ST elevation myocardial infarction thienopyridine therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Antiplatelet therapy is a mainstay of pharmacotherapy in STEMI. In the International Study of Infarct Survival 2 (ISIS 2), the thromboxane inhibitor aspirin reduced mortality in STEMI as much as streptokinase (by approximately 42%) when compared to the administration of neither agent.

Thienopyridines inhibit ADP mediated platelet activation and have been found to further improve outcomes of STEMI patients treated with a fibrinolytic agent for STEMI. There are at present three approved agents available in this class, ticlopidine, clopidogrel and prasugrel. As an adjunct to fibrinolytic therapy, clopidogrel has been associated with improved patency in the CLARITY trial (300 mg loading dose and 75 mg/day maintenance dose), and a reduction in mortality in the COMMIT trial (75 mg/day loading and maintenance dose). Among STEMI patients treated with a fibrinolytic agent, co-administration of clopidogrel at a loading dose of 300 mg and a maintenance dose of 75 mg/day should be viewed as the standard of care.

In contrast to fibrinolytic therapy, the benefit of thienopyridine therapy among primary angioplasty patients has not been established in randomized trials. The benefit of aspirin plus thienopyridine therapy versus aspirin monotherapy alone could be difficult to establish in randomized trials given that the majority of STEMI patients are treated with a stent which in turn obviates chronic thienopyridine treatment. Despite the required chronic thienopyridine therapy following stent placement, the slower onset of action of oral thienopyridines relative to that of parenteral antiplatelet agents such as glycoprotein IIb/IIIainhibitors raises important questions as to the acute / early benefits of glycoprotein IIb/IIIa inhibitors versus thienopyridines. Furthermore, the optimal timing of thienopyridine therapy in primary PCI is not well established. In so far a few patients undergo coronary artery bypass grafting (CABG) surgery urgently in the setting of STEMI, the need to define the anatomy prior to theinopyridine administration may not be as compelling as it is in the setting of stable angina, unstable angina and non-ST elevation MI.

Uncertainty remains with respect to the following issues that have not been addressed in randomized trials:

1. Is there a benefit of prasugrel (60 mg loading dose/10 mg maintenance dose) over high dose clopidogrel (600 mg loading dose followed by 150 mg daily for one week, followed by 75 mg per day thereafter) in the setting of primary PCI for STEMI?
2. What is the optimal duration of thienopyridine therapy following primary PCI for STEMI? Should the duration of therapy be extended beyond 1 year despite an absence of randomized trial data?
3. Does glyoprotein IIb/IIIa inhibition further improve outcomes among primary PCI patients treated with high doses of thienopyridines?

Efficacy and safety of Clopidogrel Among STEMI Patients Treated with a Fibrinolytic Agent

Angiographic Efficacy of Clopidogrel as Adjunctive Therapy to Fibrinolysis in STEMI Patients

The angiographic effectiveness of clopidogrel as adjunctive therapy to fibrinolytic administration was evaluated in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-TIMI 28 trial. This study randomized 3,491 STEMI patients to treatement with either placebo or a 300 mg loading dose of clopidogrel followed by a maintenance dose of 75 mg/day. The trial demonstrated a 35% relative risk reduction in the incidence of an occluded artery on angiography, death, or MI associated with clopidogrel administration.

Safety of Clopidogrel in CLARITY

Clopidogrel administration was not associated with an increase in TIMI major bleeding or intracranial hemorrhage (ICH). Indeed, the incidence of all causes of stroke was reduced by 46% (P = 0.052).

Generalizability of Results from CLARITY

There was no heterogeneity in the treatment benefit (that is a consistent benefit was observed) irrespective of:

1. Type of fibrinolytic (2/3rds of patients were treated with a fibrin-specific agent such as tPA, rPA, nPA, or TNK) or
2. Type of antithrombin administered (45.8% received UFH, 29.6% received enoxaparin, 24.5% received both or none).

It is important to note that the following patient groups were excluded from participation in CLARITY, and the results of CLARITY are not applicable to these subgroups: patients over 75 years of age, those with creatinine > 2.5 mg/dL, patients with cardiogenic shock, or patients who had previously undergone coronary artery bypass grafting (CABG). It should also be noted that the rate of PCI or CABG was high at 63%. This may be due to the fact protocol-mandated angiography was performed in countries with a high rate of adjunctive PCI such as Europe and the United States.

