January 2012 • Vol. 4 • no. 1

Journal of the Society of PhySicianS of hong Kong

ISSN 2072-4209

executive committee

PRESIDENT

Dr Lam tat chung, Paul 林達聰醫生

VIcE PRESIDENT

Dr tsang Wah tak, Kenneth曾華德醫生

HoN. SEcRETaRy

Dr Shiu cho tak, Wesely邵祖德醫生

HoN. TREaSuRER

Dr Lam how mo, ignatius 林孝武醫生

cHIEF EDIToR

Dr Lau chu Pak 劉柱柏醫生

eDitoRS

Dr chan hin Lee, henry 陳衍里醫生

Dr chan Kwok Wing, fredriech 陳國榮醫生

Dr chan Pui yiu, nicola 陳珮瑤醫生

Dr chan tak hin 陳德顯醫生

Dr chen yi tin 陳以天醫生

Dr Kung Wai chee, annie龔慧慈醫生

Dr Lam tat chung, Paul 林達聰醫生

Dr Lam cheung cheung, Barbara藍章翔醫生

Professor Leung Wai Keung 梁偉強教授

Dr ng fook hong 吳福康醫生

Dr Shiu cho tak ,Wesely 邵祖德醫生

Dr tsang Wah tak, Kenneth 曾華德醫生

Dr Wong chun yu, Benjamin 王振宇醫生

CONTENTS

3 Roflumilast in coPD: emerging therapy targeting inflammation

Dr Leung Chung Chuen, Roland (梁宗存醫生)

7 cardiovascular Risk in Patients With Psoriatic arthritis

Dr Zhu Yan Yi, Tracy (朱燕兒博士); Professor Tam Lai Shan (譚麗珊教授); Professor Li Kwok Ming, Edmund (李國銘教授)

9 Journal Report – aDhD medications Do not increase Serious cardiovascular events in adults

Dr Lam Tat Chung, Paul (林達聰醫生)

11 management of adverse gastrointestinal events in Patients on antiplatelet therapy, Part ii: gastrointestinal Bleeding induced by clopidogrel or Dual antiplatelet therapy

Dr Ng Fook Hong (吳福康醫生)

www.sophysicianshk.orgVisit the web site for our monthly CME programmes for doctors

香港內科學會THE SOCIETY OF PHYSICIANS OF HONG KONG

ThisyearweproudlyseetheproductionoftheJournalenteringthe4thyear.

It issaidthatagoodbeginningmeansthatthe job ishalfdone.Wehavecertainlymadeaverygoodstart.Articlesareofhighstandard,highly readable and are welcomed by doctors and well supportedbyouradvertisers.TheJournalhasnowmadeafirmfoothold in themedicallandscapeinHongKong.Wewishtothankallthosewhohavecontributedtoitssuccess,includingoureditorsandcontributorswhohaveworkedwithdedicationandingenuity.Ourthanksalsogototheeditorialoffice,UBMMedica.

WearealsohappythattheSocietyhasrecentlycelebratedits55thanniversary.

Dr lau Chu Pak劉柱柏醫生FRCP, MD, FHKAM (Medicine)Chief Editor

Dr lam Tat Chung, Paul林達聰醫生FRCP, FHKAM (Medicine), FHKAM (Psychiatry)President

editorial office:UBM Medica 27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong KongT +852 2559 5888 F +852 2559 6910

advertising enquiries:Ms Chloe WongT +852 2155 8557e-mail: chloe.p.wong@ubm.com

© 2012 The Society of Physicians of Hong Kong. All rights reserved. No part of this publication may be reproduced in any language, stored in or introduced into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the written consent of the copyright owner. Permission to reprint must be obtained from the publisher. Advertisements are subject to editorial acceptance and have no influence on editorial content or presentation. The Society of Physicians of Hong Kong does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature.

editorial

The 55th anniversary Dinner held at the Chater room, Hong Kong Jockey Club on Dec 4, 2011 was attended by

about 200 members and guests

Group photo of members

Front row from left: Dr Tsang Wah Tak, Kenneth; Mrs Annie Lam; Dr Lam Tat Chung, Paul; Dr the Hon. Leong Che Hung (Guest of Honour)

Middle row from left: Dr Lo Kai Fai, Peter; Dr Yeung Chiu Fat, Henry; Dr Hung Chi Bun; Dr Ng Fook Hong; Dr Shiu Cho Tak, Wesely; Dr Lam How Mo, Ignatius; Dr So Wai Woon, Peter; Dr Shum Kit Shan, Patrick; Dr Chan Hin Lee, Henry; Dr Chan Chun Kwong, Jane

Back row from left: Dr Ming Shiu Kow; Dr Wong Hon Kit, Tony; Dr Chan Yi Tin; Dr Chan Pui Yiu, Nicola

GO DEEP. DO MORE.

Journal of The Society of Physicians of Hong Kong 3

Introduction

chronic obstructive pulmonarydisease (COPD) is associatedwith significant morbidity andmortality, and is predicted to

be the fourth leading cause of deathworldwide by 2030.1 In Asia, there is ahigh prevalence of COPD risk factorssuch as cigarette smoking and the useof biomass fuels.2 The mean regionalCOPDprevalencerateforAsiaisestimatedto be 6.3%; this equates to 56.6 millionmoderate-to-severecasesofCOPDamongindividuals aged 30 years and above.2However, there is a two-fold variation inCOPDprevalenceratesacrosstheregion.In Hong Kong, there are 139,000 casesof moderate-to-severe COPD in adultsaged30yearsandabove,whichequatestoaprevalencerateof3.5%.2

Exacerbations in CoPD

COPD is a progressive disease charac-terizedbypersistentairwayandsystemicinflammation. Inflammatory cells, suchas neutrophils and macrophages, accu-mulate in the lungstriggeringan inflam-matory cascade that leads to chronicairflow limitation and systemic inflam-mation.3 The natural course of COPDincludes intermittentexacerbations – anacute worsening of symptoms – that

further amplify the inflammation that isalwayspresentinthestablestate.

Exacerbationscontributetoamorerapid decline in lung function and sub-sequentreductionsinqualityoflife(QoL).4Exacerbations increaseinfrequencyandseverityasCOPDprogresses.However,ahistoryofexacerbationsisgenerallythemost reliable predictor of future exacer-bations–suggesting that there isan in-dependent susceptibility phenotype thatisinfluencedbytherateofexacerbationsirrespectiveofdiseasestate.4

The Evaluation of COPD Longitu-dinally to Identify Predictive SurrogateEndpoints (ECLIPSE)study (n=2,318), inadultsaged40to75yearswithahistoryof≥10packyearsofsmoking,identifiedafrequent-exacerbation phenotype whichappeared to be relatively stable over aperiodof3years.Thisphenotypecouldbepredictedbasedonthepatient’srecallofprevious treatedevents, andwasas-sociated with more severe disease,prior exacerbations and a worse health-relatedQoL.4(Table)

Patients who experience frequentexacerbations have a worse prognosisthanpatientswith less frequent exacer-bations,reinforcingtheimportanceofex-acerbationpreventioninthemanagementof patients with COPD. Furthermore,giventheheterogeneousnatureofCOPD,amoreindividualizedtreatmentapproachmayenhancetreatmentoutcomes.5

Roflumilast in coPD: emerging therapy targeting inflammation

Key words: coPD (慢性阻塞性肺病), roflumilast, exacerbations (惡化 / 加劇)

Dr leung Chung Chuen, roland (梁宗存醫生)

MD (Melb), MBBS (Melb), FRACP, FHKCP, FHKAM (Medicine)

Specialist in Respiratory Medicine

table. independent predictors of exacerbation during the first year of follow-up in the ecLiPSe trialPredictor number of exacerbations

1 vs 0 (oR) ≥2 vs 0 (oR) ≥2 vs 1 (oR)

Exacerbation during previous year 2.24 (p<0.001) 5.72 (p<0.001) 2.55 (p<0.001)

FEV1 (per 100 mL decrease) 1.06 (p<0.001) 1.11 (p<0.001) 1.05 (p<0.001)

SGRQ score (per increase of 4 points)

1.01 1.07 (p<0.001) 1.06 (p<0.001)

History of reflux or heartburn 1.61 (p<0.001) 2.07 (p<0.001) 1.29 (p<0.005)

White-cell count (per increase of 1 x 103/mm3)

1.02 1.08 (p=0.002) 1.06 (<0.001)

FEV1 = forced expiratory volume in 1 second; OR = odds ratio; SGRQ = St George’s Respiratory QuestionnaireAdapted from reference 4.

4 Journal of The Society of Physicians of Hong Kong

PDE4 Inhibitors Target CoPD Inflammation

Currenttherapeuticoptionsprimarilytreatthe symptomsofCOPD rather than tar-getingtheunderlyingdiseasepathology.Therefore, many patients with COPDhave suboptimal disease control. Anti-inflammatory therapy with inhaled corti-costeroidshasamodesteffectonCOPD,and despite improving lung functionand reducing exacerbations in patientswithsevereCOPD,ithaslittleeffectondiseaseprogression.5

Phosphodiesterase-4 (PDE4) is theprimaryPDEisoenzymefoundincellsin-volvedininflammatoryairwaysdiseases,such as COPD.5 A new class of agents–PDE4 inhibitors–hasbeendevelopedspecifically to target the inflammatorycomponent of COPD. The first agent inthis class to be approved for oral once-dailytreatmentofsevereCOPDisroflu-milast.5Roflumilasthashighpotencyandselectivity for PDE4 without affectingother PDE isoenzymes found in variouscellsandtissues.

Preclinical studies demonstratethatroflumilastreducestheaccumulationof neutrophils in bronchoalveolar lavagefluid following short-term exposure to

tobacco smoke,5 decreases the pro-ductionofmucusininflamedlungs,6de-creases sputum in inflammatory cells,7reduces alveolar destruction and mayimprovemucociliaryclearance.8,9

roflumilast: The Clinical Evidence

The beneficial effects of roflumilast onlungfunctionandqualityoflifehavebeendemonstratedinpatientswithmoderate-to-severe COPD.10,11 In 1,513 patientswith severe stable COPD, oral roflu-milast500μgplusinhaledcorticosteroidsproduced a modest but significant im-provement in lung function, which wasevident after 4 weeks of treatment andmaintained over a 1-year period (39 mLvs placebo; p=0.001).10 These findingswere replicated in two multicenterstudies in outpatients aged ≥40 years

with moderate-to-severe COPD treatedwith the long-acting bronchodilators(LABA) salmeterol (M127 study; n=933)or tiotropium (M128 study; n=743).11Consistent improvements in pre-bron-chodilator FEV1 were reported with oralroflumilast 500 μg plus salmeterol (49mL; p<0.0001) and oral roflumilast 500μg plus tiotropium (80 mL; p<0.0001).(Figure 1A) Similar improvements werereported for post-bronchodilator FEV1.

11(Figure1B)Apost-hocanalysisof thesestudiesreportedareductioninthemeanannual moderate-to-severe exacer-bation rateof36.8% in theM127study(p=0.0315)and23.2%intheM128study.

Two 1-year multicenter trials(M2-124andM2-125)thatenrolledmorethan 3,000 outpatients aged 40 yearsandabovewithsevereairflowlimitation,bronchiticsymptomsandahistoryofex-acerbations demonstrated significant re-ductions in exacerbation rates followingtreatment with roflumilast.12 In additionto improving lung function, roflumilastproduced a 17% reduction in the rateof moderate-to-severe exacerbations(p=0.0003) and a 16% reduction in thetotal number of exacerbations requiringsystemic corticosteroids or antibiotictreatment(p=0.0003),andprolongedthetime tofirstmoderateor severeexacer-bation(p=0.0185)comparedwithplacebo.

Overall

Female

Male

Current smokers

Former smokers

ICS: yes

ICS: no

Anticholinergic: yes

Anticholinergic: no

Completers

Non-completers

Very severe COPD

Severe COPD

Emphysema

Chronic bronchitis ± emphysema

Chronic bronchitis ± emphysema + ICS

Chronic bronchitis ± emphysema – ICS

Cough score ≥1

Cough score <1

Sputum score ≥1

Sputum score <1

100

80

60

40

20

0

-20

-40

Pre-bronchodilator FEV1

mL

Roflumilast Placebo

SALMETEROL

∆49 (p<0.0001)

Roflumilast Placebo

TIOTROPIUM

∆80 (p<0.0001)

80

70

60

50

40

30

20

10

0

-10

-20

Post-bronchodilator FEV1

mL

Roflumilast Placebo

SALMETEROL

∆60 (p<0.0001)

Roflumilast Placebo

TIOTROPIUM

∆81 (p<0.0001)

Favours roflumilast Favours placebo

0 1.2 0.4 0.6 0.8 1 1.2 1.4

figure 1. change in mean pre-bronchodilator (a) and post-bronchodilator fev1 (B) for roflumilast plus salmeterol or tiotropium

FEV1 = forced expiratory volume in 1 second Adapted from reference 11.

“Current therapeutic options primarily treat

the symptoms of COPD”

(a) (B)

Journal of The Society of Physicians of Hong Kong 5

GiventhatpatientswithCOPDhavedifferent phenotypes, certain subgroupsof patients may derive greater benefitfrom the anti-inflammatory action of ro-flumilast thanothers.Apost-hocpooledanalysis of two 1-year studies (M2-111and M2-112; n=2,686) determined thatthe subgroup of patients most likely tobenefit from roflumilast were patientswithchroniccoughandsputum,aswellasthosewithahistoryofexacerbations.13The rate of moderate-to-severe exac-erbations was 14.3% lower with roflu-milast compared with placebo (0.52 vs0.61 exacerbations per year; p=0.026).Alowerexacerbationratewasobservedin specific subgroups of patients, in-cluding those with chronic bronchitiswith or without emphysema (26.2% re-duction; p=0.001), and those receivinginhaledcorticosteroid treatment (18.8%;p=0.014).(Figure2)

In patients with severe to verysevere COPD receiving treatment withaLABAor a short-actingmuscarinic an-

tagonist, roflumilast reduced the rate ofmoderate-to-severeexacerbationsbyupto21%(p≤0.039)andprolongedthetimetofirstandsecondexacerbations.14

In clinical trials, roflumilast is gen-erally well tolerated. Only mild andtransient adverse events were typicallyreported.5 The most common adverseevents occurring in ≥2% of patients

were diarrhoea, weight loss and naso-pharygitis. The weight loss observedwith roflumilast mainly occurred withinthefirst6monthsoftreatmentandwasgenerally<3%ofbaselineweight.5

Conclusion

Asourunderstandingof thekey roleofinflammation in the pathophysiology ofCOPD becomes more clearly defined,therapies which specifically target thisinflammatory component are likely toimprove disease management. The oralonce-dailyPDE4inhibitorroflumilast,thefirst inanemergingclassofagentsthattargets inflammation, has demonstratedefficacy in improving lung function andreducing exacerbation rates. Availabledatasupporttheuseofroflumilastinpa-tientswithsuboptimaldiseasecontrolonother therapies. In addition, increasingevidenceindicatesthatcertainsubgroupsof patients will potentially derive thegreatest benefit from targeted specifictherapiessuchasroflumilast.

references:1. World Health Organization. Global surveillance, prevention and control

of chronic respiratory diseases. http://www.who.int/gard/publications/GARD%20Book%202007.pdf. Accessed: October 14, 2011.

2. Regional COPD Working Group. COPD prevalence in 12 Asia-Pacific countries and regional projections based on the COPD-prevalence esti-mation model. Respirology 2003;8:192-198.

3. Vestbo J, Anderson W, Coxson HO, et al; ECLIPSE investigators. Eval-uation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir J 2008;31:869-873.

4. Hurst JR, Vestbo J, Anzueto A, et al; ECLIPSE investigators. Suscepti-bility to exacerbation in chronic obstructive pulmonary disease. N Eng J Med 2010;363:1128-1138.

5. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol 2010;163:53-67.

6. Cortijo J, Iranzo A, Milara X, et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviate bleomycin-induced lung injury. Br J Pharmacol 2009;156:534-554.

7. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081-1087.

8. Huang Z, Mancini JA. Phosphodiesterase 4 inhibitors for the treatment asthma and COPD. Curr Med Chem 2006;13:3253-3262.

9. Wolsen A, Hirrle A, Tenor H, Marx D, Beume R. Effect of cyclic AMP-elevating agents on airway ciliary beat frequency in central and lateral airways in rat precision-cut lung slices. Eur J Pharmacol 2010;635:177-183.

10. Calverley PMA, Sanchez-Torll F, McIvor A, Teichmann P, Breden-broeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Care Med 2007;176:154-161.

11. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodi-lators: Two randomized clinical trials. Lancet 2009;374:695-703.

12. Calverley PMA, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symp-tomatic chronic obstructive pulmonary disease: Two randomized clinical trials. Lancet 2009;374:685-694.

13. Rennard SI, Calverley PMA, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast – the importance of defining different subsets of patients with COPD. Respir Res 2011;12-18.

14. Bateman ED, Rabe KF, Calverley PMA, et al. Roflumilast with long-acting b2 agonists for COPD: Influence of exacerbation history. Eur Respir J 2011;38:553-560.

Overall

Female

Male

Current smokers

Former smokers

ICS: yes

ICS: no

Anticholinergic: yes

Anticholinergic: no

Completers

Non-completers

Very severe COPD

Severe COPD

Emphysema

Chronic bronchitis ± emphysema

Chronic bronchitis ± emphysema + ICS

Chronic bronchitis ± emphysema – ICS

Cough score ≥1

Cough score <1

Sputum score ≥1

Sputum score <1

100

80

60

40

20

0

-20

-40

Pre-bronchodilator FEV1

mL

Roflumilast Placebo

SALMETEROL

∆49 (p<0.0001)

Roflumilast Placebo

TIOTROPIUM

∆80 (p<0.0001)

80

70

60

50

40

30

20

10

0

-10

-20

Post-bronchodilator FEV1

mL

Roflumilast Placebo

SALMETEROL

∆60 (p<0.0001)

Roflumilast Placebo

TIOTROPIUM

∆81 (p<0.0001)

Favours roflumilast Favours placebo

0 1.2 0.4 0.6 0.8 1 1.2 1.4

figure 2. Rate of moderate-to-severe exacerbations according to patient subgroup

ICS = inhaled corticosteroidsAdapted from reference 13.

“Patients most likely to benefit from

roflumilast were those with chronic cough

and sputum, as well as those with a history of exacerbations”

Journal of The Society of Physicians of Hong Kong 7

Introduction

Psoriatic arthritis (PsA) is animmune-mediated inflammatoryarthritis associated with pso-riasis that occurs in 0.3–1% of

the population.1 Patients with PsA haveheterogeneous clinical presentationswith diverse articular and dermatologicalfeaturesaswellasvarieddiseasecourseand outcomes.1 There is increasingevidence suggesting that patients withPsAalsohaveanincreasedriskofcardio-vascular disease (CVD). We discuss thecurrentliteratureindicatingtherelationshipbetweenPsAandcardiovascularrisk.

Cardiovascular Morbidity and Mortality in Psa

ExcessmortalityinpatientswithPsAhasbeendocumentedinseveralstudies.Inamortalitystudyof428patientswithPsA,thestandardizedmortalityratio(SMR)forthefemalecohortwas1.59,andforthemen, it was 1.65, indicating a 59% and65%increase,respectively,indeathratecomparedwiththatofthegeneralpopu-lation.2 CVD was the leading cause ofdeath,responsiblefor36%ofallcauses.CardiovascularmortalityinPsAwas30%higher than in the general population.2A recent mortality study in Hong Kongconfirmed thesefindings.3Theage-andsex-adjusted SMR of PsA was 1.59, in-dicating a 59% increase in death ratecomparedwiththatofthegeneralpopu-lationinHongKong.3CVDaccountedfor

20%ofallcausesofmortality.3Han et al investigated the prev-

alence of CVD in 3,066 patients withPsA.4Thestandardizedprevalenceratios(SPRs)ofchronicheartfailure,ischaemicheartdisease,peripheralvasculardiseaseand cerebrovascular disease were allsignificantly higher in patients with PsAthaninhealthycontrols, indicatinganin-creased riskof cardiovascularmorbidity.Therelativeriskofcoronaryarterydiseasewas1.3inpatientswithPsA,suggestinga30%increaseinrisk.PatientswithPsAalso had increased prevalence of myo-cardial infarction and angina, with age-and sex-adjusted SPRs of 2.6 and 2.0,respectively.5 The prevalence of CVD inPsA(10%)resembledthatofrheumatoidarthritis (RA) (12%).6 The age- and sex-adjusted odds ratio of CVD showedno significant difference between RAandPsA.

Subclinical CVD in Psa

Several studies investigated the prev-alence of subclinical outcomes whichprecede cardiovascular events andmortality in PsA.7-10 Carotid intima-media thickness (IMT) of the commoncarotid artery, determined by ultra-sonography, is a useful noninvasivesurrogate marker of macrovascular ath-erosclerotic disease.11 IMT correspondsto the width of the vessel intima andmedia,whichisthesiteoflipiddepositionandplaqueformation.12IncreasedcarotidIMTisagoodindicatorofgeneralizedath-erosclerosisandcoronaryarterydisease,providing early information on athero-sclerosis in subclinical stages.12 Severalcase-control studies have demonstratedthat patients with PsA have a higherprevalenceofsubclinical arthrosclerosis.TheincreaseincarotidIMTinPsAwasupto23%comparedwithhealthycontrols.7PatientswithPsAwithoutcardiovascularrisk factorsorclinicallyevidentCVDstill

cardiovascular Risk in Patients with Psoriatic arthritis

Key words: Psoriatic arthritis (牛皮癬關節炎), cardiovascular disease (心血管疾病), cardiovascular risk factors (心血管危險因素)

Dr Zhu yan yi, Tracy (朱燕兒博士)

PhD

Postdoctoral Fellow, Division of Rheumatology, Department of Medicine and Therapeutics, Chinese University of Hong Kong

Professor Tam lai Shan (譚麗珊教授)

MD

Division of Rheumatology, Department of Medicine and Therapeutics, Chinese University of Hong Kong

Professor li Kwok Ming, Edmund (李國銘教授)

MD

Head, Division of Rheumatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong

8 Journal of The Society of Physicians of Hong Kong

hadan8.7%increaseincarotidIMT,sig-nificantly higher than healthy controls.9The prevalence of plaques, especiallymore severe plaque,8 in patients withPsAwasalsosignificantlyincreased.7

Endothelial dysfunction is con-sideredanearlyfeatureinatherogenesisand has been consistently associatedwith cardiovascular risk factors.13 Itencompasses an imbalance betweenvasodilating and vasoconstricting sub-stances, leading to an impaired abilityof the artery to dilate in response tophysical and chemical stimuli.13 Post-occlusion flow-mediated vasodilatation(FMD%)ofthebrachialarterymeasuredby ultrasonography is used to noninva-sively evaluate endothelial function.14 InpatientswithPsAwithoutcardiovascularrisk factors or clinically evident CVD,FMD% was found to be significantlylower compared with healthy controls,indicatingendothelialdysfunction inPsAas a potential basis for the associationbetweenPsAandatherosclerosis.15

Gonzalez-Juanatey et al did notfind significant subclinical cardiac ab-normalities inpatientswithPsAwithoutcardiovascular risk factors or clinicallyevident CVD.16 However, Shang et al,usingconventionalechocardiographyandtissueDoppler imaging, foundthat65%ofpatientswithPsAwithoutestablishedCVDhadevidenceofsubclinicalleftven-tricular dysfunction, a rate significantlyhigherthaninhealthycontrols.17Leftven-triculardysfunctionwasmorecommoninpatients with cardiovascular risk factorsthaninthosewithout.17

Conventional and unconventional risk Factors of CVD in Psa

Patients with PsA have an increasedprevalenceofconventionalcardiovascularrisk factors.4,5,18-21 These risk factorscontribute to not only overt but alsosubclinical CVD. The prevalence of hy-pertension,hyperlipidaemia,obesityandtype2diabetesishigherinPsApatientsthan in the general population.4,5,8 Dataonlipidprofilesareslightlycontroversial.Joneset al found that high-density lipo-protein (HDL) cholesterol and its third

subfraction,HDL3cholesterol,weresig-nificantly reduced and the densest sub-fractionof low-density lipoprotein (LDL),LDL3, was significantly increased in pa-tients with PsA.22 Lower levels of HDLcholesterolanditssubfractioninPsApa-tientswerealsofoundbySkoczynskaetal.23AstudybyTametal,however,foundthat patients with PsA had higher HDLcholesterollevels,lowertotalcholesterol(TC) and LDL cholesterol levels, and alower TC/HDL cholesterol ratio.18 A fewstudieshaveinvestigatedthelevelofapo-lipoproteinA (apo-AI) andapolipoproteinB(apo-B).Tametal foundsignificant in-creasesinserumapo-AIandapo-Blevelsin patients with PsA.18 However, Ol-ivieroetalinvestigatedapo-AIandTCinserumandsynovialfluidinpatientswithPsA,andfoundnosignificantdifferencebetweenpatientsandcontrols.24

The metabolic syndrome is acluster of traditional risk factors thatinclude abdominal obesity, atherogenicdyslipidaemia, hypertension, and insulinresistance.ArecentstudyinHongKongfound that the prevalence of the met-abolicsyndromewassignificantlyhigherin PsA patients (38%) compared withmatchedcontrols(18%)orpatientswithRA (20%) or ankylosing spondylitis (AS)(11%).19 Patients with PsA were 2.44timesmore likely tohave themetabolicsyndrome relative to patients with RAorAS.19

The increased cardiovascular riskin patients with PsA may be related tothe inflammatory process. Inflammationparticipatescentrally in all stagesof thedevelopment of atherosclerosis, fromtheinitial lesiontoend-stagethromboticcomplications.25 The increased levelsof proinflammatory cytokines, whichare characteristics of chronic inflam-matorydiseases such asPsA, canelicitasystemicinflammatorystatethatcould,over time,promote atherosclerosis con-ducive to increased cardiovascular risk.C-reactive protein (CRP) is emerging asone of the predictors of CVD,26 and itslevels also relate well with joint inflam-mation.27 Tam et al reported that low-grade inflammation as measured byhigh-sensitivityCRPwasassociatedwithobesity, hypertension, insulin resistanceanddyslipidaemiainpatientswithPsA.18The increased prevalence of obesity

in PsA patients may also increase theburden of inflammation. Adipose tissuecells secret cytokines, chemokines, andhormone-likeproteinswhichareinvolvedinadiposetissuehomeostasis,regulationof insulin sensitivity and metabolism,and also chronic inflammation.28 Adipo-nectin has anti-inflammatory properties,andits levelswerefoundtobereducedin patients with psoriasis.24 High levelsof proinflammatory cytokines, such astumour necrosis factor alpha (TNF-α),coulddownregulatetheproductionofad-iponectin and upregulate the productionof leptin, which has a proinflammatoryand proangiogenic role and can causeendothelial dysfunction in patients withinflammatorydiseases.29

Effects of Biologic Disease-modifying antirheumatic Drugs in risk of CVD in Psa

In a pilot study, Tam et al showed that12-weekanti-TNF-αtherapymightbeas-sociatedwithsignificantreductioninIMT,along with improvement in clinical andlaboratorymanifestationsinpatientswithPsA.30 The 2-year analysis showed thatfurtherregressionofmaximumIMTwaspossibleonly inpatientswhowerecon-tinued on long-term anti-TNF-α therapy,suggestingthateffectivesuppressionofinflammation inpatientswithhigh-gradeinflammation may potentially reverseearly atherosclerotic lesions. Anti-TNF-αtherapies were also shown to improveaortic stiffness and modify endothelialfunction in patients with inflammatoryarthritis,includingPsA.31,32Thesefindingssupportthepivotalroleofinflammationinatherogenesis and the favourable effectofaggressiveanti-inflammatorytherapiesoncardiovascularrisk.

recommendations for Cardiovascular risk Management

The European League Against Rheu-matismhasdevelopedrecommendations

Journal of The Society of Physicians of Hong Kong 9

for cardiovascular risk management inpatientswithRAandotherinflammatoryarthritis, including AS and PsA.33 Ag-gressive suppression of disease activityis necessary to lower cardiovascularrisk. Annual assessment of cardio-vascular risk using national guidelinesis recommended for all patients withinflammatory arthritis. Any risk factorsidentified should be managed accordingto local guidelines. In the absence oflocalguidelines,cardiovascularriskman-agement should follow the SystematicCoronary Risk Evaluation model, whichis similar to theFramingham risk score.Statins, angiotensin-converting enzymeinhibitors, and/or angiotensin II blockersare preferred treatment options due totheirpotentialanti-inflammatoryeffects.

Conclusion

PsAisassociatedwithanincreasedprev-alenceofclinicalandsubclinicalCVDdueto accelerated atherosclerosis. In PsA,chronic inflammationacts independentlyand/orsynergisticallywithtraditionalriskfactors in the pathogenesis of athero-sclerosis. Aggressive suppression of in-flammationmaypreventtheprogressionof atherosclerosis and thus provide afavourable cardioprotective effect inpatientswithPsA.

references:1. Gladman DD. Psoriatic arthritis. Rheum Dis Clin North Am

1998;24:829-844, x.2. Wong K, Gladman DD, Husted J, Long JA, Farewell VT. Mortality studies

in psoriatic arthritis: Results from a single outpatient clinic. I. Causes and risk of death. Arthritis Rheum 1997;40:1868-1872.

3. Mok CC, Kwok CL, Ho LY, Chan PT, Yip SF. Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China. Arthritis Rheum 2011;63:1182-1189.

4. Han C, Robinson DW, Jr., Hackett MV, Paramore LC, Fraeman KH, Bala MV. Cardiovascular disease and risk factors in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. J Rheumatol 2006;33:2167-2172.

5. Gladman DD, Ang M, Su L, Tom BD, Schentag CT, Farewell VT. Cardio-vascular morbidity in psoriatic arthritis. Ann Rheum Dis 2009;68:1131-1135.

6. Jamnitski A, Visman IM, Peters MJ, Boers M, Dijkmans BA, Nur-mohamed MT. Prevalence of cardiovascular diseases in psoriatic arthritis resembles that of rheumatoid arthritis. Ann Rheum Dis 2011;70:875-876.

7. Tam LS, Shang Q, Li EK, et al. Subclinical carotid atherosclerosis in patients with psoriatic arthritis. Arthritis Rheum 2008;59:1322-1331.

8. Kimhi O, Caspi D, Bornstein NM, et al. Prevalence and risk factors of ath-erosclerosis in patients with psoriatic arthritis. Semin Arthritis Rheum 2007;36:203-209.

9. Gonzalez-Juanatey C, Llorca J, Amigo-Diaz E, Dierssen T, Martin J, Gon-zalez-Gay MA. High prevalence of subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease or classic atherosclerosis risk factors. Arthritis Rheum 2007;57:1074-1080.

10. Eder L, Zisman D, Barzilai M, et al. Subclinical atherosclerosis in psoriatic arthritis: A case-control study. J Rheumatol 2008;35:877-882.

11. Simons PC, Algra A, Bots ML, Grobbee DE, van der Graaf Y. Common carotid intima-media thickness and arterial stiffness: Indicators of car-diovascular risk in high-risk patients. The SMART Study (Second Mani-festations of ARTerial disease). Circulation 1999;100:951-957.

12. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: A direct measurement with ultrasound imaging. Circulation 1986;74:1399-1406.

13. Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and En-dothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:233-246.

14. Deanfield J, Donald A, Ferri C, et al. Endothelial function and dys-function. Part I: Methodological issues for assessment in the different vascular beds: A statement by the Working Group on Endothelin and En-dothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:7-17.

15. Gonzalez-Juanatey C, Llorca J, Miranda-Filloy JA, et al. Endothelial dys-function in psoriatic arthritis patients without clinically evident cardio-vascular disease or classic atherosclerosis risk factors. Arthritis Rheum 2007;57:287-293.

16. Gonzalez-Juanatey C, Amigo-Diaz E, Miranda-Filloy JA, et al. Lack of echocardiographic and Doppler abnormalities in psoriatic arthritis patients without clinically evident cardiovascular disease or classic ath-erosclerosis risk factors. Semin Arthritis Rheum 2006;35:333-339.

17. Shang Q, Tam LS, Yip GW, et al. High prevalence of subclinical left

ventricular dysfunction in patients with psoriatic arthritis. J Rheumatol 2011;38:1363-1370.

18. Tam LS, Tomlinson B, Chu TT, et al. Cardiovascular risk profile of patients with psoriatic arthritis compared to controls--the role of inflammation. Rheumatology (Oxford) 2008;47:718-723.

19. Mok CC, Ko GT, Ho LY, Yu KL, Chan PT, To CH. Prevalence of athero-sclerotic risk factors and the metabolic syndrome in patients with chronic inflammatory arthritis. Arthritis Care Res (Hoboken) 2011;63:195-202.

20. Tobin AM, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol 2010;37:1386-1394.

21. Peters MJ, van der Horst-Bruinsma IE, Dijkmans BA, Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, par-ticularly ankylosing spondylitis and psoriatic arthritis. Semin Arthritis Rheum 2004;34:585-592.

22. Jones SM, Harris CP, Lloyd J, Stirling CA, Reckless JP, McHugh NJ. Lipoproteins and their subfractions in psoriatic arthritis: Identification of an atherogenic profile with active joint disease. Ann Rheum Dis 2000;59:904-909.

23. Skoczynska AH, Turczyn B, Barancewicz-Losek M, Martynowicz H. High-density lipoprotein cholesterol in patients with psoriatic arthritis. J Eur Acad Dermatol Venereol 2003;17:362-363.

24. Oliviero F, Sfriso P, Baldo G, et al. Apolipoprotein A-I and cholesterol in synovial fluid of patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Clin Exp Rheumatol 2009;27:79-83.

25. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-1695.

26. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation 2004;109:II2-10.

27. Danesh J, Wheeler JG, Hirschfield GM, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004;350:1387-1397.

28. Thalmann S, Meier CA. Local adipose tissue depots as cardiovascular risk factors. Cardiovasc Res 2007;75:690-701.

29. Kaur S, Zilmer K, Leping V, Zilmer M. The levels of adiponectin and leptin and their relation to other markers of cardiovascular risk in patients with psoriasis. J Eur Acad Dermatol Venereol 2011;25:1328-1333.

30. Tam LS, Li EK, Shang Q, et al. Tumour necrosis factor alpha blockade is associated with sustained regression of carotid intima-media thickness for patients with active psoriatic arthritis: A 2-year pilot study. Ann Rheum Dis 2011;70:705-706.

31. Angel K, Provan SA, Gulseth HL, Mowinckel P, Kvien TK, Atar D. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: A controlled study. Hypertension 2010;55:333-338.

32. Mazzoccoli G, Notarsanto I, de Pinto GD, et al. Anti-tumor necrosis factor-alpha therapy and changes of flow-mediated vasodilatation in psoriatic and rheumatoid arthritis patients. Intern Emerg Med 2010;5:495-500.

33. Peters MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69:325-331.

Dr lam Tat Chung, Paul (林達聰醫生)FRCP, FHKAM(Medicine), FHKAM(Psychiatry)

Specialist in Psychiatry, Private Practice

Honorary Clinical Assistant Professor, University of Hong Kong

attention deficit hyperactivitydisorder (ADHD) affects about4% of adults, and many aretreated on psychostimulants.

As such medications may cause hyper-tension and cardiac arrhythmia, there isrealistic concern about the possibility ofsignificant cardiovascular (CV) morbidityormortality.

A new study led by Dr LaurelHabel,PhDfromtheKaiserPermanenteNorthern California, Oakland, USA re-portednoincreaseofseriousCVevents.

This was a retrospective, popu-lation-basedcohortstudyusingelectronichealthcare records from four differentsites.Thestudyincluded443,198adultsaged 25–64 years, of whom 150,359were users of ADHD medications atbaseline.Thedrugsincludedmethylphe-nidate, amphetamine, atomoxetine andpemoline. During 806,182 person-yearsof follow-up, 1,357 cases of myocardialinfarction, 296 cases of sudden cardiac

deathand575casesofstrokewere re-corded. The multivariable-adjusted rateratio of serious CV events for currentusers vs nonusers was 0.83 (95% con-fidenceinterval0.72–0.96).

Thisstudygivessomereassurancetodoctorswhowishtoprescribepsycho-stimulants to theiradultADHDpatients.However, one must be aware that lessserious problems like hypertension orcardiac arrhythmia are not addressed.Also, physicians need to continue tomonitor CV status and complications intheirpatients.

Journal Report – aDhD medications Do not increase Serious cardiovascular events in adults

Reference: JAMA e-pub Dec 12, 2011.

Journal of The Society of Physicians of Hong Kong 11

Introduction

clopidogrel was approved by theFoodandDrugAdministrationforuse in secondary prevention ofheartattacksandstrokein1997.

The efficacy of clopidogrel added toaspirin has been established in patientswith acute coronary syndrome (ACS) ormyocardial infarction (MI),1,2 and percu-taneous coronary stenting.3 However,themajorcomplicationisbleeding,partic-ularlyfromthegastrointestinal(GI)tract.1

This review aims to examinethe epidemiology and management ofadverse upper GI events in patients re-ceiving clopidogrel or dual antiplatelet

therapy. Furthermore, the interactionbetweenprotonpumpinhibitor(PPI)andclopidogrelwillbereviewed.

Clopidogrel

Clopidogrel differs from aspirin in themechanism by which it inhibits plateletaggregation.4Clopidogrelinhibitsplateletaggregation by irreversibly inhibiting thebindingofadenosinediphosphate,asub-stance released from platelets duringactivation that amplifies the aggregationprocess.Thisagentdoesnotimpairpros-taglandin-dependent mucosal protectiveandulcerhealingmechanisms,which isasideeffectofaspirin.

Clopidogrel-induced Gastrointestinal Bleeding

In the Clopidogrel versus Aspirin inPatients at Risk of Ischemic Events(CAPRIE)trial,19,185patientswereran-domized to receive clopidogrel 75 mg/dayoraspirin325mg/day.5Afterameanfollow-up of 1.9 years, the incidence ofsevereadverseupperGIeventswassig-nificantly lowerforclopidogrelvsaspirin(dyspepsia, 0.97% vs 1.22%, p<0.05;severe GI bleeding [GIB], 0.52% vs0.72%,p<0.05).Therefore,clopidogrelissaferthanaspirininaverage-riskpatients.

In high-risk patients with pepticulcers,clopidogreltherapyaloneisunsafeandPPIcotherapyisrequired.Inaretro-spectivecohortstudybyNgFHetal,therate of ulcer bleeding induced by clopi-dogrel was 9% over 1 year in patientswith previous peptic ulcers.6 History ofovert upper GIB was a significant riskfactor. Three randomized controlledstudies showed similar findings. Ng FHetalcomparedtheincidenceofunhealed

ulcers in patients receiving omeprazoleplus either clopidogrel or aspirin.7 Thetreatment success rate for clopidogreland aspirin was 94% and 95%, respec-tively. No GIB was observed in bothgroups.ChanFKLetel studiedpatientswith aspirin-induced ulcer bleeding.8AfterulcerhealinganderadicationofHeli-cobacter pylori(ifinfected),patientswererandomized to receiveeitherclopidogrelplusplacebooraspirinplusesomeprazole(20 mg twice daily) for 12 months. Thecumulative incidence of recurrentbleeding was significantly higher in theclopidogrel group (8.6%) vs the aspirinplus esomeprazole group (0.7%). In LaiKCetal’sstudy,thedesignwassimilartothatofthesecondstudyexceptasmallerdoseofesomeprazole(20mgdaily)wasused.9 During a follow-up of 52 weeks,the cumulative incidence of recurrentulcer complications was 0% in patientsreceiving esomeprazole and aspirin vs13.6% in patients receiving clopidogrel.Therefore, aspirin plus esomeprazoleis superior to clopidogrel alone in thesecondary prevention of recurrent ulcerbleeding.

Gastrointestinal Bleeding Induced by aspirin and Clopidogrel Cotherapy

The major adverse event of aspirin andclopidogrel (A+C) cotherapy is bleeding.In the Clopidogrel in Unstable Anginato Prevent Recurrent Ischaemic Events(CURE) study, which recruited patientswith ACS, A+C cotherapy was asso-ciated with a significantly higher totalnumberofbleedingcomplications(8.5%)vs aspirin monotherapy (5%).1 Excessmajorbleedingmostfrequentlyoccurredin the GI tract. Major GIB occurred in

management of adverse gastrointestinal events in Patients on antiplatelet therapy, Part ii: gastrointestinal Bleeding induced by clopidogrel or Dual antiplatelet therapy

Key words: clopidogrel (氯吡格雷), proton pump inhibitor (質子泵抑製劑), esomeprazole (埃索他拉唑), gastrointestinal bleeding (消化道出血)

Dr ng Fook Hong (吳福康醫生)

MB,BS(HK), MD (HK), MRCP(UK), FRCP (Edinburgh), FRCP (London), FRCP (Glasgow), FHKCP, FHKAM (Medicine)

Specialist in Gastroenterology and Hepatology, Private Practice

Honorary Consultant in Gastroenterology and Hepatology, Ruttonjee Hospital

Honorary Assistant Professor, Department of Medicine, University of Hong Kong

12 Journal of The Society of Physicians of Hong Kong

A complete list of references can be downloaded from

www.SOPHYSICIANSHK.org

1.3% of patients treated with A+C co-therapyvs0.7%ofpatientstreatedwithaspirin alone (relative risk [RR]=1.79,95%CI1.25–2.56).Inanotherstudy,pa-tientswithischaemicstrokeortransientischaemic attacks were randomized toreceive clopidogrel or A+C cotherapy.After a follow-up of 18 months, life-threateningbleedingwasmorecommoninthegroupreceivingA+Ccotherapyvsclopidogrel alone (2.6% vs 1.3%).10 GIBwas the most common cause of life-threateningandmajorbleedsinpatientsallocatedtodualantiplatelettherapy.

adverse Impact of Gastrointestinal BleedingThe adverse impact of bleeding in ACSorMIhasbeenrecognizedrecently.11Pa-tientswithmajorbleedinghada5-foldin-creaseinmortalityrateat30days(12.8%vs2.5%inthosewithoutmajorbleeding;p=0.0001).However,minorbleedingalsosignificantly increased the risk of death(adjusted RR=2.07, 95% CI 1.15–3.72).Therefore,preventionofGIB inpatientswithACSisofparamountimportance.

Preventing Gastrointestinal Bleeding During aspirin and Clopidogrel CotherapyPPI therapy is highly effective in pre-ventingupperGIBinpatientswithACSoracuteMI(AMI).NgFHetaldemonstratedthatPPItherapycouldsignificantlyreducetheriskofupperGIBinpatientsreceivingacombinationofaspirin,clopidogrelandenoxaparin for ACS.12 The age-adjustedoddsratio(OR)forGIBwas0.068(95%CI 0.010–0.272) for coprescription witha PPI. Moreover, a case-control studyshowed that PPI therapy is associatedwith reduced risk of upper GIB within30daysof percutaneous coronary inter-vention (OR=0.08, 95% CI 0.02–0.40,p=0.002).13Inaretrospectivestudyofpa-tients receiving A+C cotherapy, the riskof major GIB was significantly lower inpatientswithcoprescriptionofPPIthaninthosewithout(11.1%vs1.8%,p=0.05).14

Recently, a large randomizedcontrolled study demonstrated thatomeprazole significantly reduces the in-cidence of the composite endpoint ofupper GIB or symptomatic ulcer in pa-tients receiving A+C cotherapy (hazardratio [HR]=0.55, 95% CI 0.36–0.85,

p=0.007).15Inasecondrandomizedcon-trolledstudy,thecombinationofesome-prazole (20 mg/day) and clopidogrelreduced the recurrence of endoscopicpepticulcers comparedwith clopidogrelalone during the 6-month period (1.2%vs11.0%,p=0.009).16Inconclusion,bothesomeprazoleandomeprazolearehighlyeffectiveforpreventionofGIBinpatientsonA+Ccotherapy.

Proton Pump Inhibitor and Clopidogrel Interaction

Both clopidogrel and PPIs are prodrugsthatrequireactivationbythehepaticcy-tochromeP450enzymes.This commonpathwaymayleadtoreducedconversionofclopidogreltoitsactivemetabolite.Thepharmacodynamic and clinical outcomestudiesaresummarizedbelow.

Pharmacodynamic StudiesAdouble-blindplacebo-controlledtrialhasdemonstrated that omeprazole signifi-cantly decreases clopidogrel’s inhibitoryeffect on platelet P2Y12.17 This is nota class effect, and this effect does nottranslate into adverse clinical outcome.A nonrandomized study found no sig-nificant difference in platelet reactivityamong patients taking esomeprazoleor pantoprazole and controls.18 In a ran-domized controlled study with pepticulcerrecurrenceasaprimaryendpoint,asubgroupof42consecutivepatientspar-ticipated in a pharmacodynamic study.19There were no differences in the per-centagesof aggregatedplateletsbeforeand28daysafteresomeprazoletherapy(31.0% ± 20.5% vs 30.1% ± 16.5%).Recently, our group has completed alargerdouble-blindrandomizedstudythatcompared esomeprazole vs famotidineon the platelet inhibitory effect of clopi-dogrel.20 Eighty-eight patients on A+Ccotherapy were randomized to receiveesomeprazole20mgdailyorfamotidine40 mg daily. The platelet reactivity uniton day 28 was 242.6 ± 89.7 and 237.5± 79.2 in the groups receiving esome-prazole and famotidine, respectively[mean difference=5.1, 95% CI -30.8 to41.0, p=0.78]. In conclusion, esome-

prazole does not reduce the platelet in-hibitoryeffectofclopidogrel.

Clinical outcome StudiesThe result of clinical outcome studiesremains controversial. Retrospectivestudies on the association between PPIuse and major adverse cardiovascularevents (MACE) demonstrated contra-dictory results.21-30 The unadjusted con-founding factors may have a significanteffect on results and their subsequentinterpretation since PPI users wereolder, with more comorbidities and co-medications.31 Two post-hoc analysesof previous large-scale randomized con-trolled studies demonstrated that PPIuse is not associated with an increasein MACE. Furthermore, a large ran-domized controlled study of 3,873 pa-tients receiving clopidogrel suggestedthattreatmentwithomeprazoledoesnotincrease the riskofMACEvsplacebo,15althoughthesamplesizemightbeunder-powered due to premature terminationfor financial reasons. MACE occurred in4.9%and5.7%ofpatientsonomeprazoleandplacebo,respectively(HR=0.99,95%CI0.68–1.44).

Conclusion

Theadditionofclopidogreltoaspirinhasbeen established in patients with ACS,AMIandpercutaneouscoronarystenting.However,themajorcomplicationisGIB,which is associated with MACE. PPIsincluding omeprazole and esomeprazoleare highly effective in preventing GIB.Pharmacodynamicstudiesdemonstratedthat omeprazole decreases clopidogrel’sinhibitory effect on platelet P2Y12. Thisisnotaclasseffect.Esomeprazoledoesnot reduce the platelet inhibitory effectof clopidogrel. Furthermore, post-hocanalyses of previous large-scale ran-domized controlled studies and a pro-spective randomized controlled studysuggest that PPI therapy does not in-creaseMACE.

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Before prescribing the product, the complete prescription information should be consulted.

References :

1. Thiboutot D, Gollnick H, Bettoli V, et al; Global Alliance to Improve Outcomes in Acne. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009;60(5)(suppl):S1-S50.

2. Dréno B, Kaufmann R, Talarico S, et al. Combination therapy with adapalene-benzoyl peroxide and oral lymecycline in the treatment of moderate to severe acne vulgaris: a multicentre, randomized, double-blind controlled study.Br J Dermatol. 2011;165(2):383-390.

3. Galderma Epiduo Gel. EU Summary of Product Characteristics. October 2010.

For the treatment of moderate to severe acne vulgaris

In moderate to severe papular/pustular acne — The Global Alliance Acne Treatment Algorithm recommends an oral antibiotic + a topical retinoid + BPO as the first choice for treatment.1

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JOURNAL OF THE SOCIETY OF PHYSICIANS OF HONG KONG

January 2012 • Vol. 4 • No. 1

1

Management of Adverse Gastrointestinal Events in Patients on

Antiplatelet Therapy, Part II: Gastrointestinal Bleeding Induced by

Clopidogrel or Dual Antiplatelet Therapy

Dr Ng Fook Hong (吳福康醫生)

MB,BS(HK), MD (HK), MRCP(UK), FRCP (Edinburgh), FRCP (London), FRCP (Glasgow),

FHKCP, FHKAM (Medicine)

Specialist in Gastroenterology and Hepatology, Private Practice

Honorary Consultant in Gastroenterology and Hepatology, Ruttonjee Hospital

Honorary Assistant Professor, Department of Medicine, University of Hong Kong

References:

1. Yusuf, S, Zhao, F, Mehta, SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in

Unstable Angina to Prevent Recurrent Events Trial 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.

2. Chen ZM, Jiang LX, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in

Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin

in 45,852 patients with acute myocardial infarction: Randomized

placebo-controlled trial. Lancet 2005;366:1607-1621.

3. Mehta SR, Yusuf S, Peters RJG, et al; Clopidogrel in Unstable angina to prevent

Recurrent Events trial (CURE) investigators. Effects of pretreatment with

clopidogrel and aspirin followed by long-term therapy in patients undergoing

percutaneous coronary intervention: The PCI-CURE study. Lancet

2001;358:527-533.

4. Schafer AI. Antiplatelet therapy. Am J Med 1996;101:199-209.

5. CAPRIE Steering Committee. A randomized blinded, trial of clopidogrel versus

aspirin in patients at risk of ischemic event (CAPRIE). Lancet 1996;348:1329-1339.

6. Ng FH, Wong SY, Chang CM, et al. High incidence of clopidogrel-associated

gastrointestinal bleeding in patients with previous peptic ulcer disease. Aliment

Pharmacol Ther 2003;18:443-449.

7. Ng FH, Wong BC, Wong SY, 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. Aliment Pharmacol Ther 2004;19:359-365.

8. Chan FKL, Ching JYL, Hung LCT, et al. Clopidogrel versus aspirin and esomeprazole

to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:238-244.

9. Lai KC, Chu KM, Hui WM, et al. Esomeprazole with aspirin versus clopidogrel for

prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol

Hepatol 2006;4:860-865.

10. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH investigators. Aspirin and

clopidogrel compared with clopidogrel alone after recent ischaemic stroke or

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double-blind, placebo-controlled trial. Lancet 2004;364:331-337.

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11. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of

bleeding on prognosis in patients with acute coronary syndromes. Circulation

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12. Ng FH, Wong SY, Lam KF, et al. Gastrointestinal bleeding in patients receiving a

combination of aspirin, clopidogrel and enoxaparin in acute coronary syndrome.

Am J Gastroenterol 2008;103:865-871.

13. Chin MW, Yong G, Bulsara MK, Rankin J, Forbes GM. Predictive and protective

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14. Ng FH, Lam KF, Wong SY, et al. Upper gastrointestinal bleeding in patients with

aspirin and clopidogrel co-therapy. Digestion 2008;77:173-177.

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16. Hsu PI, Lai KH, Liu CP. Esomeprazole with clopidogrel reduces peptic ulcer

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Gastroenterology 2011;140:791-798.

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clopidogrel with a proton pump inhibitor. Arch Intern Med 2010;170:704-710.

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after percutaneous coronary intervention with drug-eluting stents to outcomes.

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plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients

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