1 以實證醫學觀點探討藥物交互作用之影響 Clopidogrel with PPI 臨床藥師 : 邱春吉

11

以實證醫學觀點探討藥物交互作用之影響

Clopidogrel with PPI

臨床藥師 : 邱春吉

22

OutlineOutline

BackgroundBackground

– ClopidogrelClopidogrel 、、 PPIPPI

– Drug interactionDrug interaction

Clinical ScenarioClinical Scenario

EBM EBM : : 5 A5 A

– AskAsk 、、 Acquire Acquire 、、 AppraisalAppraisal 、、 Apply Apply 、、 AA

uditudit

ConclusionConclusion

33

Drug-Drug interaction

Severity Documentation Summary

Clopidogrel-Omeprazole

Major Excellent May result in increased risk for thrombosis

44

Summary Severity Reliability Rating

PPI may diminish the therapeutic effect of clopidogrel

Major Good

55

66

Significance Onset Severity Documentation

4 Delayed Moderate Possible

Effect : The antiplatelet activity of clopidogrel may be decreased by certain PPI

77

The FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others Differences in effectiveness may be due to – (1). genetic differences in the way the body metabolizes

clopidogrel– (2). using certain other drugs with clopidogrel can

interfere with how the body metabolizes clopidogrel.

88

99

ScenarioScenario This is a 58 years female patient who had history This is a 58 years female patient who had history

of DM & HTN and followed up at our Meta OPD. of DM & HTN and followed up at our Meta OPD.

This time, she suffered from chest pain for 2 days. This time, she suffered from chest pain for 2 days.

Due to Due to persisted chest painpersisted chest pain, she was sent to ER. , she was sent to ER.

( 2009/06/18 ). ( 2009/06/18 ).

At ER, EKG At ER, EKG revealedrevealed ST depression over V2-V4ST depression over V2-V4

and and elevated cardiac enzymeelevated cardiac enzyme..

Under the impression of Under the impression of NSTEMINSTEMI,, dual antiplatelet dual antiplatelet

and and heparinheparin were applied. were applied.

Then he was admitted to CCU for further care.Then he was admitted to CCU for further care.

1010Coronary Care Unit

1111NEJM Volume 352(24), 16 June 2005

1212 Lancet 2003

Ⅱa

1313

In CV perspective, Dual therapy is better than monotherapy

In CV perspective, Dual therapy is better than monotherapy

1414

1515

1616

Steps for Minimizing Gastrointestinal Bleeding

J Am Coll Cardiol, 2008; 52:1502-1517

PPI remains the treatment of choice to prevent GI bleeding!

1717

Cytochrome P450 2C19 playing a major role in

the bioactivation of clopidogrel

NEJM 2009;360:363-75

Carriers of a reduced-function CYP2C19 allele

1818

Metabolism of PLAVIX and Omeprazole: Metabolism of PLAVIX and Omeprazole: Potential for Drug–Drug InteractionsPotential for Drug–Drug Interactions

OmeprazoleOmeprazoleOmeprazoleOmeprazole

PLAVIX PLAVIX active active

metabolitemetabolite

PLAVIX PLAVIX active active

metabolitemetabolite

PLAVIX PLAVIX (Inactive Prodrug)(Inactive Prodrug)


Decreased Decreased amount of amount of

PLAVIX PLAVIX metabolitemetabolite

Decreased Decreased amount of amount of

PLAVIX PLAVIX metabolitemetabolite

OmeprazoleOmeprazoleOmeprazoleOmeprazoleOmeprazoleOmeprazole(Inactive Prodrug)(Inactive Prodrug)OmeprazoleOmeprazole(Inactive Prodrug)(Inactive Prodrug)



LIVERLIVERLIVERLIVER

PLAVIX PLAVIX PLAVIX PLAVIX

+ + + +

Gilard M et al. J Am Coll Cardiol. 2008;51:256–60Gilard M et al. J Am Coll Cardiol. 2008;51:256–60

CYP2C19

1919

Diagrammatic representation of Diagrammatic representation of interactioninteraction

studied

2020

CYP2C19 Inducers and InhibitorsCYP2C19 Inducers and Inhibitors

2121

EBM 5 stepsEBM 5 steps

Ask

– 將病人的問題寫成 PICOAcquire

– 找資料來回答問題Appraisal

– 嚴格評讀文獻Apply

– 是否可應用到病人身上Audit – 是否可自我評估以上四個步驟的表現自我評估以上四個步驟的表現

與施行效率與施行效率

2222

Ask an answerable question ?Ask an answerable question ?

Do Do proton pump inhibitorsproton pump inhibitors decrease decrease

thethe clinical benefit clinical benefit of of clopidogrelclopidogrel

following acute coronary syndrome ?following acute coronary syndrome ? Does concomitant treatment with a Does concomitant treatment with a

proton pump inhibitorproton pump inhibitor and and clopidogrelclopidogrel

after a myocardial infarction after a myocardial infarction increaseincrease the the

risk of risk of recurrent myocardial infarction recurrent myocardial infarction ??

2323

PICO : Therapy PICO : Therapy

Patient / Problem58 years female patient / NSTEMI (ACS)

Intervention Clopidogrel with PPI

Comparison Clopidogrel with placebo

OutcomeRisk of CV (recurrent MI), death or rehospitalization for ACS

2424

EBM 5 stepsEBM 5 stepsAsking

– 將病人的問題寫成 PICO

Acquire



– 是否可應用到病人身上Audit – 是否是否可自我評估以上四個步驟的表現自我評估以上四個步驟的表現


2525

Searching for the best Searching for the best available evidenceavailable evidence

DatabasesDatabases

Hierarchy of evidenceHierarchy of evidence

Searching strategiesSearching strategies

2626

searching evidencesearching evidence

medical database internet search engine

prefiltered unfiltered Google

YahooUpToDate

EBM-R

ACP Journal Club

Cochrane Library

Medline

PubMed

Searching for the Best EvidenceSearching for the Best Evidence

2727

Evidence-based textbooks: UpToDate, Clinical Evidence

Evidence-based journal abstrcts, Synopsis of CDSR, ACP Journal Club

Systematic Reviews: The Cochrane Library, PubMed Clinical Queries

Prefiltere

d

Studies

Syntheses

Synopses

Summaries

Systems

5S Levels

Original journal article: PubMedUnfiltered

The levels of organisation of evidence from research

Computerized decision support

2828

Searching strategiesSearching strategiesPrimary Term Synonym 1 Synonym 2

P NSTEMI ACS

I clopidogrel AND proton pump inhibitor

clopidogrel AND PPI

clopidogrel AND omeprazole

C clopidogrel AND placebo

O Re-infarction Recurrent myocardial infarction

CV mortality or morbidity

Limits： humans , english, full text , 2008 - 2009

2929

3030

Key words :

ACS AND clopidogrel AND propton pump inhibitor AND reinfarction

NSTEMI AND clopidogrel AND PPI AND recurrent MI

Clopigogrel AND proton pump inhibitor

Clopidogrel AND omeprazole

Limits :

humans , english, full text , 2008 - 2009

3131

EBM DatabasesEBM Databasesdatabases results

EBM ReviewsCochrane Database of Systematic Reviews

ACP Journal Club

Database of Abstracts of Reviews of Effects

Cochrane Central Register of Controlled Trials

3

Cochrane Library 2

MD Consult 5

Dynamed 44

Essential Evidence Plus 22

PubMed Clinical Queries 3

3232

標題：標題： Influence of omeprazole on the

antiplatelet action of clopidogrel

associated with aspirin

文獻：文獻： J Am Coll Cardiol 2008;51:256–60

實證等級：實證等級： IbIb

建議等級：建議等級： AA

搜尋到的第一篇文章標題及文獻等級搜尋到的第一篇文章標題及文獻等級

3333

3434



Acquire

– 找資料來回答問題

Appraisal




3535

3636

Critical appraisalCritical appraisal

VValidity / Reliability alidity / Reliability

IImportance / Impactmportance / Impact

PPractice / Applianceractice / Appliance

3737

3838

3939

4040

JAMA 1993

vol 270(21)

2598-2601

4141

J Am Coll Cardiol 2008;51:256–60

4242

MethodsPatients and study protocol

We conducted a prospective, double-blind, placebo-controlled, randomized trial.

patients were randomized to 2 treatment groups: associated 20 mg/day omeprazole or placebo, for 7 days.

Platelet reactivity

Blood samples were collected on sodium citrate on Day 1 and 7 in both groups.

Laboratory physicians performed VASP phosphorylation analysis blinded to treatment group.

4343


Syntheses

Studies

filter

unfilter

4444

Oxford Center for Evidence-based Medicine Oxford Center for Evidence-based Medicine Levels of EvidenceLevels of Evidence and and Grades of Recommendations

Grade of Recommendation

Level of Evidence

Therapy/Prevention, Aetiology/Harm

A

1a1a SR (with homogeneity*) of RCT

1b Individual RCT (with narrow Confidence Interval)

1c1c All or none

BB

2a2a SR (with homogeneity*) of cohort study

2b2b Individual cohort study (include low quality RCT; e.g., <80% follow-up)

2c2c “Outcomes” Research

3a3a SR (with homogeneity*) of case-control studies

3b3b Individual Case-Control Study

CC 44 Case-series (and poor quality cohort and case-control studies)

DD 55 Expert opinion without explicit critical appraisal, or based on physiology bench research or “first principles”

4545

J. Am. Coll. Cardiol. 2008;51;256-260

Omeprazole

( n=70 )

Placebo

( n=70 )

Analyzed (n=64)

Analyzed (n=60)

Randomization ( n=140)

4646

J. Am. Coll. Cardiol. 2008;51;256-260

83.9% 83.2%

51.4%

39.8%Platelet Reactivity Index

VASP : vasodilator stimulated phosphoprotein

4747

J. Am. Coll. Cardiol. 2008;51;256-260

omeprazoleplacebo

Platelet Reactivity Index

- 43.3%

- 32.6%

4848

ConclusionsAspirin–clopidogrel antiplatelet dual therapy is widely prescribed worldwide

PPIs frequently associated to prevent gastrointestinal bleeding.

In this randomized study, omeprazole significantly decreased the effect of clopidogrel on platelet as tested by VASP phosphorylation.

The clinical impact of these results remains uncertain but merits further investigation.

Recommend not adding systematically a PPI treatment to the antiplatelet dual therapy without formal indication.

4949

Critical Appraisal Skills Programme Critical Appraisal Skills Programme RCT:CASP (1)RCT:CASP (1)

Are the results of the study Are the results of the study valid / reliablevalid / reliable ? ? Screening Questions Yes No

Did the study ask a clearly focused question? vvWas this a randomised controlled trial (RCT)

and was it appropriately so?vv

Were participants appropriately allocated to

intervention and control groups?vv

Were participants, staff and study personnel

‘blind’ to participants’ study group?vv

Were all of the participants who entered the

trial accounted for at its conclusion? Intension to treat ? followed up complete ? (140-124)

vv

5050

Critical Appraisal Skills Programme RCT:CASP (1)

Are the results of the study Are the results of the study valid / reliablevalid / reliable ? ?

Screening Questions Yes No

Were the participants in all groups followed

up and data collected in the same way?vv

Aside from the experimental intervention, were the groups treated equally ?

vv

Were the groups similar at the start of the trial ?

vv

Did the study have enough participants to

minimise the play of chance? (n=120, 80% statistical power and 5% alpha risk) (124/140)

vv

5151


What were the results ? Importance / ImpactImportance / Impact

Screening Questions Yes NoHow large was the treatment effect ? (ARI , NNH)

vv

How precise are these results? (CI , p value) vv

Outcome ARI RR NNHEER CER EER - CER EER/CER 1/ARI

95% CI

EER : Experimental Event Rate CER : Control Event Rate ARI : Absolute Risk Increase RR : Relative Risk NNH : Number Needed to Harm CI : Confidence Interval

5252


Will the results help me in caring for my patients ? Practice / AppliancePractice / Appliance

Screening Questions Yes No

Were all clinically important outcomes considered ?

vv

Can the results be applied to my patient care

?vv

Are the likely treatment benefits worth the potential harms and costs ?

vv

5353



Acquire


– 嚴格評讀文獻

Apply



5454

Clinical ApplicationClinical Application

這個研究之有效且重要的證據能實際應用到我們照顧的病人這個研究之有效且重要的證據能實際應用到我們照顧的病人病人類似性病人類似性 ((coronary stent implantationcoronary stent implantation))診療環境之合理可行性診療環境之合理可行性病人從治療中可預防危險病人從治療中可預防危險結合實證醫學的結果、臨床專業經驗結合實證醫學的結果、臨床專業經驗– 給予病人建議給予病人建議結合病人價值觀結合病人價值觀– 幫助病人做出最後的決定幫助病人做出最後的決定

證據之外推


Level of Evidence

Therapy

A1a Systemic review of RCTs

1b Single RCT

1c ‘All-or-none’

5555



Acquire



– 是否可應用到病人身上Audit – 是否可自我評估以上四個步驟的表現自我評估以上四個步驟的表現


5656

Evaluation performance Evaluation performance measurement measurement

評估表現與施行效率評估表現與施行效率 Self – Evaluation （自我評估） Evaluation (Audit) by Expert or peer （專家監督或同儕彼此評估） Audit by organization Audit by third party (NHI, Insurance) Audit by computer

5757

Step 5: EvaluationStep 5: EvaluationSelf-evaluation: Step 1Self-evaluation: Step 1

步驟 1 ：在提出臨床問題方面 1. 我有提出任何臨床問題嗎？ 2. 我提出的問題結構是否完整？ 3. 是否知道自己設定的問題類型？

5858


步驟 2 ：在搜尋最佳證據方面1. 我知道在我的臨床領域中現有的最佳證據來源嗎？2. 我是否擁有搜尋所需的軟硬體及獲得最佳證據的管道？

5959


步驟 3 ：在文獻評讀方面1. 對我而言，應用研究證據之評讀指引變的更簡單嗎？2. 我可以更正確、更有效率的使用一些審慎評估度量工具 ( 如： NNT) ？

6060


步驟 4 ：在整合證據與病患的價值觀方面1. 我盡力將審慎評估之結果融入治療中嗎？2. 為了適用於我的病人，我在調整一些嚴格評讀的度量值 ( 機率、 NNT等 ) 方面越來越精準及有效率？

6161

標題：標題： Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome

文獻：文獻： JAMA. 2009;301(9):937-44

實證等級：實證等級： II bII b

建議等級：建議等級： BB

搜尋到的第二篇文章標題及文獻等級搜尋到的第二篇文章標題及文獻等級

6262

JAMA. 2009;301(9):937-944

6363

Context

– Prior studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel.

– Yet the clinical significance of these findings is not clear.

Objective

– To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS).

Design, Setting, and Patients

– Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006.

6464


Syntheses

Studies

filter

unfilter

6565



Level of Evidence


A



1c1c All or none

BB


2b Individual cohort study (include low quality RCT; e.g., <80% follow-up)



3b Individual Case-Control Study



6666JAMA. 2009;301(9):937-944

CER EER

6767

JAMA. 2009;301(9):937-944

Clopidogrel without PPI

Clopidogrel with PPI

Proportion of death or recurrent ACS

Period since discharge

6868

Conclusion (1)

This study found that concomitant use of

clopidogrel and PPI after hospital discharge

for ACS is associated with a higher risk of

adverse outcomes ( recurrent ACS )

compared with clopidogrel use without PPI.

These findings, coupled with prior studies,

suggest that concomitant PPI use may

attenuate the benefits of clopidogrel use after

ACS.

6969

Conclusion (2)

Pending further studies to confirm these

results and prospectively assess

cardiovascular outcomes for patients taking

clopidogrel plus PPI vs clopidogrel without PPI

The results of this study may suggest that PPIs

should be used for patients with a clear

indication for the medication, rather than routine

prophylactic prescription.

JAMA. 2009;301(9):937-944

7070

標題：標題： A population-based study of the drug

interaction between proton pump

inhibitors and clopidogrel

文獻：文獻： CMAJ 2009 ;180(7):713-28

實證等級：實證等級： III bIII b

建議等級：建議等級： BB

搜尋到的第三篇文章標題及文獻等級搜尋到的第三篇文章標題及文獻等級

7171

CMAJ 2009; 180(7):713-28

7272

7373


Syntheses

Studies

filter

unfilter

7474



Level of Evidence


A



1c1c All or none

BB


2b2b Individual cohort study (include low quality RCT; e.g., <80% follow-up)



3b Individual Case-Control Study



7575

31-90 daysWithin 30 days

91-180 days

Cases 734 (with recurrent MI): patients who died or readmitted for MI within 90 days after discharge following AMI

Controls 2057 (without recurrent MI): patient were at risk but were not readmitted because of MI before the index date

CMAJ 2009 180(7); 713-28

7676

EER 0.264 CER 0.206 OR 1.27

EER 0.063 CER 0.061 OR 1.02

EER 0.202 CER 0.145 OR 1.40

CMAJ 2009 180(7);713-28

Recurrent MI No recurrent MI

EER 0.050 CER 0.052 OR 0.94

7777

CMAJ 2009 180(7);713-28

Recurrent MI No recurrent MI

7878

Pantoprazole not associated with Pantoprazole not associated with increased risk of increased risk of recurrent myocardial recurrent myocardial

infarctioninfarction

PantoprazoleCMAJ 2009 180(7);713-28

7979

Conclusion (1)

In summary, patients taking clopidogrel following

acute myocardial infarction, the concomitant use of

a proton pump inhibitor that inhibits cytochrome

P450 2C19 ( omeprazole, lansoprazole or

rabeprazole ) was associated with an increased risk

of recurrent myocardial infarction.

This effect, which was not seen with pantoprazole

(inhibits cytochrome P450 2C9) therapy,

presumably reflects inhibition of the metabolic

bioactivation of clopidogrel.

8080

Conclusion (2) Pending further data regarding the clinical

significance of drug interactions.

Concomitant treatment with clopidogrel and proton

pump inhibitors should be minimized when possible.

If a proton pump inhibitor is required, pantoprazole

should be used preferentially in patients who are

also receiving clopidogrel.

Ranitidine or another H2-receptor antagonist

may be an appropriate alternative for patients who

require acid-lowering therapy.

8181

ACP Journal Club

Source Reference :

A population-based study of the drug interaction between proton pump inhibitors and clopidogrel

CMAJ 2009;180:713-8

Issue : Volume 151(2), August 2009, pp JC2-13

8282

ACP Journal ClubIssue: Volume 151(2), August 2009, pp JC2-13

8383

ACP Journal Club

AbstractAbstractQuestionQuestion– In older patients discharged from hospital after In older patients discharged from hospital after

acute MI , does acute MI , does concomitant use of a proton-concomitant use of a proton-pump inhibitor with clopidogrel lead to adverse pump inhibitor with clopidogrel lead to adverse eventsevents ? ?

ConclusionConclusion– concomitant use of a proton-pump inhibitor concomitant use of a proton-pump inhibitor

with clopidogrel was associated with with clopidogrel was associated with increased increased risk for readmission or death from MIrisk for readmission or death from MI within 90 within 90 days of initial discharge.days of initial discharge.

8484

Drug-Drug interaction

Severity Documentation Summary

Clopidogrel-Omeprazole

Major Excellent May result in increased risk for thrombosis

8585

8686

Warning :Warning : Concurrent use of Concurrent use of clopidogrelclopidogrel and and omeprazoleomeprazole may may

result in result in increased risk for thrombosis.increased risk for thrombosis.

Onset : Onset : Delayed Delayed

Severity : Severity : Major Major

Documentation : Documentation : Excellent Excellent

Probable Probable

Mechanism : Mechanism : decreased platelet inhibitory decreased platelet inhibitory effecteffect of clopidogrel by omeprazole of clopidogrel by omeprazole

MicroMedex

8787

Clinical Management Clinical Management

– the the clinical implications remain uncertainclinical implications remain uncertain

– the addition of the addition of proton pump inhibitorproton pump inhibitor therapy therapy

to to clopidogrel clopidogrel plus aspirin should be carefully plus aspirin should be carefully

considered and considered and onlyonly when when clearly indicatedclearly indicated..

– Consider using a Consider using a histamine-2 receptor histamine-2 receptor

antagonistantagonist in patients who required acid-in patients who required acid-

lowering therapy. lowering therapy.

– If a proton pump inhibitor is required, If a proton pump inhibitor is required,

pantoprazolepantoprazole may be preferred. may be preferred.

MicroMedex

8888

Summary Severity Reliability Rating

PPI may diminish the therapeutic effect of clopidogrel

Major Good

8989

9090

9191

55

Until further information is available, FDA recommends the following:

Clopidogrel能降低血栓風險可繼續使用使用Clopidogrel時, 能同時使用PPI嗎 ? 依據病人之病情由醫師評估是否須同時給予PPI

同時給予 omeprazole時需特別審慎

Conclusion

9292

Until further information is available Until further information is available FDA recommendsFDA recommends

Healthcare providers should Healthcare providers should continue to continue to

prescribeprescribe and patients should and patients should continue to takecontinue to take

clopidogrelclopidogrel as directed. as directed.

Because Because clopidogrelclopidogrel has demonstrated has demonstrated

benefits in benefits in preventing blood clotspreventing blood clots that could that could

lead to a heart attack or stroke. lead to a heart attack or stroke.

Healthcare providers shouldHealthcare providers should re-evaluatere-evaluate the the

need for need for startingstarting or or continuingcontinuing treatment with treatment with

aa PPIPPI in patients in patients taking clopidogreltaking clopidogrel..

9393

Pharmacist’s comments

Concomitant use of clopidogrel and PPI Concomitant use of clopidogrel and PPI associated with a higher risk of recurrent MI.associated with a higher risk of recurrent MI.

The clinical impact remains uncertain.The clinical impact remains uncertain. Pending further data regarding the clinical Pending further data regarding the clinical

significance of drug interactions.significance of drug interactions. PPIs should be used for patients with a clear PPIs should be used for patients with a clear

indication.indication. If a proton pump inhibitor is required, If a proton pump inhibitor is required,

pantoprazole may be preferred. pantoprazole may be preferred. Ranitidine or another H2-receptor antagonist Ranitidine or another H2-receptor antagonist

may be an appropriate alternative.may be an appropriate alternative.

9494

Apply these results to our patient

藥品名稱劑量用法途徑Aspirin 100 mg/cap 1pc QD PO

Clopidogrel 75 mg/tab 1pc QD PO

Heparin sodium 25000 u/5ml/vial

20000 u in 500 ml D5S, run 16 cc/hr

IVF

Rosuvastatin 10 mg/tab ½ pc QD PO

Carvedilol 25 mg/tab ½ pc BID PO

Actrapid HM 100 iu/ml, 10 ml/vial

8 u TID SC

Pantoprazole 40 mg/tab 1pc QD PO

9595

保衛康治潰樂保栓通

去學術化術語

9696

Evidence-Based Clinical Evidence-Based Clinical DecisionsDecisions

LiveUpdateResearch

evidences

Pt’s preferences and actions

Clinical states and environmental resources

Clinical expertises Clinical expertises & experience& experience

以病人為中心的安全醫療照護

Modified from R Brain Haynes et al.: Evid. Based Med. 2002;7;36-38.

Evidence is never enough

9797

謝謝謝謝 ! ! 請多指請多指教教 !!

Chiu Chun Chi

9898

N Engl J Med 2009;360:354-62.

9999

Cytochrome P-450 Polymorphisms and Response to Clopidogrel

Carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001).

Carriers also had an absolute reduction in maximal platelet aggregation (MPA) in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001).NEJM 360;4 january 22, 2009

100100

Cytochrome P-450 Polymorphisms and Response to Clopidogrel

NEJM 360;4 january 22, 2009

Death from cardiovascular causes, MI , stroke

Documents

1 以實證醫學觀點探討藥物 交互作用之影響 Clopidogrel with PPI 臨床藥師 : 邱 春 吉

1 以實證醫學觀點探討藥物交互作用之影響 Clopidogrel with PPI 臨床藥師 : 邱春吉