Reduction in Mortality Associated with Clopidogrel Administration in Conjunction with Fibrinolytic Agents: Results of COMMIT

The COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group evaluated the safety and efficacy of clopidogrel as an adjunct to fibrinolytic therapy in 45,852 patients at 1250 Chinese hospitals who presented in the first 24 hours of STEMI (93% had ST segment elevation or left bundle branch block, the rest had ST segment depression). As adjunctive therapy to 162 mg of aspirin daily, patients were randomized to clopidogrel 75 mg daily without a 300 mg loading dose which continued until discharge or up to 4 weeks in hospital (mean 15 days in survivors)(n=22,961) or placebo (n=22,891). Clopidogrel administration was associated with a 9% relative reduction (95% CI 3-14) in the co-primary endpoint of death, reinfarction, or stroke (2121 [9.2%] clopidogrel vs 2310 [10.1%] placebo; p=0.002). This would translate into to nine fewer deaths, re MIs or strokes per 1000 patients treated for two weeks. Likewise, there was a 7% relative risk reduction (95% CI 1-13) in all cause death (1726 [7.5%] vs 1845 [8.1%]; p=0.03). The benefits were consistent across a broad range of subgroups, antithrombins and fibrinolytic agents.

With respect to safety, there was no excess of fatal stroke or intracranial hemmorhage associated with clopidogrel administration, either in patients of all ages (134 [0.58%] vs 125 [0.55%]; p=0.59), or among patients who were over 70 years of age.

Timing and Dosing of Clopidogrel in STEMI

Fibrinolytic Therapy Patients

Data from the non-ST elevation MI population does demonstrate that a 600 mg oral dose achieves sustained inhibition more rapidly than a 300 mg dose. A 600 mg dose does not, however, achieve a higher level of inhibition. The FDA package insert loading dose is 300 mg, but in clinical practice both 300 and 600 mg doses are used. A loading dose of 600 mg of clopidogrel has not been studied in conjunction with fibrinolytic therapy and cannot be recommended.

Primary PCI Patients

Current guidelines recommend pre-loading with 300 to 600 mg of clopidogrel in the primary PCI setting. Again, it should be emphasized that this is not based upon randomized trial data enrolling STEMI patients undergoing primary PCI, but rather from data originating from non-randomized subgroup analyses and registries. One registry demonstrated that pre-loading with clopidogrel in the setting of STEMI was associated with a 2.2 fold improvement in normal TIMI myocardial perfusion grade 3 (O.R. 1.2-3.9, p=0.01) was well as a reduced risk of recurrent MI (0% vs 3.2%, respectively, p= 0.04) . In a subgroup of 2707 patients managed with primary PCI in the Acute Coronary Syndromes (ACOS) registry, 1 year mortality was significantly reduced among patients treated with aspirin plus clopidogrel versus aspirin alone (OR 0.38, 95% CI 0.23-0.62]. It should be noted that this data is limited by the fact that neither the loading dose nor timing of clopidogrel were reported . It should also be realized that in registries, clopidogrel administration is often a surrogate or a marker of the use of a stent, and it is not clear whether the benefit was mediated by the stent or by the clopidogrel. Finally, Gibson et al in a substudy from CLARITY have demonstrated that non-emergent PCI after fibrinolytic therapy was associated with improved mortality among patients randomized to clopidogrel (OR 0.34, 95% CI 0.13-0.92, P = .034) but not placebo (OR 1.41, 95% CI 0.63-3.19, P = .40, interaction P = .028).

The optimal loading dose in patients with STEMI undergoing primary PCI has not been rigorously evaluated in randomized trials. The ARMYDA 2 trial evaluated the efficacy of 300 mg vs 600 mg of clopidogrel before elective PCI, and the benefits observed in this trial (a reduction in the risk of death, MI or target vessel revascularization from 12% to 4%, p=0.041) may not be applicable to the STEMI population. In the HORIZONS AMI trial, a loading dose of 600 vs 300 mg of clopidogrel was associated with a lower rate of death (3.1% vs 1.9%, p=0.03) as well as reinfarction (2.4% vs 1.3%, p=0.02) and a trend toward lower rates of stroke (1.0% vs 0.4%, p=0.058). There was no difference in pre-PCI flow between the two strategies. 30 day stent thrombosis was lower among patients treated with a 600 mg loading dose of clopidogrel (1.7% vs 3.5%, p=0.03). An important confounder was the fact that 7.5% of patients treated with a 600 mg loading dose received a GP IIb/IIIa inhibitor in the emergency room compared to only 3.2% of those treated with a 300 mg loading dose (p<0.0001). There were also large and significant imbalances in Killip class, femoral access, closure device use, and peak ACT between the two loading doses (all p<0.0001). In a multivariate model, a 600 mg loading dose of clopidogrel was independently associated with a lower rate of 30 day major adverse cardiac events (MACE) when compared to the lower 300 mg loading dose (OR 0.72, p=0.036). A 600 mg loading dose was not a multivariate predictor of the specific endpoint of death/MI or bleeding. Given the non randomized nature of this analysis, and the potential confounders, these findings should be interpreted with caution and no firm recommendations can be made regarding the optimal loading dose of clopidogrel before primary PCI from this analysis.

