Aspirin intolerance is defined as either a proven

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Aspirin intolerance is defined as either a proven

    Protocol for Oral Antiplatelet Therapy

    Approved by the All Wales Medicine Strategy Group (AWMSG) on 12 August 2009

Primary prevention of Aspirin 75mg daily provided blood pressure is controlled No clinical evidence to (1) vascular events in high-risk support the use of other (< 145/90 mmHg) groups antiplatelet drugs for A Cochrane review concluded that for primary prevention primary prevention and in patients with elevated blood pressure antiplatelet they are not licensed therapy with aspirin cannot be recommended since the for this indication. magnitude of the benefit, reduced myocardial infarctions, is similar to the magnitude of harm, increased major (2) haemorrhagic events Further trials are in progress. High-risk groups are those with a 10 year CVD risk ? 20% and aged over 50 years, patients with diabetes ? 50

    years of age, those who have had diabetes > 10 years

    and patients with diabetes who are receiving (1)antihypertensive treatment

    A recent trial found that aspirin was ineffective for the

    primary prevention of cardiovascular events in patients

    with diabetes and asymptomatic peripheral arterial

    disease. However studies with sufficient power are

    required to confirm these findings a small absolute (3) benefit may remain a possibility.

    Current evidence does not support the use of a

    combination of aspirin and clopidogrel. The CHARISMA (4)study concluded that in a high-risk population overall,

    clopidogrel plus aspirin was not significantly more effective

    than aspirin alone in reducing the rate of MI, stroke or

    death from cardiovascular causes.

    Acute ischaemic stroke/ Aspirin 300mg daily should be commenced within 48hours Clopidogrel 75mg (5)(6)Transient ischaemic attack of ischaemic stroke and continued for at least 14 days. evidence for daily

    (TIA) its use in recurrent TIAs MR-Dipyridamole 200mg twice daily PLUS aspirin 75mg where resistance to (NOT associated with atrial daily for a period of 2 years (based on 2 year trial aspirin is suspected is fibrillation) evidence from the ESPS-2 study) from the most recent still awaited. event. Thereafter, or if MR dipyridamole not tolerated,

     SPC states: clopidogrel preventative therapy should revert to standard care

     cannot be (including long-term treatment with low dose aspirin 50-(6)recommended in acute 325mg daily) In practice, aspirin 75mg daily is generally ischaemic stroke. used in the UK. The decision to continue or discontinue dipyridamole beyond 2 years should be made after Initiate from 7 days until appropriate assessment of risks and benefits on an less than six months individual basis. after the ischaemic

    stroke. Note-NICE intends to conduct a review of TA 90. The (7) ESPRIT trial (aspirin versus combination aspirin and dipyridamole) where patients were followed for a mean of (8) 3.5 years and the PRoFESS trial (combination aspirin and dipyridamole versus clopidogrel) have been published since the original appraisal.

    Protocol for Oral Antiplatelet Therapy

    For patients intolerant to dipyridamole: Aspirin 75mg (6)daily.

     There is no consensus on the best approach for patients

    who continue to have TIAs or have a further ischaemic

    stroke. Current evidence does not support the use of a (9)combination of aspirin and clopidogrel (or of MR-

    dipyridamole alone, or standard-release dipyridamole ;

    aspirin). Such patients should be investigated fully for

    potential causes of further ischaemic strokes or TIAs.

    (6)Peripheral arterial disease Aspirin 75mg daily Clopidogrel 75mg daily (6).(symptomatic)

    Atrial fibrillation Warfarin is highly effective in the prevention of stroke in No clinical evidence to

    atrial fibrillation, with a 64% risk reduction compared with support the use of other (10).22% for aspirin antiplatelet drugs for

    primary prevention and However for patients at ‗low-risk‘ of stroke or they are not licensed thromboembolism (less than 65yrs of age with no for this indication. moderate or high risk factors): Aspirin 75mg to 300mg (11)daily if no contraindications.

    Consider anticoagulation or aspirin in patients at moderate

    risk ( 65 years of age or older with no high risk factors or

    age less than 75 years with hypertension, diabetes or

    vascular disease)

    Consider aspirin for moderate or high risk patients who

    have contraindications to warfarin.

    No clinical evidence for the combination of clopidogrel and

    aspirin in preference to warfarin for the prevention of

    vascular events in patients with AF at high risk of stroke (12)the ACTIVE-W study was stopped early due to a

    significant difference in efficacy in favour of warfarin.

    Valve disease For patients with rheumatic mitral valve disease not

    candidates for warfarin: Aspirin 75mg daily

    Valve surgery In combination with warfarin, for specific indications, MR-Dipyridamole accordingto the analysis of the benefit and the increased 200mg twice daily (13)risk of majorbleeding. (14)Aspirin 75mg daily commonly prescribed

    There is no evidence to support the long-term use of

    antiplatelet agents in patients with a bioprosthesis who do

    not have an indication other than the presence of the . (14)bioprosthesis itself

    Acute coronary syndromes In people who are at moderate to high risk of MI or death: Clopidogrel

    (ACS) without persistent ST-monotherapy should be With or without PCI: Initially 300mg clopidogrel and segment elevation (NSTEMI) considered as an 150mg (-325mg) aspirin as stat doses then, alternative treatment. clopidogrel 75mg daily PLUS aspirin 75-325mg daily for up to twelve months after the most recent episode of (15) NSTEMI ACS, thereafter aspirin 75-325mg dailyunless

    there are other indications to continue dual antiplatelet

    therapy.(N.B. Aspirin 75mg daily is generally used in UK)

    Clopidogrel ST elevation MI (STEMI) Initiate, during the first 24 hours after the MI ,clopidogrel monotherapy should be 300mg stat (in patients less than 75 years of age) and considered as an then 75mg daily in combination with aspirin 300mg stat alternative treatment. and then 75mg daily and continue for at least four weeks(16)

    For patients unable to Thereafter, standard treatment including low-dose aspirin tolerate either aspirin or should be given, unless there are other indications to

    Page 2 of 10

    Protocol for Oral Antiplatelet Therapy

    continue dual antiplatelet therapy e.g. coronary stenting clopidogrel, treatment (17). with moderate-intensity

    warfarin (INR 23) For patients intolerant to clopidogrel and have a low risk of should be considered bleeding, treatment with aspirin and moderate-intensity (17)for up to four years, and warfarin (INR 23) combined should be considered see (17).possibly longer information on page 4 on co-prescribing

    Post-CABG Aspirin 300mg daily for first 12 months then aspirin (75-Clopidogrel 75mg daily (18)(19)325mg) daily continued indefinitely (‗OFF LABEL‘ use)

    Aspirin 75mg daily continued indefinitely Post-carotid endarterectomy

    Both types of stent (Bare Metal and Drug Eluting) require Elective PCI (without recent (20):the use of an antiplatelet drug in addition to aspirin acute coronary syndrome) Bare Metal Stent (BMS) Aspirin (75mg - 300mg daily NOTE: Do not discontinue for one month then 75mg daily (lifelong) PLUS combination early except in clopidogrel 300mg stat at least 6 hours before PCI then exceptional circumstances. 75mg daily for one month. (if patient has bare metal stent and NSTEMI ACS then

    the latter takes precedence i.e. patient will be on

    clopidogrel for twelve months)

    Drug Eluting Stent (DES) Aspirin 300mg daily for one

    month reducing to 75mg daily thereafter (lifelong)

    PLUS clopidogrel 300mg stat at least 6 hours before

    PCI then 75mg daily for twelve months.(see part review

    of NICE TAG 71 (Final appraisal determination)

    Dosage and duration of antiplatelet therapy may vary

    amongst interventional cardiologists depending on

    complexity of coronary intervention/type of stents -

    patients will have detailed instructions as to

    recommendations. Antiplatelet therapy should not be

    stopped earlier than recommended (particularly with

    DESs) without discussing the case with a cardiologist


    There is little evidence to support advice on how best to

    manage patients who have both AF and a DES who also (21)require anticoagulation

    All existing patients with a history of prior stroke/TIA, MI and those with chronic stable angina should be on

    aspirin 75mg daily, as a minimum, unless contraindicated.


    For full prescribing information consult the Summary of Product Characteristics (SmPC).

Aspirin intolerance is defined by NICE as either: a proven hypersensitivity to aspirin-containing (6)medicines or a history of severe dyspepsia caused by low-dose aspirin .

    Page 3 of 10

    Protocol for Oral Antiplatelet Therapy

    Intolerance to antiplatelet doses of aspirin can take many forms, but four types of reaction are commonly cited: Gastrointestinal (GI), haemorrhage, allergy and bronchospasm.

For patients experiencing gastrointestinal symptoms with aspirin:-

     Ensure 75mg dose is being taken and that medication is taken with food.

     Consider co-prescribing a proton pump inhibitor (PPI) e.g. lansoprazole 15mg or omeprazole

    20mg daily (check outcome)

     Evidence from two studies supports this approach:

     The combination of aspirin (80mg daily) plus esomeprazole (20mg twice daily) (n=159) was

     superior to clopidogrel (75mg daily) (n=161) in preventing recurrent ulcer bleeding at 12 (22) months .

     Patients with aspirin- induced peptic ulcer (low to moderate risk of bleeding or rebleeding)

     were randomised to either a combination of aspirin 100mg plus omeprazole 20mg daily or a

     combination of clopidogrel 75mg plus omeprazole 20mg daily with no difference in GI (23) outcomes at eight weeks .

    Summary of contra-indications/special precautions that apply to clopidogrel and aspirin:

     Use aspirin? Use clopidogrel?

    Active pathological No No

    bleeding (e.g. peptic


    (22,23)History of Recent studies Caution - patients should be

    peptic/duodenal ulcer suggest use cautiously followed carefully for any signs of

    with PPI bleeding

    Clotting/bleeding No Caution - patients should be

    disorders (e.g. followed carefully for any signs of

    haemophilia) bleeding

    Aspirin allergy (e.g. rash) No Yes - note rash still seen with

    clopidogrel (uncommon >1/1,000,


    History of asthma Caution Yes

    Under 16 years old No Unlicensed in children and


    Breast-feeding No No

     (24) Recurrent vascular events in patients taking aspirin have many possible causes .

    Prescribers should be aware of the potential for ibuprofen to reduce the effectiveness of

    aspirin, although the evidence from observational studies does not yet confirm a clinically

    important effect. Consideration can be given to taking the aspirin and ibuprofen at different (25)times of the day

Aspirin and warfarin in combination

    For patients already on aspirin commencing warfarin for atrial fibrillation:

     Start low dose warfarin and stop aspirin at the same time (the advice to GP to stop aspirin

    once INR reaches 2 is considered probably unnecessary and may risk inadvertent co-

    prescribing in Primary Care)

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    Protocol for Oral Antiplatelet Therapy

     Patients admitted to secondary care on aspirin for AF generally stay on aspirin until the INR

    is therapeutic.

For patients with recent coronary events with an additional indication for long-term anticoagulation:

    The decision to co-prescribe aspirin and warfarin will depend on the perceived risk of future coronary events according to non-invasive +/- angiography data by the physician in Secondary Care. Combination therapy was associated with a significant reduction in the combined risk of death, non-(26)fatal MI or thromboembolic stroke in the WARIS II study . Rate ratio as compared with aspirin =

    0.71 (95% CI, 0.60 to 0.83; P=0.001). Patients with recent coronary events with an additional indication for long-term anticoagulation (e.g. AF, previous DVT or prosthetic heart valve) will be likely candidates.

     Patients should be counselled at initiation on the increased risk of bleeding.

     Consideration should be given to prescribing a prophylactic PPI.

     ?Clopidogrel (Plavix) (16)For full prescribing information consult the Summary of Product Characteristics (SmPC).


    The prevention of atherothrombotic events in:

    Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Patients suffering from non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction) including patients undergoing a stent placement following percutaneous coronary intervention in combination with aspirin 75mg daily. -ST segment elevation acute MI in combination with aspirin in medically treated patients eligible for thrombolytic therapy.

     The indication and duration of clopidogrel should be clearly recorded and, where relevant,

    communicated between secondary and primary care.

     The duration of treatment of clopidogrel should be documented and flagged on GP clinical

    system for patients with unstable angina/ACS or stents.

     Patients should be advised to inform other practitioners/prescribers that they are taking

    clopidogrel. For elective surgical/dental procedures, in which an antiplatelet effect is not

    required clopidogrel should be discontinued 7 days before surgery.

    Is clopidogrel safer/better tolerated than aspirin? (27)In the CAPRIE study clopidogrel was compared head-to-head with aspirin. Although all

    reported GI haemorrhage was less common with clopidogrel (1.99% vs. 2.66%, P < 0.05) the

    dose of aspirin used was 325mg daily. Severe rash was more common with clopidogrel (0.26%

    vs. 0.1%, P = 0.017) than with aspirin although one of the trial‘s exclusion criteria was a history

    of aspirin sensitivity.

    Yellow Card submissions for suspected adverse reactions for Adverse event No. clopidogrel (to the MHRA up to November 2008) indicate that

    GI haemorrhage 100 GI haemorrhage is the most frequently reported event. Rash,

    pruritis and urticaria have also been commonly reported (see Contusion/brusiing 97

    table at right). Haematological effects have also been reported; Haematemesis 83

    most notably neutropenia and thrombocytopenia (32 and 45 Rash 71

    reports respectively). Pruritis 74

    Urticaria 66

    Page 5 of 10

    Protocol for Oral Antiplatelet Therapy

Current evidence does not support using clopidogrel in combination with a PPI.

There have also been preliminary reports, currently being investigated by the manufacturers, that (28) PPIs may make clopidogrel less effective The following advice was issued recently from MHRA (29)and CHM

     Review the need for PPI therapy in patients who are also taking clopidogrel and avoid

    concomitant use of these medicines unless considered essential.

     Prescribe PPIs in line with their licensed indications wherever possible.

     Consider whether another gastrointestinal therapy would be more suitable

     Check whether patients who are taking clopidogrel are buying over-the-counter omeprazole.

    ; Is the combination of aspirin and clopidogrel safe?

    Results from the CLARITY-TIMI 28 and COMMIT studies suggest that short-term concomitant

    use (up to 16 days) is not associated with an increase in bleeding complications. However, three (30)(9)(4)longer-term studies (CURE , MATCH , and CHARISMA ) found statistically significant

    increases in bleeding associated with the combination of clopidogrel plus aspirin (compared to

    either clopidogrel or aspirin used alone):

    Trial Event Rate with Rate with Rate with P value

    Clopidogrel Aspirin Clopidogrel

    +Aspirin alone alone

    MATCH Life-threatening 2.6% 1.3% <0.0001


    CURE Major bleeding 3.7% 2.7% 0.001

    CHARISMA Moderate 2.1% 1.3% <0.001


     Patients taking aspirin and clopidogrel should be advised of the risks.

     When co-prescribed with clopidogrel, the total daily dose of aspirin should not exceed 100mg.

     ?Dipyridamole 200mg M/R (Persantin Retard)

    For full prescribing information consult the Summary of Product Characteristics (SmPC)


    Secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in conjunction with aspirin.‘ (NOTE the 25mg and 100mg preparations of dipyridamole do not have this ?indication although Asasantin does)

    An adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated with prosthetic heart valves.

     ?The only contraindication to Persantin Retard is hypersensitivity to any of its constituents. It should be used with caution in patients with bleeding disorders. (31)In the large (n = 6602) European Stroke Prevention Study found that bleeding episodes (any site)

    were significantly more frequent in the MR-dipyridamole plus aspirin (8.7%) and the aspirin alone (8.2%) groups compared with the MR-dipyridamole alone (4.7%) and placebo (4.2%) groups.

    Page 6 of 10

    Protocol for Oral Antiplatelet Therapy

    As an indication of frequency of adverse events with dipyridamole (all preparations including Asasantin) the table below lists the Yellow Card submissions for suspected adverse reactions to the MHRA up to November 2008) in order of frequency:

     Adverse event No. Headache 142 Diarrhoea 50 Dizziness 48 Rash 33 Vomiting 39

    Dipyridamole acts as a potent vasodilator. It should therefore be used with caution in patients with severe coronary artery disease including unstable angina and/or recent MI, left ventricular outflow obstruction or haemodynamic instability (e.g. decompensated heart failure).

Peri-operative management of anti-platelets

     Although some surgery can be completed without suspension of clopidogrel, most surgeons

    would prefer a 5-7 day dose-free period prior to any elective surgery. The SPC for clopidogrel

    states that ―if a patient is to undergo elective surgery and antiplatelet effect is not

    necessary,clopidogrel should be discontinued 7 days prior to surgery‖.

     However it is extremely important that due consideration is given to the indication for

    clopidogrel and aspirin use. Decisions on when to stop antiplatelets are needed on a case-

    by-case basis based on patient-and procedure-related risk factors for thrombosis and

    bleeding, weighing up anti-platelet indications (e.g. primary prevention, high or low risk (32). secondary prevention) against timing and type of surgery

     If given for primary prevention of cardiovascular disease aspirin can generally be

    discontinued 10 days before surgery and clopidogrel can be discontinued 7 days before (32) . surgery

     Serious thrombotic risks are associated with the discontinuation of these agents when used (32). as secondary prevention of vascular disease or after coronary revascularisation

     Patients requiring elective surgery and who are receiving dual antiplatelet therapy should

    ideally, have surgery postponed until the recommended duration of clopidogrel is finished. If

    such a delay is unacceptable the cardiologist, the surgeon and the anaesthetist should

    consider the balance of perioperative risk (for example stent thrombosis) compared with the possibility of increased surgical bleeding related to the procedure.

    Page 7 of 10

    Protocol for Oral Antiplatelet Therapy

    Relative costs of oral antiplatelet therapy

Primary care costs of 28 days treatment with oral antiplatlets (Drug Tariff July 2009)

    0.82 Aspirin disp 75mg od

    2.56 Aspirin disp 75mg od and omeprazole 20mg od

    7.82 Aspirin disp 75mg od and dipyridamole MR 200mg bd

    Aspirin disp 75mg od and omeprazole 20mg bd 4.3

     Clopidogrel 75mg od 33.92

     0 5 10 15 20 25 30 35 40 Value(?)

    Page 8 of 10

    Protocol for Oral Antiplatelet Therapy


    1. National Library for Health. Available at: treatment

     (accessed 11/03/09)

    2. Lip GYH, Felmeden DC. Antiplatelet agents and anticoagulants for hypertension. Cochrane

    Database of Systematic Reviews 2004, Issue 3. 10.1002/14651858.CD003186.pub2.

    3. Belch Je t al The prevention of progression of arterial disease and diabetes (POPADAD) trial:

    factorial randomised placebo-controlled trial of aspirin and antioxidants in patients with

    diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840. 4. Bhatt DL et al. Clopidogrel and aspirin versus aspirin alone for the prevention of

    atherothrombotic events (CHARISMA study) New Engl J Med 2006;354:17061717

    5. Anon. Management of patients with stroke or TIA SIGN 2008 Guideline No 108 6. Anon. Clopidogrel and modified-release dipyridamole in the prevention of occlusive vascular

    events. NICE Technology Appraisal90 May 2005 Note

    NICE is currently conducting a review of TA 90

    7. The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral

    ischaemia of arterial origin (ESPRIT): randomised controlled trial. The Lancet


    8. Sacco RL et al (for the PRoFESS Study Group) Aspirin and extended-release dipyridamole

    versus clopidogrel for recurrent stroke. N Eng J Med 2008: 359:1238-1251 9. Diener H-C et al (the MATCH Investigators). Aspirin and clopidogrel compared with

    clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high risk

    patients (MATCH):randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-


    10. Hart RG et al. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have

    nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867.

    11. Anon 2006 NICE Clinical Guideline 36 Atrial fibrillation. 2006


    12. Connolly S et al Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the

    Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE

    W): a randomised controlled trial. The ACTIVE Investigators. Lancet 2006; 367: 1903-1912.

    13. Vahanian A et al (The Task Force on the Management of Valvular Heart Disease of the

    European Society Cardiology) Eur Heart J 2007;. 28: 230-268.

    14. Little SH, Massel DR. Antiplatelet and anticoagulation for patients with prosthetic heart valves.

    Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003464. DOI:


    15. Anon. NICE TA080 Clopidogrel in the treatment of non-ST-segment-elevation acute coronary

    syndrome. NICE Technology Appraisal 80 July 2004 (

    16. Plavix. Summary of product characteristics (www.emc updated 28/09/07

    17. Anon. NICE CG048 MI: secondary prevention. NICE Clinical Guideline 48 May 2007 18.Lim E et al. Indirect comparison meta- analysis of aspirin therapy after coronary surgery.

     BMJ ;327:1309-1313.

    19.Bhatt DL et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery Circulation 2001;103:363-368.

    20. Anon. Drug-eluting stents for the treatment of coronary artery disease NICE Technology Appraisal 71 2003NICE TA071 Ischaemic heart disease - coronary artery stents. 2003. Note

    NICE is currently conducting a part review of TA71. (

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    Protocol for Oral Antiplatelet Therapy

    21.Silber S et al. ESC Guidelines for Percutaneous Coronary Interventions. European Heart

    Journal 2005

    22. Chan FKL et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer

    bleeding N Engl J Med 2005;352:238-244.

    23. Ng FH et al. Clopidogrel plus omeprazole compared with aspirin plus omeprazole for aspirin-

    induced symptomatic peptic ulcers / erosions with low to moderate bleeding / re-bleeding risk

    a single-blind, randomized controlled study. Alimentary Pharmacology and Therapeutics 2004;

    19(3): 359365.

    24. Hankey, GJ Eikelboom JW Aspirin resistance BMJ 2004;328:477-479

    25. Anon. Cardiovascular and gastrointestinal safety of NSAIDs .MeReC Extra Issue 2008: No


    26.Hurlen M et al. Warfarin, aspirin or both after myocardial infarction N Engl J Med


    27.CAPRIE Steering Committee. A randomised ,blinded, trial of clopidogrel versus aspirin in

    patients at risk of ischaemic events (CAPRIE) Lancet 1996;348:1329-1339

    28. Anon NPCi Blog. FDA investigates possible safety concerns over clopidogrel

    29.Anon. Clopidogrel and proton pump inhibitors: interaction. Drug Safety Update 2009:2(12)2-3

    30.The CURE Investigators. Effects of clopidogrel in addition to aspirin in patients with acute

    coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.

    31. Diener H-C et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid

    in the secondary prevention of stroke. (ESPS-2) J Neurol Sci 1996;142:1-13.

    32. Thachil J et al Management of surgical patients receiving anticoagulation and antiplatelet

    agents. British Journal of Surgery 2008 ;95 :1437-1448

Further Information

    MeReC Bulletin Volume 15, Number 6 (July 2005) Prescribing antiplatelet drugs in primary care.

    WeMeReC Bulletin Volume 11, Number 1 (February 2004) Prescribing clopidogrel.

    MeReC Bulletin Volume 14, Number 2 (August 2003) Antiplatelet agents for stroke patients.

    Update: National Clinical Guidelines for Stroke , 3rd edition , RCP, & Clinical Effectiveness and Evaluation Unit . Page 67

    The All Wales Prescribing Advisory Group (AWPAG) wish to acknowledge the contribution of Jonathan Simms, Stuart Evans, Trevor Batt and Robert McArtney in the development of this document.

    Page 10 of 10

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