journal of the society of physicians of hong kongsophysicianshk.org/journal/2012_09.pdf · wk ip...

September 2012 • Vol. 4 • No. 5

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 Wong chun yu, Benjamin 王振宇醫生

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 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

62 update on chronic hepatitis B: hBsag Quantification and tenofovir

Dr Ng Fook Hong (吳福康醫生)

66 hepatic Resection for hepatocellular carcinoma

Dr Liu Chi Leung (廖子良醫生); Dr Ip Wai Kit, Edmund (葉維傑醫生)

68 the challenge of managing gastro-oesophageal Reflux Disease in asian Patients

Dr Wong Chun Yu, Benjamin (王振宇醫生)

71 contemporary guidelines on cardiovascular Disease Prevention and updated Recommendations on the use of antithrombotics

Dr Kathy Lee (李麗芬醫生)

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

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The 56th Anniversary Dinner, held at the Chater Room, Hong Kong Jockey Club,on September 2, 2012, was attended by about 200 members and guests.

The President, Dr Lam Tat Chung Paul, preparing for the cake cutting ceremony. Standing to his right: Mrs Annie Lam and Dr Tse Sing Sang Bell; standing to his left: Dr Tsang Wah Tak Kenneth and Dr Lau Chu Pak

From left: Dr Lam Tat Chung Paul, Mrs Annie Lam, Mrs Christine Siu, Dr Siu Kin Fan Francis

From left: Dr Tsang Wah Tak Kenneth, Mrs Annie Lam, Dr Lam Tat Chung Paul

From left: Dr Lau Chu Pak, Professor Sydney Tam, Ms Wyeman Tan

From left: Dr Clara Ooi, Mrs Janet Tsang, Dr Michael Cheng, Dr James Griffith

In this issue, there are two themes – chronic hepatitis and metabolic syndrome. In patients with chronic hepatitis B infection, manifes-tations range from carrier state to chronic hepatitis, compensated or decompensated cirrhosis and hepatocellular carcinoma (HCC).

The first part of this issue will focus on the management of chronic hepatitis B. Dr FH Ng discusses the role of quantitative HBsAg (a new biomarker) in assessing prognosis and treatment response, and the use of tenofovir in the management of chronic hepatitis B. Dr CL Liu and Dr WK Ip address recent advances in hepatic resection for HCC, including more accurate preoperative evaluation, improved perioperative care and improved operative techniques, leading to satisfactory results with low operative mortality and good long-term survival outcomes. In a recent survey in Southern China, the prevalence of metabolic syndrome was 7.3%, translating to a total of 4.0 million residents aged 20 years or above having the condition. A higher prevalence of the syndrome was observed in the urban population than in the rural popu-lation.1 Obesity is a risk factor for gastro-oesophageal reflux disease, erosive oesophagitis, and oesophageal adenocarcinoma.2 In the next section, Dr BCY Wong addresses the challenges in managing gastro-oesophageal reflux disease and discusses the limi-tations of therapy with current proton-pump inhibitors. Dr Kathy Lee provides an update on management of cardiovascular disease and the use of new antithrombotics. We hope that our readers will find these articles informative and useful.

1. Lao XQ, Zhang YH, Wong MC, et al. The prevalence of metabolic syndrome and cardiovascular risk factors in adults in southern China. BMC Public Health 2012;12:64.2. Corley DA, Kubo A, Zhao W. Abdominal obesity, ethnicity and gastro-oesophageal reflux symptoms. Gut 2007;56:756.

Dr Ng Fook Hong 吳福康醫生FRCP, MD, FHKAM (Medicine)Editor

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

Editorial

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: [email protected]

© 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.

56th Anniversary Scientific Meeting (Free admission for doctors) November 11, 2012 (Sunday)

FIRST ANNOUNCEMENTSpeakers: Dr Tsang Wah Tak, Kenneth (曾華德醫生) MD, FRCP, Specialist in Respiratory Medicine

Dr Chan Hin Lee, Henry (陳衍里醫生) MSc, MD, PhD, FRCP, Specialist in Dermatology

Dr Lau Chu Pak (劉柱柏醫生) MD, FRCP, Specialist in Cardiology

Dr Lam Tat Chung, Paul (林達聰醫生)FRCP, FRCPsych, FHKAM (Medicine), FHKAM (Psychiatry), Specialist in Psychiatry

Dr Wong Chun Yu, Benjamin (王振宇醫生) MD, PhD, FRCP, Specialist in Gastroenterology

Dr Ooi Gaik Cheng, Clara (黃鈺清醫生) MRCP, Specialist in Radiology

Dr Chow Wing Sun (周榮新醫生) Specialist in Endocrinology, Diabetes & Metabolism

Speaker in Rheumatology pending

Place: The Langham Hotel, 8 Peking Road, TST, Kowloon (尖沙咀北京道朗廷酒店)

Sponsors: Eisai (HK) Co. Ltd.; AstraZeneca Hong Kong Limited; GlaxoSmithKline Limited; Boehringer Ingelheim (HK) Ltd; Eli Lilly Asia, Inc

First come first serve basis. Pre-registration is required. CME under application. No confirmation will be sent for registration.

Unsuccessful applicants will be notified. Please check the website for updated information before you attend.

