Unstable angina non ST elevation myocardial infarction thienopyridines

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editors-in-Chief: Varun Kumar, M.B.B.S.; Lakshmi Gopalakrishnan, M.B.B.S.; Smita Kohli, M.D.

Thienopyridines

A number of drugs are currently being studied for use in ACS patients. Agents available in this category include:

Clopidogrel in the Management of Unstable angina/NSTEMI

Mechanism of action:

  • This class of drugs inhibits platelet aggregation and reduces blood viscosity by inhibiting adenosine diphosphate (ADP) action on platelet receptors, specifically the P2Y12 component of the ADP receptor.

Clinical trial data:

  • Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial[1] led to widespread use of Clopidogrel in ACS and stroke patients. Trial enrolled a total of 19,185 patients who were randomized to receive ASA 325 mg per d or clopidogrel 75 mg per d in patients with atherosclerotic vascular disease(manifested as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease). Follow up ranged from 1-3 yrs. Results showed that long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death.
  • The results of the CURE trial[2] further reinforced the benefits of Clopidogrel in patients with Unstable angina/NSTEMI.

Clopidogrel Dosing:

  • A loading dose of 300mg is typically used, although some studies have used higher dose(600-900mg) and shown improved outcomes, but also increase incidence of side effects.
  • Duration of treatment recommended at present is maintenance dose of either 75mg daily Clopidogrel or 10mg daily Prasugrel for minimum 12 months in patients undergoing PCI with either BMS or DES[3].
  • It is recommended to empirically with-hold the drug for 5days before planning for CABG[2].

Disadvantage of Clopidogrel:

  • A limiting factor in the use of clopidogrel is its inter-individual variability in response (hyporesponders) which has growing concern in patients with PCI and its impact on the incidence of stent thrombosis.


Prasugrel in the Management of Unstable angina/NSTEMI

Mechanism of benefit:

  • It has similar mechanism of action but more potent antiplatelet effect.

Clinical trial data:

  • TRION-TIMI 38 trial[4] which was a multicenter, randomized, double blind study enrolling 13,608 patients with moderate to high-risk ACS led to the FDA approval and its inclusion in ACC/AHA guidelines for PCI as one of the recommended thienopyridine agent. Results of this study showed that in patients with acute coronary syndromes with scheduled percutaneous coronary intervention,Prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.

Prasugrel Indications:

  • Prasugrel is being increasingly used in high risk patients with ACS undergoing PCI.
  • Also in patients with failed clopidogrel therapy.
  • In high-risk situations such as with history of diabetes or prior MI, in which its effect appears to be greater and its use may be considered.

Prasugrel Contraindications:

  • In patients with history of stroke, TIA and other bleeding disorders.
  • Prasugrel is usually not recommended in patients ≥75 years of age because of the increased risk of fatal and intracranial bleeding and uncertain benefit except in high-risk situations (see above).
  • Prasugrel should not be started in patients who are likely to undergo urgent CABG. Patient should not be taken for surgery at least for 7days following stoppage of the drug[5].

Prasugrel Dosing:

  • Duration of treatment recommended at present is maintenance dose of either 75mg daily Clopidogrel or 10mg daily Prasugrel for minimum 12 months in patients undergoing PCI with either BMS or DES[6].
  • Dose adjustment of prasugrel is required in patients weighing <60 kg as they have increased risk of bleeding secondary to increased exposure to active metabolites when consuming 10mg daily. Lowering the maintenance dose to 5mg daily should be considered, although at present there are no prospective studies about its effectiveness and safety at this dose.


Ticagrelor in the Management of Unstable angina/NSTEMI

Clinical Trial Data:

  • This drug was investigated in a multicenter, double-blind, randomized PLATO trial[7] which enrolled 18,624 patients with ACS. This trial compared Clopidogrel with Ticagrelor and showed improved outcomes in patients on Ticagrelor in both STEMI and NSTEMI group with regards to death from vascular causes, MI and stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding.
  • CHAMPION PCI[8] and CHAMPION PLATFORM[9] trials have studied the role of IV platelet inhibition with Cangrelor and both trials did not show superiority of Cangrelor over Clopidogrel or Placebo, respectively.


ACC / AHA Guidelines for Antiplatelet therapy in Unstable Angina/NSTEMI (DO NOT EDIT) [10]

“

Class I

1. Clopidogrel (loading dose followed by daily maintenance dose) should be administered to Unstable angina / NSTEMI patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)

2. Patients with definite Unstable angina / NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual-antiplatelet therapy on presentation. (Level of Evidence: A) ASA should be initiated on presentation. (Level of Evidence: A) The choice of a second antiplatelet therapy to be added to ASA on presentation includes 1 of the following:

Before PCI:

At the time of PCI:

3. For Unstable angina / NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose) or an intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A) Abciximab as the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B)

4. For Unstable angina / NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, HF, or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (Level of Evidence: A). Either an IV GP IIb/IIIa inhibitor (eptifibatide or tirofiban (Level of Evidence: A) or clopidogrel (loading dose followed by daily maintenance dose (Level of Evidence: B)) should be added to ASA and anticoagulant therapy before diagnostic angiography (upstream). (Level of Evidence: C)

5. A loading dose of thienopyridine is recommended for Unstable angina/NSTEMI patients for whom PCI is planned. Regimens should be one of the following:

  • Clopidogrel 300 to 600 mg should be given as early as possible before or at the time of PCI (Level of Evidence: A) or
  • Prasugrel 60 mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI. (Level of Evidence: B)

6. The duration and maintenance dose of thienopyridine therapy should be as follows:

  • In Unstable angina / NSTEMI patients undergoing PCI, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months. (Level of Evidence: B)
  • If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by thienopyridine therapy, earlier discontinuation should be considered. (Level of Evidence: C)

Class III: Harm

1. In Unstable angina / NSTEMI patients with a prior history of stroke and/or TIA for whom PCI is planned, prasugrel is potentially harmful as part of a dual-antiplatelet therapy regimen. (Level of Evidence: B)

Class IIb

1. Prasugrel 60 mg may be considered for administration promptly upon presentation in patients with Unstable angina / NSTEMI for whom PCI is planned, before definition of coronary anatomy if both the risk for bleeding is low and the need for CABG is considered unlikely. (Level of Evidence: C)

”


2. In patients with definite Unstable angina / NSTEMI undergoing PCI as part of an early invasive strategy, the use of a loading dose of clopidogrel of 600 mg, followed by a higher maintenance dose of 150 mg daily for 6 days, then 75 mg daily may be reasonable in patients not considered at high risk for bleeding. (Level of Evidence: B)}}

Concomitant use of Proton pump inhibitors and Thienopyridines

ACC/AHA Guidelines- ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines[11] (DO NOT EDIT)

“
  1. Clopidogrel reduces major CV events compared with placebo or aspirin.
  2. 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.
  3. Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
  9. 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.
  10. 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.
  11. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.
 ”

See Also

Sources

  • The ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction[12]
  • 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina / Non–ST-Elevation Myocardial Infarction (Updating the 2007 Guideline) [10]
  • ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines[11]

References

  1. ↑ "A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee". Lancet. 348 (9038): 1329–39. 1996. PMID 8918275. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  2. ↑ 2.0 2.1 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001). "Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation". The New England Journal of Medicine. 345 (7): 494–502. doi:10.1056/NEJMoa010746. PMID 11519503. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  3. ↑ [1]
  4. ↑ Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM (2007). "Prasugrel versus clopidogrel in patients with acute coronary syndromes". The New England Journal of Medicine. 357 (20): 2001–15. doi:10.1056/NEJMoa0706482. PMID 17982182. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  5. ↑ [2]
  6. ↑ [3]
  7. ↑ Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M (2009). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". The New England Journal of Medicine. 361 (11): 1045–57. doi:10.1056/NEJMoa0904327. PMID 19717846. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  8. ↑ Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, Pollack CV, Montalescot G, Mahaffey KW, Kleiman NS, Goodman SG, Amine M, Angiolillo DJ, Becker RC, Chew DP, French WJ, Leisch F, Parikh KH, Skerjanec S, Bhatt DL (2009). "Platelet inhibition with cangrelor in patients undergoing PCI". The New England Journal of Medicine. 361 (24): 2318–29. doi:10.1056/NEJMoa0908628. PMID 19915221. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  9. ↑ Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, Kleiman NS, Goodman SG, White HD, Mahaffey KW, Pollack CV, Manoukian SV, Widimsky P, Chew DP, Cura F, Manukov I, Tousek F, Jafar MZ, Arneja J, Skerjanec S, Harrington RA (2009). "Intravenous platelet blockade with cangrelor during PCI". The New England Journal of Medicine. 361 (24): 2330–41. doi:10.1056/NEJMoa0908629. PMID 19915222. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  10. ↑ 10.0 10.1 Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE, Ettinger SM, Fesmire FM, Ganiats TG, Jneid H, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP (2011). "2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines". Circulation. doi:10.1161/CIR.0b013e31820f2f3e. PMID 21444889. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)
  11. ↑ 11.0 11.1 Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB; et al. (2010). "ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents". Circulation. 122 (24): 2619–33. doi:10.1161/CIR.0b013e318202f701. PMID 21060077.
  12. ↑ Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Chavey WE, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B (2007). "ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine". Journal of the American College of Cardiology. 50 (7): e1–e157. doi:10.1016/j.jacc.2007.02.013. PMID 17692738. Retrieved 2011-04-12. Unknown parameter |month= ignored (help)

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