# Clopidogrel (Plavix®) Criteria for Use in Veteran Patients

# VHA Pharmacy Benefits Management Services and the Medical Advisory Panel

*The following recommendations are based on current medical evidence.
The content of the document is dynamic and will be revised as new
clinical data becomes available. The purpose of this document is to
assist practitioners in clinical decision-making, to standardize and
improve the quality of patient care, and to promote cost-effective drug
prescribing. The clinician, however, must make the ultimate judgment
regarding the propriety of any course of treatment in light of
individual patient situations.*

## The following document briefly outlines recommendations for clopidogrel for various indications and clinical situations, as outlined below. These are not meant to be all inclusive. For other clinical situations and for those with insufficient evidence to determine risk and benefit, consultation with local experts is advised.

## Recommendations for use of clopidogrel post percutaneous coronary intervention (PCI)/stent^1,5,\ 22-33^

-   Patients who receive coronary stents will require dual anti-platelet
    therapy with aspirin and clopidogrel in order to maintain patency of
    the artery.

-   Clopidogrel should be initiated at the time of the procedure, if not
    before and ideally continued for 12 months. American Heart
    Association (AHA) guidelines indicate the minimal duration of
    clopidogrel therapy may be guided by stent type \[bare metal 1
    month, sirolimus (Cypher®), Cordis 3 months and paclitaxel (Taxus®),
    Boston Scientific 6 months\]. (Level A)

-   There is recent evidence that drug eluting stents (DES) may confer a
    rare but increased risk of late stent thrombosis in certain patient
    populations (including left main DES, DES of bifurcations,
    overlapping DES, prior history of late stent thrombosis, and DES of
    bypass graft), suggesting a longer duration of dual therapy may be
    needed.  The exact duration of clopidogrel therapy in these
    situations has not been conclusively established, however when
    making this determination providers must weigh the benefit of
    prolonged or indefinite clopidogrel therapy against the risk for
    bleeding on a patient by patient basis. (Level C)^22-32^  

-   Data emerging from pooled meta-analyses and registries suggest the
    need for uninterrupted dual antiplatelet therapy (aspirin 325 mg,
    clopidogrel 75 mg daily) throughout the post-stenting treatment
    period. Any elective procedures which would require stopping or
    interrupting this therapy (dental work, colonoscopy, etc.) should be
    delayed until the minimum treatment duration based on stent type is
    completed.^33^

-   The dose of aspirin following a PCI/stent is 325mg daily.  This
    higher dose of aspirin should be given for one month following bare
    metal stents, 3 months following sirolimus (Cypher ®), Cordis)
    stenting, and 6 months post paclitaxel (Taxus(r), Boston Scientific)
    stents, after which aspirin should be continued indefinitely at a
    dose of 75 to 162 mg daily.

-   Patients undergoing brachytherapy should receive clopidogrel 75 mg
    and aspirin 325 mg daily for an indefinite period unless there is a
    bleeding risk. (Level C)

## 

## Recommendations for use of clopidogrel in NSTEMI/Unstable angina acute coronary syndromes^1,3,5,6,9,11,13^

-   In patients with acute coronary syndrome and /or unstable angina in
    whom no revascularization procedure is planned, clopidogrel should
    be added to aspirin as soon as possible for at least 1 month
    (Level A) and up to 12 months (Level B).

-   Clopidogrel will be discontinued after 12 months unless compelling
    clinical reasons exist to maintain therapy for a longer period
    (Refer to the section on PCI/Stent for specific guidance on drug
    eluting stents {DES}).