Registration form: Fax to 2561 5042 Attention: Ms Cindy Lui, of Eisai

Web registration and further details: www.SOPHYSICIANSHK.org

I wish to attend the Sunday Symposium and Buffet Lunch on November 11, 2012 (Free admission for doctors)

Name of Doctor (Surname first): Tel:

62 | Journal of The Society of Physicians of Hong Kong September 2012

Introduction

More than 400 million people worldwide are chronically infected by the hepatitis B virus (HBV). Up to 40% of those with chronic hepatitis B (CHB) may develop complications, including cirrhosis, decom-pensated liver disease and hepatocellular carcinoma.1

Transmission of HBV occurs by the parenteral route. The HBV binds onto the surface receptors of the host hepatocytes. Once the HBV enters the hepatocyte, the partially double-stranded viral relaxed circular DNA undergoes repair, and covalently closed circular DNA (cccDNA) forms within the nucleus. The cccDNA serves as a transcriptional template to form pregenomic RNA. This is subsequently reverse-transcribed into the first negative strand of the HBV DNA. After completion of the second positive strand of HBV DNA, the resultant double-stranded DNA can be exported as new HBV progeny.2

Serum HBV surface antigen (HBsAg) level has been suggested to be a biomarker for treatment response in CHB. HBsAg level reflects the tran-

scriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Tenofovir disoproxil fumarate is an acyclic adenine nucleotide analogue effective against HBV. Tenofovir treatment is associated with sustained and pro-nounced viral suppression and significant regression of fibrosis/cirrhosis, with no resistance to tenofovir being detected. Tenofovir is generally well tolerated, even in patients with decompensated liver disease and during pregnancy. This review will present updated evidence on HBsAg quantification and focus on tenofovir treatment for HBV infection.

HbsAg Quantification During Nucleos(t)ide Analogue treatment

Introduction In recent years, many studies have been conducted to address the use of serum HBsAg level in predicting treatment response in CHB.

HBsAg kinetics between patients treated with interferon alfa and nucleos(t)

update on chronic hepatitis B: hBsag Quantification and tenofovir

Key words: Hepatitis B (乙型肝炎), tenofovir (替諾福韋); HBsag (乙肝表面抗原)

Dr Ng Fook Hong (吳福康醫生)

MBBS (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

Perc

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0Baseline Year 1 Year 5

Ishak fibrosis scores

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figure. change in ishak fibrosis scores at baseline, year 1 and year 5 for the 344 patients who had baseline liver biopsy

Marcellin P, Buti M, Gane EJ, et al. Five years of treatment with tenofovir DF (TDF) for chronic hepatitis B (CHB) infection is associated with sustained viral suppression and significant regression of histological fibrosis and cirrhosis. Presented at the 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011); 4–8 November 2011; San Francisco; Abstract 1375.

September 2012 Journal of The Society of Physicians of Hong Kong | 63

ide analogues (NA) were compared in three studies.3-5 HBsAg decline during NA therapy is slower and less pro-nounced compared with interferon treatment. Based on HBsAg kinetics, the predicted median time to HBsAg loss in NA-treated patients is in the range of 10 to 30 years. This is because NAs only inhibit the reverse transcription of the pregenomic RNA but do not target the cccDNA directly.4

HbeAg-positive patientsWhether or not the measurement of quantitative HBsAg values during NA treatment predicts HBsAg loss is an important practical question. For HBV ‘e’ antigen (HBeAg) positive patients, in the pivotal trial of tenofovir, the probability of losing HBsAg over 3 years was 8%. Patients who achieved HBsAg loss, with a high baseline necroinflammatory score and higher HBV DNA and HBsAg levels, were: those with genotypes A (60%), D (35%), or F (5%); all non-Asians; those with bridging fibrosis or cirrhosis (65%); and mostly males.5

HbeAg-negative patientsAmong entecavir- and tenofovir-treated patients, the decline in HBsAg is less pronounced, by about 5-fold, in HBeAg-negative patients than in HBeAg-positive patients.5,6 In a small study in Hong Kong, among 53 HBeAg-negative patients on lamivudine treatment for a mean of 19 months, the end-of-treatment HBsAg level (reduction by >1 log to <100 IU/mL) was found to predict sustained viral suppression.7 A large case-control study in Hong Kong demonstrated that serum HBsAg <200 IU/mL and 0.5-log reduction

in HBsAg predicted HBsAg seroclearance within 3 years of follow-up.8 However, in a German study with predominantly HBeAg-negative patients on NA therapy, early on-treatment decline did not predict HBsAg loss.9

tenofovir

Tenofovir disoproxil fumarate, like adefovir dipivoxil, is a nucleotide reverse tran-scriptase inhibitor that has activity against HBV.

HbeAg-positive CHbA total of 266 nucleoside-naïve patients with HBeAg-positive CHB were randomly assigned to tenofovir 300 mg or adefovir 10 mg.10 Significantly more patients in the tenofovir group achieved an HBV DNA level of <400 copies/mL (76% vs 13%), alanine aminotransferase (ALT) normali-sation (68% vs 54%), and HBsAg loss (3% vs 0%) than those in the adefovir group. Follow-up data on 214 HBeAg-positive patients who completed a total of 3 years of tenofovir treatment were recently reported; among these patients, 72% had HBV DNA levels <400 copies/mL, 34% lost HBeAg and 8% had HBsAg loss.5

HbeAg-negative CHbA total of 375 nucleoside-naïve patients with HBeAg-negative CHB were randomly assigned to tenofovir 300 mg or adefovir 10 mg.10,11 At week 48, signifi-cantly more patients receiving tenofovir achieved a serum HBV DNA level of <400 copies/mL (93% vs 63%). No patient lost HBsAg. Safety and tolerability of each NA

were similar. A follow-up report described the outcomes of 328 HBeAg-negative patients who completed a total of 3 years of tenofovir treatment, among whom 87% had HBV DNA <400 copies/mL, and 81% had normal ALT levels.11

resistance

No HBV polymerase/reverse tran-scriptase mutations associated with tenofovir were detected after up to 144 weeks of treatment in NA-naïve or NA-exposed patients.11 Most cases of viro-logical breakthrough were attributed to noncompliance. At the 22nd Conference of the Asian Pacific Association for the Study of the Liver, in February 2012, no resistance to tenofovir was reported following up to 240 weeks (~5 years) of treatment in patients with HBeAg-positive and HBeAg-negative CHB.12

previous exposure to lamivudine

Tenofovir is effective in suppressing lami-vudine-resistant HBV, including patients who had incomplete virus suppression after switching to adefovir. The efficacy of tenofovir was evaluated in 131 patients with CHB infection who had previously received HBV treatment with either lami-vudine or adefovir, sequential therapy with lamivudine and adefovir, or add-on combination therapy with both drugs.13 All patients without adefovir resistance achieved HBV DNA levels of <400 copies/mL after a median of 23 months.