Prasugrel in the Management of Primary PCI Patients

The safety and effectiveness of prasugrel has been compared to clopidogrel in the management of STEMI patients in a substudy of the randomized TRITON TIMI 38 trial . Among the 26% of patients in the TRITON trial that were diagnosed with a STEMI (n= 3,534), the risk of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke by 15 months was reduced with prasugrel (60 mg loading dose/10 mg maintenance dose) versus clopidogrel (300 mg loading dose/75 mg maintenance dose) (174 [10.0%] vs 216 [12.4%]; 0.79 [0.65-0.97]; p=0.0221). It should be noted that although the primary analysis included all STEMI patients, when the results were examined in those 69% of patients who underwent primary PCI, there was a numerically lower event rate for prasugrel that was not statistically significantly different than clopidogrel (10.2% vs 11.6%, HR 0.87 [95% CI 0.68-1.11]; p=0.2662). It should be noted that the benefit of prasugrel over clopidogrel was confined to those patients with an anterior MI location (p for interaction 0.0053). Among patients with an anterior MI the incidence of the primary endpoint was 16.3% for clopidogrel vs 9.8% for prasugrel; hazard ratio 0.57 [95% CI 0.42-0.78]; p=0.0003), while among patients with non-anterior myocardial infarction there was a numerically but not statistically significantly higher event rate in prasugrel patients: 9.9%% for clopidogrel vs 10.1% for prasugrel; HR 1.02 [0.78-1.34]; p=0.87). The test for heterogeneity of the effect of prasugrel as a function of infarct location was highly statistically significant (p=0.0053). While the STEMI substudy of TRITON is of interest, it should be noted that the results of the STEMI substudy cohort in TRITON are homogenous with those of patients who did not have a STEMI (i.e. the test of heterogeneity was not statistically significant).

Ticagrelor in the Management of Primary PCI Patients

Although it is often lumped together with the thienopyridines, ticagrelor is actually a non-thienopyridine (it is a novel Cyclo-Pentyl-Triazolo-Pyrimides (CPTP) agent). This agent is not yet approved for clinical use but has been evaluated in the the PLATelet inhibition and patient Outcomes (PLATO) trial. One of the potential benefits of ticagrelor in the setting of STEMI is that it has a more rapid onset of action and it is semi-reversible with a return of platelet activity within a few hours. This more rapid return of platelet function may confer a safety advantage over the permanent platelet inhibition associated with clopidogrel and prasugrel administration .

The potential benefit of ticagrelor among STEMI patients treated with primary PCI was evaluated in a subgroup analysis of 8,430 patients (38% of the patient population) in the PLATO study . The drugs were administered at the time of PCI in the following doses: clopdigogrel 300 mg loading dose (if no load had been administered in the prior 5 days)/75 mg daily maintenance dose; vs ticagrelor 180 mg loading dose/ 90 mg daily maintenance dose.

In this STEMI subgroup, ticagrelor was associated with a significant reduction in the rate of the primary endpoint (death from vascular causes, MI, or stroke) at 12 months (11% vs. 9.3%; p=0.02). This benefit was predominantly due to a significant reduction in recurrent MI (6.1% vs. 4.7%; p=0.01). The risk of stent thrombosis was significantly reduced by ticagrelor as well.

Side Effects of Thienopyridines

Ticlopidine administration has been associated with neutropenia and thrombotic thrombocytopenia (TTP). It is as a result of these potential side effects that clopidogrel is often prescribed instead. Clopidogrel may also be preferred because of the lack of need for laboratory monitoring, and once-daily dosing. It should be noted, however, that approximately one third to one quarter of patients may be resistant to clopidogrel, which is a pro-drug. For those patients who develop stent thrombosis while on clopidogrel, ticlopidine may be an optimal substitution because it is not a pro-drug and is not metabolized by the same pathway as clopidogrel. Prasugrel is associated with an increase in the risk of TIMI major bleeding, life threatening bleeding and fatal bleeding. The risks of bleeding vs efficacy must be carefully evaluated in individual patients.

2013 Revised and 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) (DO NOT EDIT)

Use of Thienopyridines (DO NOT EDIT)

Class I

"1. A loading dose of a P2Y12 receptor inhibitor should be given as early as possible or at time of primary PCI to patients with STEMI. Options include

"a. Clopidogrel 600 mg (Level of Evidence: B)"

"b. Prasugrel 60 mg (Level of Evidence: B)"

"c. Ticagrelor 180 mg (Level of Evidence: B)"

"2. P2Y12 inhibitor therapy should be given for 1 year to patients with STEMI who receive a stent (bare-metal or drug-eluting) during primary PCI using the following maintenance doses:

"a. Clopidogrel 75 mg daily (Level of Evidence: B)"

"b. Prasugrel 10 mg (Level of Evidence: B)"

"c. Ticagrelor 90 mg (Level of Evidence: B)"

"3. For STEMI patients undergoing nonprimary PCI, the following regimens are recommended: "

"(i) If the patient has received fibrinolytic therapy and has been given clopidogrel, clopidogrel should be continued as the thienopyridine of choice. (Level of Evidence: C)"

"(ii) If the patient has received fibrinolytic therapy without a thienopyridine, a loading dose of 300 to 600 mg ofclopidogrel should be given as the thienopyridine of choice. (Level of Evidence: C) "

"(iii) If the patient did not receive fibrinolytic therapy, either a loading dose of 300 to 600 mg of clopidogrel should be given or, once the coronary anatomy is known and PCI is planned, a loading dose of 60 mg of prasugrel should be given promptly and no later than 1 hour after the PCI. (Level of Evidence: B)"

"4. The duration of thienopyridine therapy should be as follows:"

"a. In patients receiving a stent (BMS or drug-eluting stent [DES]) during PCI for ACS, clopidogrel 75 mg daily (Level of Evidence: B) or prasugrel 10 mg daily (Level of Evidence: B) should be given for at least 12 months;"

"b. If the risk of morbidity because of bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered. (Level of Evidence: C)"

"5. In patients taking a thienopyridine in whom CABG is planned and can be delayed, it is recommended that the drug be discontinued to allow for dissipation of the antiplatelet effect. (Level of Evidence: C) The period of withdrawal should be at least 5 days in patients receiving clopidogrel (Level of Evidence: B) and at least 7 days in patients receiving prasugrel (Level of Evidence: C), unless the need for revascularization and/or the net benefit of the thienopyridine outweighs the potential risks of excess bleeding. (Level of Evidence: C)"

Class III (Harm)

"1. Prasugrel should not be administered to patients with a history of prior stroke or transient ischemic attack. (Level of Evidence: B)"

Class IIb

"1. Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing DES placement.(Level of Evidence: C)"

Adjunctive Antiplatelet Therapy with Fibrinolysis (DO NOT EDIT)

Class I

"1. Aspirin (162- to 325-mg loading dose) and clopidogrel (300-mg loading dose for patients <75 years of age, 75-mg dose for patients >75 years of age) should be administered to patients with STEMI who receive fibrinolytic therapy.(Level of Evidence: A)"

"2. Aspirin should be continued indefinitely (Level of Evidence: A) and clopidogrel (75 mg daily) should be continued for at least 14 days (Level of Evidence: A)and up to 1 year (Level of Evidence: C) in patients with STEMI who receive fibrinolytic therapy."

Class IIa

"1. It is reasonable to use aspirin 81 mg per day in preference to higher maintenance doses after fibrinolytic therapy.(Level of Evidence: B)"

Antiplatelet Therapy to Support PCI After Fibrinolytic Therapy (DO NOT EDIT)

Class I

"1. Clopidogrel should be provided as follows:

"a. A 300-mg loading dose should be given before or at the time of PCI to patients who did not receive a previous loading dose and who are undergoing PCI within 24 hours of receiving fibrinolytic therapy (Level of Evidence: C)";

"b. A 600-mg loading dose should be given before or at the time of PCI to patients who did not receive a previous loading dose and who are undergoing PCI more than 24 hours after receiving fibrinolytic therapy (Level of Evidence: C)"; and

"c. A dose of 75 mg daily should be given after PCI.(Level of Evidence: C)"

Class IIb

"1. Prasugrel, in a 60-mg loading dose, is reasonable once the coronary anatomy is known in patients who did not receive a previous loading dose of clopidogrel at the time of administration of a fibrinolytic agent, but prasugrel should not be given sooner than 24 hours after administration of a fibrin-specific agent or 48 hours after administration of a non-fibrin specific agent.(Level of Evidence: B)"

"2. Prasugrel, in a 10-mg daily maintenance dose, is reasonable after PCI.(Level of Evidence: B)"

2010 ACCF/ACG/AHA Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines (DO NOT EDIT)

“

Clopidogrel reduces major CV events compared with placebo or aspirin. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding. Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding. Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy. Other clinical characteristics that increase the risk of GI bleeding include advanced age; concurrent use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin; and Helicobacter pylori infection. The risk of GI bleeding increases as the number of risk factors increases. Use of a PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs. PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications. Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. It is not established that changes in these surrogate endpoints translate into clinically meaningful differences. Observational studies and a single randomized clinical trial (RCT) have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.

”

Sources

• The 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction
• The 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction
• The 2009 ACC/AHA Focused update on the guidelines for STEMI and PCI
• ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines
• 2013 Revised ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction