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  • We have been using clopidogrel for just over 10 years now. There is good evidence base for its use- defining trials I will show you today.
  • Fibrinogen bridges between platelets
  • 1 st study: Less indigestion, GI haemorrhage, LFTs derangement
  • Clopidogrel as adjunctive reperfusion therapy N= 3491 Fibrinolytic agent plus aspirin pre PCI within 24 hours of STEMI
  • PCI reduces length of stay Reasons why stents do not work: balloon angioplasty and rupture of atheromatous plaque exposes vasculature- thrombogenic (platelet activation)
  • BMS- overgranulation within stent of endothelial lining cf hypertrophic scars reduces lumen size of vessel DES- antineoplastic agents inhibit miotic processes- prevent endothelialisation- for how long? Devices not drugs- 6/12 evidence
  • Description: To evaluate the incidence, predictors, and clinical outcome of stent thrombosis after implantation of sirolimus-eluting (SES) and paclitaxel-eluting stents (PES) in routine clinical practice, investigators conducted a prospective observational cohort study in Germany and Italy. A total of 2,229 consecutive patients underwent successful SES implantation (1,062 patients, 1,996 lesions, 2,272 stents) or PES implantation (1,167 patients, 1,801 lesions, 2,223 stents). Independent predictors of subacute, late, and cumulative stent thrombosis are shown here. The key predictors of stent thrombosis were premature antiplatelet therapy discontinuation, renal failure, bifurcation lesions, diabetes, and low ejection fraction. For subacute thrombosis, stent length was also a predictor: for each 1 mm increase in length, there was 1.03 times greater risk of thrombosis. Citation: Reproduced with permission from the American Medical Association. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30. Copyrighted 2000, American Medical Association.
  • With more widespread use of clopidogrel, investigators have been interested in determining the risk of late thrombotic events when clopidogrel treatment is withdrawn. At ACC 06, results from the Late Clinical Events Related to Late Stent Thrombosis After Stopping Clopidogrel (BASKET LATE) trial showed a significantly greater incidence of cardiac death or MI in DES patients (n = 499) compared to BMS patients (n = 244) following discontinuation of clopidogrel (Slide 3). Although not reaching statistical significance, late stent thrombosis occurred twice as frequently among the DES versus BMS patients (2.6% vs. 1.3%, p = 0.23). Median time to a late thrombotic event was 116 days after clopidogrel discontinuation, but events occurred throughout the 12-month follow-up.
  • Given the available evidence, the bottom-line risk of stent thrombosis is still a hot topic. A paper presented at the 2006 ESC meeting drew considerable attention among attendees. In a meta-analysis of first-generation DES versus BMS, investigators evaluated all available data from company-supported randomized trials, including a total of 878 SES patients (who were compared to 870 BMS recipients) and 1,685 PES patients (versus 1,675 BMS controls). The focus was on rates of death or Q-wave MI as these were thought to reflect the incidence of stent thrombosis best. Based on the latest available follow-up (up to 3 years), the evidence suggests greater caution is needed in the widespread use of DES: death or Q-wave MI was 38% higher with sirolimus-eluting stents and 16% higher with paclitaxel-eluting stents versus BMS (Slide 4). The investigators cautioned against the systematic use of drug-eluting stenting and called for more risk-benefit analyses.
  • Cadaver data: Regrowth of vessel wall within 6 months with BMS
  • Swedish registry data (2006) risk of combination antiplatelets: OR adjusted for corticosteroid use, recent GI bleed Clopidogrel not in TxA2/COX pathway so not inhibit gastric mucosal protection Aspirin and clopidogrel increases GI bleeding risk 7 fold compared to the 4 fold increased risk of MI if stop Tx
  • Aspirin allergy lifelong: if GI intolerance use aspirin plus high-dose PPI (NEJM 2005) 8.6% recurrent bleeding with clopidogrel after 12 months and 0.7% incidence with PPI.
  • Improved since last audit as mechanisms put in lace by hospital trusts: cannot dispense clopidpgrel without duration or cannot electronically prescribe without duration and indication
  • Licensed in Germany
  • Clopidogrelincardiol..

    1. 1. Clopidogrel in Cardiology Patients Rachel Hughes Specialist cardiology pharmacist GSTFT 22/11/07
    2. 2. Introduction <ul><li>Evidence for clopidogrel use </li></ul><ul><ul><li>Stroke </li></ul></ul><ul><ul><li>NSTEMI/ACS </li></ul></ul><ul><ul><li>STEMI </li></ul></ul><ul><ul><li>PCI: BMS/DES </li></ul></ul><ul><li>Risk: benefit profile </li></ul><ul><li>SELCN guidance </li></ul><ul><li>Clopidogrel cards </li></ul>
    3. 3. Platelet Function Thrombin TxA2 ADP heparin aspirin ticlopidine clopidogrel Glycoprotein IIb/IIIa Platelet abciximab
    4. 4. CAPRIE study Lancet 1996, 348: 1329-1339 <ul><li>N = 19,185, multicentre double-blind trial </li></ul><ul><li>Clopidogrel reduces the risk of death/MI/stroke in patients with previous MI, stroke or PVD by RRR 8.7% compared to high-dose aspirin </li></ul><ul><li>For every 1000 patients treated 5 combined end points would be prevented </li></ul><ul><li>NNT 200 patients </li></ul><ul><li>A/E: diarrhoea, rash </li></ul><ul><li>Increased cost to NHS £200,000 </li></ul><ul><li>Super aspirin will save your life </li></ul>
    5. 5. Ringleb, P. A. et al. Stroke 2004;35:528-532
    6. 6. CURE NEJM 2001; 345: 494-502 <ul><li>Clopidogrel vs placebo in 12,562 pts with ACS </li></ul><ul><ul><li>Inclusions: </li></ul></ul><ul><ul><ul><li>ECG changes (no ST elevation) or </li></ul></ul></ul><ul><ul><ul><li> cardiac enzymes </li></ul></ul></ul><ul><ul><li>Exclusions: </li></ul></ul><ul><ul><ul><li>C/I to antithrombotic or antiplatelet therapy </li></ul></ul></ul><ul><ul><ul><li>pts. with high risk of bleeding (?criteria) </li></ul></ul></ul><ul><ul><ul><li>severe heart failure </li></ul></ul></ul><ul><ul><ul><li>PCI or CV surgery within past 3 months </li></ul></ul></ul><ul><ul><ul><li>GPIIb/IIIa within last 3 days </li></ul></ul></ul>
    7. 7. CURE - Methods <ul><li>Pts randomised within 24 hrs of admission </li></ul><ul><li>Regimen : Clopidogrel 300mg loading dose then 75mg daily </li></ul><ul><ul><ul><ul><li>vs placebo </li></ul></ul></ul></ul><ul><li>Treated for an average of 9 months (3 - 12 months) </li></ul><ul><li>All patients received baseline Aspirin </li></ul><ul><ul><ul><ul><li>Aspirin doses varied </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Combined with heparin and GP2b3aI (standard) </li></ul></ul></ul></ul><ul><li>Primary outcome: composite of CV death/MI/ stroke </li></ul>
    8. 8. CURE - Results <ul><li>Primary endpoint: </li></ul><ul><ul><li>9.3% clopidogrel vs. 11.4% placebo </li></ul></ul><ul><ul><li>ARR = 2.1%; p<0.001 (on top of standard treatment) </li></ul></ul><ul><ul><li>primarily due to reductions in AMI (5.2 vs. 6.7%) </li></ul></ul><ul><li>Reductions in : </li></ul><ul><ul><li>In-hospital refractory or severe ischaemia </li></ul></ul><ul><ul><li>heart failure </li></ul></ul><ul><ul><li>revascularisation procedures </li></ul></ul>
    9. 9. Primary Outcome - Death / MI / Stroke Cumulative Hazard Rates for the First Primary Outcome (Death from cardiovascular Causes, Nonfatal Myocardial Infarction, or Stroke) during the 12 Months of the Study.