table. cross-resistance profiles of lamivudine, telbivudine, entecavir, adefovir and tenofovir

hBv variantsLevel of susceptibility

Lamivudine telbivudine entecavir adefovir tenofovir

Wild-type S S S S S

M204V R S I I S

M204I R R I I S

L180M + M204V R R I I S

A181T/V I S S R S

N236T S S S R I

L180M + M204V/I ± I169T ± V173L ± M250V R R R S S

L180M + M204V/I ± T184G ± S202I/G R R R S S S, sensitive; I, intermediate susceptibility; R, resistant.


In contrast, only 52% of patients with adefovir resistance achieved DNA nega-tivity. Loss of HBeAg occurred in 24% of patients. Virological breakthrough was not observed in any of the patients. The Table shows cross-resistance data of the most common resistant HBV variants.14

Fulminant Spontaneous reactivation of CHb

Tenofovir is effective for the treatment of severe spontaneous reactivation of CHB. In a placebo-controlled trial involving 27 patients with severe spontaneous re-activation (total bilirubin ≥85 µmol/L and an International Normalised Ratio >1.5), treatment with tenofovir (300 mg daily) resulted in a significantly better 3-month survival (57% vs 15%).15 A favourable outcome was predicted by more than a 2-log reduction in HBV DNA levels after 2 weeks of treatment.

pregnancy

The United States Food and Drug Administration (FDA) lists tenofovir as a category B drug. The safety of entecavir in pregnancy is unknown; however, tenofovir should be preferred,16 because it has a better resistance profile and more extensive safety data in pregnant, HBV-positive women.17,18

Conventional measures to prevent perinatal HBV transmission, which occurs mainly at the time of delivery, have been administration of hepatitis B immuno-globulin (HBIg) and HBV vaccination. However, this may not be effective in newborns from highly viraemic (serum HBV DNA >106–7 IU/mL) and mostly HBeAg-positive mothers. These babies have more than 10% risk of vertical HBV transmission despite HBIg and vaccination.19,20 These mothers should be considered for NA therapy to reduce their viral loads.21 Lamivudine and telbi-vudine therapy, during the last trimester of pregnant HBsAg-positive women with high viral loads, reduced the risk of intrauterine and perinatal transmission of HBV when these therapies were given in addition to passive and active vac-

cination.22,23 Tenofovir (as a potent FDA category B agent) should be considered in high-risk mothers.

Safety

Tenofovir is eliminated by the kidneys. Creatinine clearance should be calculated prior to initiating therapy, and monitored. The dosing interval needs to be modified in patients with a creatinine clearance of <50 mL/min.

Renal failure has not been observed in two clinical trials of tenofovir in patients with HBV monoinfection after treatment for 72 weeks.10 Furthermore, creatinine and creatinine clearance remained stable over 3 years.11

Decrease in bone density has been reported in HIV-infected patients and may be related to an increased loss of phosphate through the kidneys. Fewer than 1% patients experienced a reduction in serum phosphorus, which can be resolved with continued tenofovir therapy, without any additional inter-vention.11

Conclusion

HbsAg quantification• Serum HBsAg decline is slow and

does not correlate with HBV DNA levels during treatment with NAs.11

• A rapid serum HBsAg decline during NA therapy after complete virological response may identify patients who will clear HBsAg in the long term. However, the supporting evidence remains limited, thus warranting further validation in large-scale, multi-center studies.

tenofovir• Tenofovir is highly effective in sup-

pressing HBV DNA and normalising ALT in HBeAg-positive and -negative CHB patients.

• Tenofovir has a high barrier to mu-tation; no resistance was reported fol-lowing up to 240 weeks of treatment.

• Tenofovir (as a potent FDA category B agent) may be used for the prevention of perinatal and intrauterine HBV trans-

mission in the last trimester of pregnant women with high levels of viraemia (serum HBV DNA >106–7 IU/mL).

• Tenofovir is safe; renal failure was not observed over 3 years of treatment. Decrease in bone density and re-duction in serum phosphorus is ex-tremely rare.

• Tenofovir can be used as first-line monotherapy for CHB.

• Tenofovir is the first-line therapy for CHB patients harbouring lamivudine-/telbivudine-resistant HBV mutants.

references

1. Lai CL, Ratziu V, Yuen MF, et al. Viral hepatitis B. Lancet 2003;362: 2089-2094.

2. Nassal M. Hepatitis B viruses: Reverse transcription a different way. Virus Res 2008;134:235-249.

3. Brunetto MR, Moriconi F, Bononi F, et al. Hepatitis B virus surface antigen levels: A guide to sutained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009;49:1141-1150.

4. Chan HL, Thompson A, Martinot-Peignoux M, et al Hepatitis B surface antigen quantification: Why and how to use it in 2011 – A core group report. J Hepatol 2011;55:1121-1131.

5. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011;140:132-143.

6. Reijnders JG, Rijckborst V, Sonneveld MJ, et al. Kinetics of hepatitis B surface antigen differ between treatment with peginterferon and entecavir. J Hepatol 2011;54:449-454.

7. Chan HL, Wong GL, Chim AM, et al. Prediction of off-treatment response to lamivudine by serum hepatitis B surface antigen quantification in hepatitis B e antigen-negative patients. Antivir Ther 2011;16:1249-1257.

8. Seto WK, Wong DK, Fung J, et al. A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance. Hepatology 2012;DOI:10.1002/hep.25718.

9. Jaroszewicz J, Ho H, Markova A, et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon-inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide analogues. Antivir Ther 2011;16:915-924.

10. Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis. New Engl J Med 2008;359:2442-2455.

11. Snow-Lampart A, Chappell B, Curtis M, et al. No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus. Hepatology 2011;53:763-773.

12. Gordon SC, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate (TDF) following up to 240 weeks of treatment in patients with HBeAg+ and HBeAg- chronic hepatitis B virus infection. Presented at the 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL); 16–19 February 2012: Taipei, Taiwan.

13. van Bömmel F, de Man RA, Wedemeyer H, et al. Long-term efficacy of tenofovir monotherapy for hepatitis B virus-monoinfected patients after failure of nucleoside/nucleotide analogues. Hepatology 2010;51:73-80.

14. Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 2009;137:1593-1608.

15. Garg H, Sarin SK, Kumar M, et al. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 2011;53:774-780.

16. Anonymous. FDA pregnancy class definitions. Available at: http://en.wikipedia.org/wiki/Pregnancy_category. Accessed 5 September 2012.

17. Anonymous. Antiretroviral pregnancy registry. Available at: http://www.apregistry.com. Accessed 5 September 2012.

18. Bzowej NH. Hepatitis B therapy in pregnancy. Curr Hepat Rep 2010;9:197-204.

19. del Canho R, Grosheide PM, Mazel JA, et al. Ten year neonatal hepatitis B vaccination program, The Netherlands, 1982–1992: Protective efficacy and long-term immunogenicity. Vaccine 1997;15:1624-1630.

20. Han GR, Cao MK, Zhao W, et al. A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol 2011;55:1215-1221.

21. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185.


Introduction

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is the third leading cause of cancer mortality in Hong Kong. There are about 1,700 new cases per year, and about 1,500 patients died from the disease in 2002. The incidence of HCC in Hong Kong is much higher than in Western countries, and is related to the high incidence of hepatitis B virus (HBV) infection in Southeast Asia. More than 80% of all HCC in Hong Kong is asso-ciated with chronic HBV infection. Other aetiologies include hepatitis C infection, alcohol abuse, metabolic diseases and unknown causes. Hepatic resection remains the treatment of choice and can offer a meaningful chance of long-term survival for patients with HCC.

preoperative evaluation and Selection Criteria for resection

Careful preoperative evaluation of tumour status and patient condition are essential for the successful surgical management of HCC. Evaluation should include liver function tests, chest X-ray, ultrasonography, and contrast-enhanced helical computed tomography (CT) scan or magnetic resonance imaging (MRI) of the upper abdomen. CT scan and MRI are considered suitable for assessing the relationship of the tumour to major hepatic vasculature, and detecting sat-ellite nodules or intrahepatic metastases and tumour invasion of major vessels, including the inferior vena cava and the portal vein.1 Positron emission tomography (PET), especially with 11C-acetate, has recently been shown to be useful in the differentiation of HCC from other benign hepatic lesions and in the detection of distant metastases.2

The usual criteria for selecting

patients for hepatic resection include the absence of extrahepatic metastases and the absence of tumour thrombus in the inferior vena cava or main portal vein, although hepatic resection with removal of tumour thrombus in these major vessels has been advocated. The role of hepatic resection for bilobar HCC is more controversial. Major hepatic resection in one lobe combined with wedge resection for a smaller lesion in the other lobe, is possible in some patients. Alterna-tively, hepatic resection in one lobe can be combined with removal of a smaller lesion in the contralateral lobe using radiofrequency ablation. Previous studies have shown that hepatic resection for patients with bilobar HCC resulted in better survival outcomes compared with non-resectional therapies.3

Attention to the general medical fitness of patients is one of the most important selection criteria for hepatic resection for HCC. The presence of comorbid illness, including cardio-vascular disease, diabetes or renal function impairment, is associated with an increased risk of operative mor-bidity and mortality. Since the majority of patients with HCC have underlying chronic liver disease, including cirrhosis, a careful assessment of the liver function reserve is important, to avoid postop-erative liver failure and mortality. Indo-cyanine green clearance test is a useful investigation for predicting postoperative mortality in patients undergoing major hepatic resection.4

Measurement of the liver remnant volume by CT volumetry has been shown to be helpful in selecting patients for major hepatic resection.5

For patients who require major hepatic resection for HCC, but have inadequate liver remnant volume, preoperative portal vein embolisation can be used to induce atrophy of the right lobe of the liver.6 This allows for safer hepatic resection in patients who have a small

hepatic Resection for hepatocellular carcinoma

Key words: Hepatocellular carcinoma (肝細胞癌), hepatectomy (肝切除術), operative morbidity (手術併發症), survival outcomes (存活結果)

Dr liu Chi leung (廖子良醫生)

MBBS (HK), MS (HK), MD (HK), FRCS (Edin) FACS, FCSHK, FHKAM (Surgery)

Hong Kong Hepatobiliary and Pancreatic Centre

Dr Ip Wai Kit, edmund (葉維傑醫生)

BSc (HK), MBBS (HK), FRCS (Edin), FCSHK FRCSEd (Gen), FHKAM (Surgery)

Hong Kong Hepatobiliary and Pancreatic Centre


liver remnant, and helps to minimise postoperative morbidity and mortality.

operative techniques

Bilateral subcostal incision with upward midline extension is sufficient in most circumstances for hepatic resection for HCC. With a self-retaining retractor, the costal arch is pulled up cranially and the entire anterior surface of the liver can be exposed. The use of an ultrasonic dissector is recommended for accurate and safe parenchymal transection of the liver, with less operative blood loss and a wider tumour-free resection margin compared with modified finger-fracture technique.7

Right or extended right hepatic resection for large HCC represents one of the major challenges to surgeons. Complete mobilisation of the right lobe of the liver with the right hepatic vein controlled outside the liver before paren-chymal transection, has been the con-ventional approach for major right hepatic resection for HCC. However, injudicious mobilisation of the liver in the course of this approach may result in excessive bleeding due to avulsion of the hepatic veins and caval branches, prolonged ischaemia of the liver remnant from rotation of the hepatoduodenal ligament, and iatrogenic tumour rupture with spillage of cancer cells into the systemic circulation. Alternatively, the anterior approach can be adopted for patients undergoing major right hepatic resection for HCC. The technique involves initial vascular inflow control, completion of parenchymal transaction, and complete venous outflow control, before the right lobe is mobilised.8 This approach is con-sidered to be beneficial in preserving the function of the liver remnant by avoiding warm ischaemia of the latter related to pedicle torsion during mobilisation of a large tumour. A prospective randomised study of 120 patients with large right-lobe HCC has shown that the anterior approach is associated with significantly better operative and survival outcomes.9

Traditionally, an abdominal drain is routinely inserted into the subphrenic or subhepatic space close to the resection surface in patients who undergo hepatic resection. This serves to release the intra-

abdominal tension due to ascitic fluid accumulation, and allows monitoring for the occurrence of postoperative bleeding, as well as detection and drainage of any bile leakage. In a prospective study, 104 patients who had underlying chronic liver disease were randomised to have either closed-suction abdominal drainage or no drainage after elective hepatic resection. Significantly higher overall operative morbidity was observed in the drainage group, which was asso-ciated with a higher incidence of wound complications and septic complications compared with the non-drainage group. The mean postoperative hospital stay of patients in the drainage group was also significantly longer than that of patients in the non-drainage group.10 Based on these findings, abdominal drainage after hepatic resection for HCC is no longer recommended.

Laparoscopic liver resection has recently been advocated for, and is con-sidered feasible in, a selected group of patients with HCC. Lesions located in the posterior or superior part of the liver are generally considered unsuitable for a laparoscopic approach because of limited visibility and anticipated difficulty in controlling bleeding. Therefore, lapa-roscopic resection is usually performed in patients with small, and peripherally and anteriorly located tumours.11 In the hands of trained surgeons with expertise in hepatobiliary and laparoscopic surgery, the technique is safe and is asso-ciated with acceptable postoperative and oncologic outcomes. However, the question of whether it is com-parable to conventional open resection

in terms of operative and long-term survival outcomes requires evaluation in a prospective, randomised, controlled trial setting.

operative outcomes

About a decade ago, hepatic resection was considered a risky operation, asso-ciated with large operative blood losses and increased operative mortality. More than 95% of patients received blood transfusion, and hospital mortality rates were as high as 10%, especially in patients with liver cirrhosis.12 With careful operative and perioperative management, hepatic resection has become a relatively safe operation, and operative mortality rarely occurs. Operative blood loss has significantly decreased in recent years, and blood transfusion is only required in about 3% of patients.12 Current estimated 3-year and 5-year survival rates of patients who undergo hepatic resection for HCC are >60% and >50%, respectively.12

Summary

Given recent advances, including a more accurate preoperative evaluation, improved perioperative care and improved operative techniques, hepatic resection for HCC has yielded more satisfactory results, with lower rates of operative mortality and better long-term survival outcomes.

references1. Fan ST, Lo CM, Liu CL, et al. Hepatectomy for hepatocellular carcinoma:

Toward zero hospital deaths. Ann Surg 1999;229:322-330.2. Ho CL, Chen S, Yeung DW, et al. Dual-tracer PET/CT imaging in evaluation

of metastatic hepatocellular carcinoma. J Nucl Med 2007;902:909.3. Liu CL, Fan ST, Lo CM, et al. Hepatic resection for bilobar hepatocellular

carcinoma: Is it justified? Arch Surg 2003;138:100-104.4. Fan ST, Lai EC, Lo CM, et al. Hospital mortality of major hepatectomy

for hepatocellular carcinoma associated with cirrhosis. Arch Surg 1995;130:198-203.

5. Kubota K, Makuuchi M, Kusaka K, et al. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumours. Hepatology 1997;26:1176-1181.

6. Farges O, Belghiti J, Kianmanesh R, et al. Portal vein embolization before right hepatectomy: Prospective clinical trial. Ann Surg 2003;237:208-217.

7. Fan ST, Lai EC, Lo CM, et al. Hepatectomy with an ultrasonic dissector for hepatocellular carcinoma. Br J Surg 1996;83:117-120.

8. Liu CL, Fan ST, Lo CM, et al. Anterior approach for major right hepatic resection for large hepatocellular carcinoma. Ann Surg 2000;232:25-31.

9. Liu CL, Fan ST, Cheung ST, et al. Anterior approach versus conventional approach right hepatic resection for large hepatocellular carcinoma: A prospective randomized controlled study. Ann Surg 2006;244:194-203.

10. Liu CL, Fan ST, Lo CM, et al. Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases. Ann Surg 2004;239:194-201.

11. Buell JF, Cherqui D, Geller DA, et al. The international position on laparoscopic liver surgery: The Louisville Statement, 2008. Ann Surg 2009;250:825-830.

12. Fan ST, Lo CM, Poon RT, et al. Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: A 20-year experience. Ann Surg 2011;253:745-758.

“Laparoscopic resection is usually

performed in patients with small, and peripherally and

anteriorly located tumours”


epidemiology

The prevalence of gastro-oesophageal reflux disease (GERD) is increasing across the Asian region.1,2 A population-based survey of Chinese households in Hong Kong (N=2,209) reported weekly, monthly and 1-year GERD prevalence rates of 2.5%, 8.9% and 29.8%, respec-tively.3 A 2008 survey conducted in China showed that the weekly prevalence of GERD was 5.2%.4

GERD is a chronic condition that has a substantial impact on quality of life (QoL). In particular, nocturnal symptoms have a significant effect on health-related QoL.5 Nighttime heartburn was par-ticularly prevalent in a US-based survey of 1,000 adults with regular heartburn (≥1 episode/week), affecting 79% of respondents, and resulting in sleeping dif-ficulties and impaired next-day function.6 Individuals with nocturnal GERD expe-rienced significantly more pain than those with hypertension and diabetes (p<0.001), and similar pain compared with those with angina and congestive heart failure.6

management

Appropriate treatment is important, par-ticularly since nocturnal symptoms are associated with GERD-related compli-cations, such as oesophageal erosions, ulceration and respiratory symptoms.6

However, current evidence indicates that patients frequently experience inad-equate relief from GERD.7 The recent GERD in Asia-Pacific Survey (GAPS) included patients from Thailand, Korea, Indonesia, the Philippines, Hong Kong and Taiwan. All patients experienced GERD symptoms within the past 6 months and were currently receiving proton pump inhibitors (PPIs).8 Both qualitative data, collected through focus groups, and quantitative data, collected through face-to-face interviews (N=450), were included. PPI monotherapy was the most common treatment regimen prescribed to patients, with approximately 50% of patients using a PPI more than once-daily. About 50% of patients continued to self-medicate with adjunctive over-the-counter (OTC) agents in addition to taking their prescribed PPI. Notably, only 23% of

the challenge of managing gastro-oesophageal Reflux Disease in asian Patients

Key words: GERD (胃食道反流性疾病), proton pump inhibitors (質子泵抑制劑)

Dr Wong Chun Yu, benjamin (王振宇醫生)

MBBS, MD (HK), PhD (HK), FHKCP FHKAM (Medicine), MRCP (UK) FRCP (London, Edinburgh, Glasgow)

Specialist in Gastroenterology and Hepatology

Honorary Clinical Professor Department of Medicine University of Hong Kong

Those with breakthrough symptoms most often have symptoms at night

16%

45%

65%

28%

In the morning

In the middle of the day

At night

During sleep

N=1064

No breakthrough symptoms

62%Breakthrough

symptoms

38%

figure. Proportion of geRD patients in the american gastroenterological association survey with breakthrough symptoms on current PPi therapy9


patients currently felt that their pain was completely under control. Breakthrough symptoms were commonly reported: 94% of PPI-treated patients experienced some breakthrough symptoms and 62% of PPI-treated patients experienced nocturnal symptoms.8

These findings are supported by an American Gastroen-terological Association online survey of 1,064 patients with phy-sician-diagnosed GERD who had taken once-daily PPI for at least 3 months.8 A total of 38% of patients experienced breakthrough symptoms, and these symptoms were most commonly expe-rienced at night (65%; Figure).

Evidence from both the US and Asia Pacific surveys shows that symptoms are poorly-controlled in some patients on PPI therapy, and consequently a significant proportion of patients require addi-tional medications.8,9 In an effort to control the symptoms of GERD, adjunctive OTC medications were used to supplement current PPI therapy in 56% of patients in the US (OTC antacid, 49%; OTC acid reducer, 7%).9

The majority of patients in the US (77%) on PPI therapy were not completely satisfied with their current regimen.9 Over 70% of Asian patients stated that they would like a 24-hour symptom control to provide nighttime symptom relief, and 50% would prefer a flexible PPI dosing regimen.8

limitations with Current ppIs

PPIs have had a dramatic impact on the management of acid-related disorders. However, the use of currently available PPIs is associated with certain limitations. PPIs function by inhibiting the gastric H+/K+-ATPase via covalent binding to cysteine residues of the proton pump.9,10 However, not all proton pumps are active at any given time, and therefore, a single dose of a PPI will inhibit only 70%–80% of active pumps. In practical terms, this means that up to 30% of acid production capacity may not be inhibited by a PPI dose.11 Furthermore, proton pumps are continually regenerated, and consequently, newly-synthesised pumps or those still active after plasma PPI levels have decreased below therapeutic levels, may not be inhibited.10,11 In addition, current PPIs typically have an elimination half-life of approximately 1–2 hours. Due to once-daily dosing, there is effectively no circulating PPI by the end of the dosing interval.10 Therefore, these short-acting PPIs are unable to completely control acid secretion over a 24-hour period with a single dose, and nocturnal acid breakthrough (intragastric pH <4 for ≥1 continuous hour) occurs in the majority of patients receiving PPI treatment.11

“Over 70% of Asian patients would like a 24-hour symptom control to provide nighttime

symptom relief, and 50% would prefer a flexible PPI

dosing regimen”


references1. Goh KL. Gastresophageal reflux disease in Asia: A historical perspective and present challenges. J Gastro Hepatol

2011;26 (suppl 1):2-10.2. El Serag HB. Time trends of gastresophageal reflux disease: A systematic review. Clin Gastroenterol Hepatol

2007;5:17-26.3. Wong WM, Lai KC, Lam KF, et al. Prevalence, clinical spectrum and healthcare utilization of gastro-oesophageal reflux

disease in a Chinese population: A population-based study. Aliment Pharmacol Ther 2003;18:595-604.4. Chen MJ, Wu MS, Lin JT, et al. Gastroesophageal reflux disease and sleep quality in a Chinese population. J Formos

Med Assoc 2009;106:53-60.5. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastresophageal reflux disease

on health-related quality of life. Arch Intern Med 2001;161:45-52.6. Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem that impacts

sleep and daytime function: The results of a Gallup survey conducted on behalf of the American Gastorenterological Association. Am J Gastroenterol 2003;98:1487-1493.

7. Ipsos Healthcare. GERD in Asia Pacific Survey (GAPS). Multicountry qualitative and quantitative study. December 2011-March 2012.

8. American Gastroenterological Association. GERD patient study: Patients and their medications. Harris Interactive Inc; 2008.

9. Sachs G, Shin JM, Howden CW. Review article: The clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther 2006;23 (suppl 2):2-8.

10. Katz PO, Scheiman JM, Barkun AN. Review article: acid-related – what are the unmet clinical needs? Aliment Pharmacol Ther 2006;23 (suppl 2):9-22.

11. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763-767.

12. Wittbrodt ET, Baum C, Peura DA. Delayed release dexlansoprazole in the treatment of GERD and erosive esophagitis. Clin Exp Gastroenterol 2009;2:117-128.

13. Scarpignato C, Pelosini I. Review article: The opportunities and benefits of extended acid suppression. Aliment Pharmacol Ther 2006;23 (suppl 2):23-34.

14. Hunt RH. Review article: The unmet needs in delayed-release proton-pump inhibitor therapy in 2005. Aliment Pharmacol Ther 2005;22 (suppl 3):10-19.

Proton pumps are primarily activated by food and, thus, optimal inhibition of acid secretion is reliant upon dosing prior to meals.10,12 Currently available PPIs should be administered less than 60 minutes prior to the morning meal to ensure optimum efficacy.13 However, evidence suggests that at least 50% of patients on PPI therapy who experience suboptimal efficacy, take their medication incorrectly.13

The clinical limitations of currently available PPI therapy and the suboptimal adherence to treatment have created unmet needs in the management of patients with GERD. Given that the clinical efficacy of PPIs is related to the degree of acid suppression, a rapid-acting PPI with an extended half-life may have a prolonged antisecretory effect and provide an effective 24-hour control,10

thereby further improving symptom relief.13,14

Conclusion

GERD is a common problem that is associated with a significant reduction in QoL. It is a clinical challenge to effectively manage GERD. Current evidence suggests that in the majority of patients, this disorder is not optimally managed with current PPI therapy. The dosing requirements, short plasma half-life, and variable clinical response to currently available PPIs may lead to patient dis-satisfaction.

Sunday Symposium

October 14, 2012

Oncology and Haematology

Please see details on

www.SOPHYSICIANSHK.org


Cardiovascular Disease preventionAtherosclerotic cardiovascular disease (CVD) is one of the most important causes of mortality and morbidity. It is a chronic disorder that evolves throughout life, from an early or mild form to an advanced disease with debilitating symptoms. A lifelong approach to pre-venting CVD should also be adopted. Over three-quarters of all cardiovascular mortality may be prevented by lifestyle modification and control of risk factors. The latest joint European Society of Car-diology guidelines on CVD prevention were released earlier in 2012.1 These focus on new scientific evidence in trying to resolve controversies in clinical practice, and provide a useful update on preventive cardiology for physicians and other healthcare workers. This article aims to highlight salient features that are especially relevant to general practitioners and non-cardiologists.

european Union public Health Statement on “How to Stay Healthy”

• No use of tobacco• Adequate physical activity: At least 30

minutes, five times a week• Healthy eating habits• No overweight• Blood pressure below 140/90 mmHg• Blood cholesterol below 5 mmol/L

(190 mg/dL)• Normal glucose metabolism• Avoidance of excessive stress

psychosocial risk FactorsPsychosocial risk factors in CVD are often overlooked. It has been found that low socioeconomic status, social isolation, low social support, stress at work or in family life, depression, anxiety, hostility, anger and type D personality, increase risk of CVD and contribute to worse clinical outcomes. Type D personality is described as “distressed” and involves an enduring tendency to experience a broader spectrum of negative emotions and inhibit self-expression in relation to others. These traits are associated with unhealthy lifestyle, increased healthcare utilisation, low compliance to treatment plan, and direct physiological adverse effects such as disturbing autonomic and endocrine functions, the inflammatory process and endothelial functions.

risk Assessment

Risk charts such as SCORE are intended to facilitate risk estimation in apparently healthy individuals. The SCORE system estimates the 10-year risk of a first fatal cardiovascular event, based on parameters such as age, gender, smoking habit, systolic blood pressure and total cholesterol. Ten-year risk of 5% or more is considered an increased risk, and man-agement of risk factors should be inten-sified. Updated SCORE charts based on data derived from high CVD (Figure 1) and low CVD (Figure 2) countries are available.

The risk-age of a person with several cardiovascular risk factors is the age of a person with the same level of risk, but with ideal levels of risk factors. For example, the risk of a 40 year old male smoker with risk factors is the same as that of a 60 year old man with ideal risk factor levels, therefore his risk-age

contemporary guidelines on cardiovascular Disease Prevention and updated Recommen-dations on the use of antithrombotics

Dr Kathy lee (李麗芬醫生)

MBBS, MRCP (Lond), FRCP (Edin), FACC FHKCP, FHKAM (Medicine)

Specialist in Cardiology

Honorary Assistant Professor Faculty of Medicine University of Hong Kong

Key words: cardiovascular disease (心血管疾病), cardiovascular risk (心血管疾病的風險), preventive cardiology (預防心臟病學)


is 60 years. Risk-age can be estimated by looking at the SCORE chart or auto-matically calculated as part of the latest version of HeartScore (www.HeartScore.org).

Update on Hypertension

Hypertension is diagnosed at different cutoffs with different types of blood pressure measurement. Although clinic

blood pressure is used most often, ambulatory or home blood pressure measurements are considered important objective assessment tools for diagnosis and monitoring treatment effect. A clinic blood pressure of 140/90, a home blood pressure of 135/80, a daytime ambu-latory blood pressure of 135/85, or a nighttime blood pressure of 120/70 can be used as thresholds for diagnosing hypertension. In general, blood pressure-

lowering treatment including life-style modification, low salt diet or pharmaco-logical agents should be initiated before end-organ damage develops or becomes irreversible. The decision to start anti-hypertensive treatment also depends on blood pressure and total cardiovascular risk. The goal of treatment should be to lower the blood pressure to below systolic 140 mmHg and diastolic 90 mmHg. Although intensive treatment of

table 1. intervention strategies as a function of total cardiovascular risk and low-density lipoprotein cholesterol (LDL-c)

total cv risk (ScoRe) %

LDL-c levels

<1.8 mmol/L 1.8 to <2.5 mmol/L 2.5 to <4.0 mmol/L 4.0 to <4.9 mmol/L ≥4.9 mmol/L

<1 No lipid intervention Lifestyle intervention Lifestyle intervention, consider drug if

uncontrolled

≥1 to <5 Lifestyle intervention Lifestyle intervention, consider drug if uncontrolled

>5 to <10, or high risk Lifestyle intervention, consider drug Lifestyle intervention and immediate drug intervention

≥10 or very high risk Lifestyle intervention, consider drug

Lifestyle intervention and immediate drug intervention

figure 1. ScoRe chart: 10-year risk of fatal cvD in countries at high cvD risk based on the following risk factors: age, sex, smoking, systolic blood pressure, and total cholesterol.

High CVD risk countries are all those not listed under the low risk chart (Figure 2). Of these, some are at very high risk, and the high-risk chart may underestimate risk in these. These countries are America, Azerbaijan, Belarus, Bulgaria, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Macedonia FYR, Moldova, Russia, Ukraine, and Uzbekistan.

Adapted from reference 1

figure 2. ScoRe chart: 10-year risk of fatal cvD in countries at low cvD risk. note that the risk of total (fatal + nonfatal) cvD events will be approximately three times higher than the figures given.

Low CVD countries are Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, the Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, and the United Kingdom.

Adapted from reference 1

10-year risk of total CVD in populations at high CVD risk

15% and over10%–14%5%–9%

3%–4%2%1%

<1%SCORE

10-year risk of total CVD in populations at high CVD risk

15% and over10%–14%5%–9%

3%–4%2%1%

<1%SCORE

http://www.HeartScore.org

http://www.HeartScore.org


blood pressure in diabetes reduces the risk of macrovascular and microvascular outcomes, previous recommendations to aim at a lower systolic blood pressure of <130 mmHg in patients with diabetes or high cardiovascular risk have not been proven in randomised clinical trials. Blood pressure goal in diabetics is <140/80 mmHg. A J-curve for causing harm in lowering blood pressure beyond 130 mmHg cannot be excluded.2

Update on Diabetes

Intensive management of hyper- glycaemia in diabetes reduces the risk of microvascular complications and, to a lesser extent, that of CVD.3 Target HbA1C for the prevention of CVD is <7.0%.4 Further reduction in HbA1C to a target of <6.5% may be useful in reducing micro-vascular outcomes for younger patients or those with a long history of diabetes. Excessive weight gain must be avoided, and metformin should be used as first-line therapy if tolerated and not contrain-dicated.

Update on HyperlipidaemiaIncreased total and low-density lipoprotein cholesterol (LDL-C) are main risk factors for CVD. For patients at high risk for CVD, an LDL-C target of <2.5 mmol/L is recom-mended. In patients at very high CVD risk, the recommended LDL-C target is <1.8 mmol/L or at least 50% LDL-C reduction when the target cannot be reached. Patients with diabetes, familial hypercho-lesterolaemia, peripheral vascular disease, carotid disease, chronic kidney disease, non-haemorrhagic stroke and established atherosclerotic disease, are all considered high risk groups. Intervention strategies are derived from total cardiovascular risk and LDL-C level (Table 1).5

Update on Diet and NutritionA healthy diet is characterised by:• Saturated fatty acid to account for

<10% of total energy intake, through

replacement by polyunsaturated fatty acid

• Trans-unsaturated fatty acid: as little as possible, preferably no intake from processed food, and <1% of total energy intake from natural origin

• <5 g of salt per day• 30–45 g of fibre per day, from whole

grain products, fruits and vegetables• 200 g of fruits per day (2–3 servings)• 200 g of vegetables per day (2–3

servings)• Fish at least twice a week, one serving

of which should be oily fish• Consumption of alcoholic beverages

should be limited to two glasses per day for men and one glass per day for women

Many believe that vitamins may protect against CVD; however, clinical trials have failed to establish such benefit for vitamins A, E, B6, folic acid, or B12. Clinical studies on the effect of vitamin D in CVD prevention are underway.

Updated Guidelines on using Antithrombotics in CVD prevention

The new guidelines also include an important summary on the use of anti-thrombotics in CVD prevention. Long-term aspirin should not be recommended for primary prevention in individuals without CVD or cerebrovascular disease because of doubtful value and unfavourable risk to benefit ratio. