRUG	PATENT EXPIRES
Prasugrel (Effient®)	APR 2017
Ticagrelor (Brilinta™)	JUL 2018

NOTE: Drug companies typically file multiple patents on their drugs in order to protect them from competition. The patent expiration listed here is the date that the earliest patent on the drug expires (accounting for pediatric exclusivity). Because drug companies use numerous techniques to extend the life of their patents, it does not necessarily mean a generic will become available around this date.

COST SAVINGS OPPORTUNITIES

Clopidogrel is available as a generic and is cheaper than prasugrel and ticagrelor which do not have generics
There are some differences between the drugs - see class differences below
Ticlopidine is not widely prescribed anymore because of unfavorable side effects

DIFFERENCES BETWEEN DRUGS IN CLASS

P2Y12 Inhibitors differ by their drug interactions
P2Y12 Inhibitors differ by their effectiveness
P2Y12 Inhibitors differ by their side effects
P2Y12 Inhibitors differ by their cost

BIBLIOGRAPHY

What is PMID?
PI = Manufacturer's Package Insert

# PMID
1 - 23247304 AHA GL on STEMI
2 - 22800849 AHA GL on non-ST MI
3 - 23166211 AHA GL on CAD
4 - 8918275 CAPRIE
5 - 16531616 CHARISMA
6 - 15276392 MATCH
7 - 18753638 PROFESS
8 - 20966421 AHA GL on secondary stroke prevent
9 - 16765759 ACTIVE W
10 - 19336502 ACTIVE A
11 - 22858728 2012 AHA GL on A fib
12 - Clopidogrel PI
13 - Prasugrel PI
14 - 17982182 TRITON TIMI 38
15 - Ticagrelor PI
16 - 19717846 PLATO
17 - 21545948
18 - Ticlopidine PI
19 - 20925534 COGENT
20 - 19106084 TRITON POST-HOC
21 - 20979470 CURE and ACTIVE-A POST-HOC
22 - 21060077 AHA/ACC statement on CYP2C19
23 - 21182487
24 - 23991622
25 - 24177257
26 - 25037988
27 - 25399658
28 - 25641006 in vitro platelet reversibility
29 - 25564918 - Case study on ticagrelor
30 - 23609292 - platelet transfusion study
31 - 25773268 - PEGASUS-TIMI 54
32 - 24682347 - AHA 2014 A fib GL
33 - 27840332 - 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary

P2Y12 INHIBITORS

ACUTE HEART ATTACK

SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE

PRIMARY PREVENTION OF STROKE

SECONDARY PREVENTION OF STROKE

ATRIAL FIBRILLATION

PERIPHERAL ARTERY DISEASE (PAD)

All P2Y12 Inhibitors

Clopidogrel (Plavix®)

Ticagrelor (Brilinta™)

Ticlopidine (Ticlid®)