    10. 10. Adverse Effects <ul><li>Major Bleeds </li></ul><ul><ul><li>(disabling bleed, intra-ocular bleed causing blindness or </li></ul></ul><ul><ul><li>bleed requiring > 2 units transfusion) </li></ul></ul><ul><ul><li>3.7% clopidogrel gp vs. 2.7% placebo </li></ul></ul><ul><ul><li>Absolute increased risk of bleed of 1%; p = 0.001 </li></ul></ul><ul><ul><li>no difference in life-threatening bleeds </li></ul></ul><ul><li>Minor bleeds </li></ul><ul><ul><ul><li>(5.1% vs. 2.4%) </li></ul></ul></ul><ul><ul><li>majority of bleeds - GI </li></ul></ul>
    11. 11. NICE TA80- Clopidogrel and NSTEMI/ACS (July 2004) <ul><li>Clopidogrel, together with a low dose of aspirin, should be used for people with non-ST-segment-elevation acute coronary syndrome who have a moderate to high risk of a major heart attack (myocardial infarction) or death. </li></ul><ul><ul><li>New ECG changes </li></ul></ul><ul><ul><li>Blood tests- damage to cardiac tissue </li></ul></ul><ul><li>Treatment with clopidogrel and low-dose aspirin should be continued for up to 12 months after the most recent attack. After this time, doctors should give the normal treatment, which includes a low dose of aspirin. </li></ul>
    12. 12. Timing of Release of Various Biomarkers After Acute Myocardial Infarction Anderson, J. L. et al. J Am Coll Cardiol 2007;50:e1-e157
    13. 13. COMMIT trial <ul><li>Lancet 2005; 366: 1607–21 </li></ul><ul><li>n=45 852 acute MI plus aspirin 162 mg Tx until discharge or up </li></ul><ul><li>to 4 weeks in hospital (mean 15 d) composite end point: </li></ul><ul><li>death, reinfarction, </li></ul><ul><li>or stroke; </li></ul>
    14. 14. PCI- CLARITY JAMA 2005;294:1224–32
    15. 15. NICE guidelines for STEMI <ul><li>After an ST elevation MI patients treated with a combination of aspirin and clopidogrel should continue this treatment for at least 4 weeks. Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy </li></ul>
    16. 16. PCI-CURE Lancet 2001, 358; 527-533 <ul><li>CURE sub-study in 2,658 patients undergoing coronary intervention </li></ul><ul><ul><li>Studying effect of EARLY treatment and LONG-TERM therapy </li></ul></ul><ul><ul><li>Pts randomised early to Clopidogrel 75mg daily or placebo (as for CURE) </li></ul></ul><ul><ul><li>Underwent PCI (median of 10 days post randomisation) and majority treated with Clopidogrel open-label for 4 weeks post-PCI </li></ul></ul><ul><ul><li>Then, re-entered trial at ~40 days post-randomisation to end of follow-up (average 9 months) </li></ul></ul>
    17. 17. PCI - Primary Outcome at 30 days
    18. 18. PCI-CURE End of Follow-up
    19. 19. PCI-CURE results <ul><li>Overall reduction in risk of death or MI of 3.8% from time of randomisation to end of follow-up </li></ul><ul><ul><li>12.6% placebo vs. 8.8% Clopidogrel; p=0.002 </li></ul></ul><ul><li>Majority of benefit gained from randomisation to 30 days post-PCI </li></ul><ul><li>No significant difference in outcome between Clopidogrel and placebo groups from 30 days to end of follow-up </li></ul><ul><ul><li>Similar ARR of 0.5%, as in CAPRIE study </li></ul></ul><ul><li>No excess of bleeds in the Clopidogrel-treated group </li></ul>
    20. 22. Independent risks of stent thrombosis Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126-30
    21. 23. BASKET LATE: Late Thrombotic Events Following Clopidogrel Discontinuation
    22. 24. Meta-Analysis of Stent Trials: Incidence of Serious Adverse Events (Death or MI) Based on Latest Available Follow-up
    23. 25. Endothelialization in Drug-Eluting Stents (DES) Versus Bare-Metal Stents (BMS) Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193-202.
    24. 26. Crude and adjusted odds ratios for association between use of antithrombotic drug and serious upper gastrointestinal bleeding BMJ, doi:10.1136/bmj.38947.697558.AE (published 19 September 2006)
    25. 27. Recommended Clopidogrel Indications and Durations (SELCN) <ul><li>*STEMI – should be given for at least one month but the optimal duration has not yet been established, many local consultants now recommend continuing for one year, as for other ACS </li></ul><ul><li>**Drug-eluting stents – durations of more than one year are being recommended in high-risk patients by some consultants due to concerns regarding late stent thrombosis on cessation of clopidogrel therapy. </li></ul>
    26. 28. “ You never tell us the duration ” <ul><li>Most common complaint from primary to secondary care regarding clopidogrel prescriptions </li></ul><ul><li>Audited communication with primary care on discharge from secondary care: </li></ul><ul><ul><li>Is the indication clear? </li></ul></ul><ul><ul><li>Is the duration clear? </li></ul></ul><ul><ul><li>Was pharmacy involved in clarifying the duration? </li></ul></ul><ul><li>Audited all discharge prescriptions issued during Oct 06 from cardiology across 4 of the 6 acute trusts in SE London </li></ul>
    27. 29. October 2006 audit results <ul><li>249 prescriptions for clopidogrel from 4 acute Trusts were audited </li></ul><ul><li>Indication for clopidogrel were clear on 185 / 249 (74%) </li></ul><ul><ul><li>For 69 of 249 patients (26%) the indication unclear </li></ul></ul><ul><li>Duration of clopidogrel clear on 174 / 249 (70%) </li></ul><ul><ul><li>For 75 of 249 patients (30%) the duration of clopidogrel was unclear </li></ul></ul><ul><ul><li>Duration added or amended by pharmacist on 49/249 (20%) of TTAs </li></ul></ul>
    28. 30. Duration: Recommendations <ul><li>Agree a standard set of durations for use across the sector </li></ul><ul><li>Request that acute Trust pharmacy departments do not dispense clopidogrel unless indication and duration of therapy is clear </li></ul><ul><li>For one month supply at discharge – secondary care to give full supply so no need to add to GP repeat prescribing systems </li></ul><ul><li>All patients to be issued with clopidogrel cards by secondary care </li></ul>
    29. 31. Communication from secondary to primary care- progress……. <ul><li>September 2007 audit for SELondon: </li></ul><ul><li>295 prescriptions for clopidogrel from 4 acute Trusts </li></ul><ul><li>Indication for clopidogrel clear on 273 / 295 (92.5%) </li></ul><ul><ul><li>For 22 of 295 patients (7.5%) the indication unclear </li></ul></ul><ul><li>Duration of clopidogrel clear on 282 / 295 (95.6%) </li></ul><ul><ul><li>For 13 of 295 patients (4.4%) the duration of clopidogrel was unclear </li></ul></ul><ul><ul><li>Duration added or amended by pharmacist on 49/295 (16.6%) of TTAs </li></ul></ul>
    30. 33. “ My patient has developed a rash 3 days after starting clopidogrel ” <ul><li>Clopidogrel has been associated with hypersensitivity reactions, most commonly with the development of skin rashes </li></ul><ul><li>It is UNUSUAL within the first few days of therapy </li></ul><ul><li>The most common cause of a rash is the administration of x-ray contrast dye during the angiogram and / or angioplasty </li></ul>
    31. 34. Recommended management of rash <ul><li>Advise the patient to PERSIST with the clopidogrel therapy for at least another week </li></ul><ul><li>Treat the rash in the short term with an ANTIHISTAMINE either chlorpheniramine 4mg four times a day or a longer-acting non-sedating agent </li></ul><ul><li>ADVISE the patient to contact the GP surgery if the rash worsens within the week or to seek urgent medical advice should any symptoms of serious HYPERSENSITIVITY reaction develop, such as difficulty breathing, swelling of the face, mouth or throat etc. </li></ul><ul><li>DO NOT stop therapy without first consulting the cardiologist: HIGH risk of in-stent thrombosis </li></ul>
    32. 35. “ My patient has a rash after 3 weeks of clopidogrel treatment ” <ul><li>LIKELY to be caused by the clopidogrel, UNLESS there have been any other recent changes in treatment (i.e. the introduction of another new drug) </li></ul><ul><li>Check the DURATION of clopidogrel for the patient: </li></ul><ul><li>If only a further week of therapy (ie. to complete a one month course), PERSIST with therapy, and take a short course of antihistamine to control the symptoms </li></ul><ul><li>MORE than one month (most cases will be), then CONTACT the initiating cardiologist for advice on an alternative therapy </li></ul><ul><li>Due to the high risk of stent thrombosis, clopidogrel should NOT be discontinued prematurely without discussion with the initiating clinician </li></ul>
    33. 36. Alternatives to clopidogrel <ul><li>Ticlopidine works in the same way as clopidogrel, but is unlicensed in the UK </li></ul><ul><li>A higher risk of developing neutropenia during treatment (2%) </li></ul><ul><li>Ticlopidine therapy should usually be initiated under the supervision of the interventional cardiologist at a dose of 250mg BD in combination with low-dose aspirin. </li></ul>
    34. 37. In summary: Take Home Messages <ul><li>The DURATION of therapy and INDICATION for clopidogrel should be clearly stated on the discharge summary and patient-held clopidogrel card </li></ul><ul><li>RISKS of early cessation (in-stent thrombosis) and inappropriate continuation of therapy (GI/intracranial haemorrhage) </li></ul><ul><li>The need for appropriate review by GP: monitor CP, ischaemic episodes, cardiac interventional history BEFORE stopping clopidogrel </li></ul><ul><li>Clopidogrel is NOT an alternative to aspirin if GI intolerance- use aspirin plus PPI </li></ul><ul><li>Rash could not be a complete CI to clopidogrel use: consider other causes of rash and treatment options </li></ul>