**Recommendations for use of clopidogrel in STEMI acute coronary
syndrome^18-20^**

-   In patients with STEMI \< 75 years of age receiving fibrinolytics
    clopidogrel should be administered as a 300mg loading dose followed
    by 75mg once daily until hospital discharge (up to 8 days) or longer
    if undergoing angiography/coronary intervention as described below
    in recommendations post PCI/Stent. (Level A)

-   In patients of any age with STEMI regardless of whether
    fibrinolytics are utilized clopidogrel should be administered at a
    dose of 75mg once daily until hospital discharge or up to 4 weeks or
    longer if undergoing angiography/coronary intervention as described
    below in recommendations post PCI/Stent. (Level A)

-   In patients with STEMI who do not undergo PCI consideration can be
    given to continuing clopidogrel 75mg once daily for up to 1-year
    based on extrapolation from trials in NSTEMI/Unstable angina. 
    (Level B)

-   A potential benefit of dual anti platelet therapy may be conferred
    in patients who have experienced a recent plaque rupture
    ([\<]{.underline} 30 days)^34^.

**Recommendations for use of clopidogrel in stable coronary artery
disease (CAD)^17^**

-   There is insufficient evidence to recommend initiation in those
    patients with stable CAD and who do not meet criteria in this
    document.

-   It is recommended that clopidogrel not be added to aspirin therapy
    for stable/asymptomatic atherosclerosis and/or for patients with
    multiple cardiovascular risks unless there are other criteria that
    have been met. (Level A)

## 

## Recommendations for use of clopidogrel in aspirin adverse events^16^

## Clopidogrel should be used in patients who are aspirin allergic, i.e.; anaphylaxis, aspirin induced bronchospasm. (Level A)

-   In patients with a history of gastrointestinal complications from
    aspirin (i.e.; bleeding, stomach upset), adding a proton pump
    inhibitor to aspirin therapy is preferred over switching to
    clopidogrel. (Level B)

## 

## Recommendations for use of clopidogrel for Coronary Artery Bypass Grafting (CABG)^1,14^

-   In patients receiving clopidogrel for ACS, discontinuation is
    suggested 3-5 days prior to elective CABG. (Level B) and restarted
    as soon as patient's clinical condition tolerates for up to 12
    months**.**

## For those patients undergoing saphenous vein bypass graft and allergic to aspirin, clopidogrel, 300mg, as a loading dose 6 hours after the operation followed by 75mg daily may be initiated. (Level B). 

## Clopidogrel may be continued for 1-3 months post CABG. (Level C)

**Recommendations for the use of clopidogrel in Peripheral Vascular
Disease (PVD)^2,4,12^**

-   Clopidogrel is not recommended for PVD except in cases of aspirin
    allergy. (Level B)

## Recommendations for the use of clopidogrel in recurrent cerebral ischemic events^7,10,21^

-   Patients with recurrence of cerebral ischemic events while on
    therapy with aspirin should be changed to extended release
    dipyridamole/aspirin. (Level B)

-   Clopidogrel is an [alternative]{.underline} for those patients who
    have had recurrent cerebrovascular events, who have a documented
    aspirin allergy, as mentioned above or are intolerant of extended
    release dipyridamole (recurrent headache). ( Level B)

-   The combination of aspirin and clopidogrel is not advised for
    secondary stroke prophylaxis due to increased risk of adverse events
    demonstrated in the MATCH trial. (Level B)

## Recommendations for the use of clopidogrel in noncardiac stenting^15^

-   Patients who undergo carotid artery stenting may be initiated on
    clopidogrel 75 mg/day and continued for 4-6 weeks post stent. (Level
    B)

-   Patients who undergo intracranial stents may require longer
    durations of therapy and can be continued up to 1 year. (Level B)

-   Patients who undergo renal artery stenting may be initiated on
    clopidogrel 75 mg daily for up to 12 months post intervention. (
    Level I)

-   Patients who undergo other peripheral stents (inguinal, popliteal,
    etc) may be continued on clopidogrel 75 mg daily for 30 days post
    intervention. ( Level C)

# Recommendation Grading

  ------- ------------------------------------------------------------------
  **A**   A strong recommendation that the intervention is always indicated
          and acceptable

  **B**   A recommendation that the intervention may be useful/effective

  **C**   A recommendation that the intervention may be considered

  **D**   A Recommend that a procedure may be considered not useful /
          effective, or may be harmful.

  **I**   Insufficient evidence to recommend for or against -- the clinician
          will use their clinical judgment
  ------- ------------------------------------------------------------------

**[References]{.underline}**

1.  Smith SC, Feldman TE, Hirshfeld JW, et al. ACC/AHA/SCAI 2005
    Guideline Update for Percutaneous Coronary Intervention-Summary
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2.  Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA Guidelines for the
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    extremity, renal, mesenteric and abdominal arota). Accessed January
    17, 2006 <http://www.acc.org/clinical/guidelines/pad/index.pdf>

3.  Yusuf S, Mehts SR, Zhaao F, et al. Early and late effects of
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4.  Clagett GP, Sobel M, Jackson MR, et al. Antithrombotic therapy in
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5.  Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during
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6.  Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy
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7.  Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic
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8.  Weintraub WS, Mahoney EM, Lamy A, et al; CURE Study Investigators.
    Long-term cost-effectiveness of clopidogrel given for up to one year
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9.  Sabatine MS, Cannon CP, Gibson CM, et al; CLARITY-TIMI 28
    Investigators. Addition of clopidogrel to aspirin and fibrinolytic
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    J Med. 2005 Mar 24;352(12):1179-89.

10. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH investigators.
    Aspirin and clopidogrel compared with clopidogrel alone after recent
    ischemic stroke or transient ischemic attack in high-risk patients
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11. Kastrati A, von Beckerath N, Joost A, et al. Loading with 600 mg
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    5;110(14):1916-9.

12. Jagroop IA, Matsagas MI, Geroulakos G, Mikhailidis DP. The effect of
    clopidogrel, aspirin and both antiplatelet drugs on platelet
    function in patients with peripheral arterial disease. Platelets.
    2004 Mar;15(2):117-25.

13. Patti G, Giusepp C, Pasceri V et al. Randomized Trial of High
    Loading Dos of Clopidogrel for Reduction of Periprocedural
    Myocardial Infarction in Patients Undergoing Coronary Intervention.
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    2005;111:2099-2106.

14. Cannon CP, Mehta SR, Aranki SF. Balancing the Benefit and Risk of
    Oral Antiplatelet Agents in Coronary Artery Bypass Surgery. Ann
    Thorac Surg 2005;80:768-79.

15. Payne DA, Jones CI, Hayes PD et al. Beneficial Effects of
    Clopidogrel Combined with Aspirin in Reducing Cerebral Emboli in
    Patients Undergoing Carotid Endarterectomy. Circulation 2004;
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16. Chan FKL, Ching JYL, Hung LCT, et al. Clopidogel versus aspirin and
    esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med
    2005;352:238-44.

17. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and Aspirin versus
    Aspirin Alone for the Prevention of Atherothrombotic Events. N Engl
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18. Hahn SA, Chandler C. Diagnosis and management of ST elevation
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19. Sabatine MS, Morrow DA, Montalescot G, et al; Clopidogrel as
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    outcomes in patients receiving low-molecular-weight heparin versus
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20. Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive
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21. Sacco RL, Adams R, Albers G, et al; American Heart
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22. Park DW, Park SW, Park KH,et al. Frequency of and risk factors for
    stent thrombosis after drug-eluting stent implantation during
    long-term follow-up. Am J Cardiol. 2006 Aug 1;98(3):352-6.

23. Buhk JH, Wellmer A, Knauth M.Late in-stent thrombosis following
    carotid angioplasty and stenting. Neurology. 2006 May
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24. Stone GW, Aronow HD. Long-term care after percutaneous coronary
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25. Urban P, Gershlick AH, Guagliumi G, e-Cypher Investigators. Safety
    of coronary sirolimus-eluting stents in daily clinical practice:
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    21;113(11):1434-41.

26. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent
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27. Iakovou I, Schmidt T, Bonizzoni E,et al. Incidence, predictors, and
    outcome of thrombosis after successful implantation of drug-eluting
    stents. JAMA. 2005 May 4;293(17):2126-30.

28. Zimarino M, Renda G, De Caterina R. Optimal duration of antiplatelet
    therapy in recipients of coronary drug-eluting stents. Drugs.
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29. Spertus JA, Kettelkamp R, Vance C,et al. Prevalence, predictors, and
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> PREMIER registry. Circulation. 2006 Jun 20;113(24):2803-9.

30. Pfisterer ME. Basel Stent Cost-effectiveness Trial-Late Thrombotic
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    Atlanta, GA**.** 2006

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#  Criteria Checklist for Clopidogrel

Pharmacy Benefits Management Strategic Healthcare Group and the Medical
Advisory Panel

+-----------------------------------------------------------+----------+
| ***Indication for therapy***                              | ***Res   |
|                                                           | ponse*** |
+-----------------------------------------------------------+----------+
| Patient with one of the following conditions:             | -   yes  |
|                                                           |          |
| -   unstable angina                                       | -   no   |
|                                                           |          |
| -   Acute coronary syndrome( NSTEMI or STEMI)             | ***If    |
|                                                           | no,      |
| -   Post PCI/stent placement                              | patient  |
|                                                           | is       |
| -   Documented aspirin allergy requiring antiplatelet     | in       |
|     therapy                                               | eligible |
|                                                           | to       |
| -   Intracranial/carotid stent                            | receive  |
|                                                           | clopid   |
| -   Brachytherapy                                         | ogrel*** |
|                                                           |          |
| -   Peripheral stent (renal, inguinal, popliteal)         |          |
|                                                           |          |
| -   Cerebrovascular disease with recurrent ischemia       |          |
+-----------------------------------------------------------+----------+
| ***Duration of therapy***                                 |          |
+-----------------------------------------------------------+----------+
| -   1 month-post stent placement                          |          |
|                                                           |          |
| -   3 months- post ACS                                    |          |
|                                                           |          |
| -   9 months- high risk post ACS                          |          |
|                                                           |          |
| -   12 month- post stent placement                        |          |
|                                                           |          |
| -   Indefinite- left main DES, DES of bifurcations,       |          |
|     overlapping DES, prior history of late stent          |          |
|     thrombosis, and DES of bypass graft                   |          |
|                                                           |          |
| -   indefinite- aspirin allergic patient                  |          |
|                                                           |          |
| -   peripheral stent duration\_\_\_\_\_\_ months          |          |
|                                                           |          |
| -   other                                                 |          |
|     \_\_\_\_\_\_\_\_\                                     |          |
| _\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ |          |
+-----------------------------------------------------------+----------+
| ***Dosing***                                              |          |
+-----------------------------------------------------------+----------+
| -   ACS- 300 mg load orally then daily dose of 75 mg      |          |
|                                                           |          |
| -   ACS-600 mg load orally than daily dose of 75 mg       |          |
|                                                           |          |
| -   Post stent placement-300 mg load orally then daily    |          |
|     dose of 75 mg                                         |          |
|                                                           |          |
| -   Non acute conditions- 75 mg daily                     |          |
+-----------------------------------------------------------+----------+
| ***Monitoring***                                          |          |
+-----------------------------------------------------------+----------+
| -   Out-patients should have a cardiology referral for    |          |
|     indefinite ACS use or longer than 3 month occurrence  |          |
|     of ACS                                                |          |
|                                                           |          |
| -   Patients with cerebrovascular disease should have a   |          |
|     neurology referral if clopidogrel and aspirin are     |          |
|     used together                                         |          |
|                                                           |          |
| -   Patients should be followed for development of        |          |
|     neutropenia or thrombotic thrombocytopenic purpura    |          |
+-----------------------------------------------------------+----------+
| ***Contraindications***                                   |          |
+-----------------------------------------------------------+----------+
| Any of the following:                                     | -   yes  |
|                                                           |          |
| -   Active bleeding                                       | -   no   |
|                                                           |          |
| -   History of bleeding diathesis                         | ***If    |
|                                                           | yes,     |
| -   Known hypersensitivity to clopidogrel or any          | patient  |
|     component of the product                              | is       |
|                                                           | in       |
|                                                           | eligible |
|                                                           | to       |
|                                                           | receive  |
|                                                           | clopid   |
|                                                           | ogrel*** |
+-----------------------------------------------------------+----------+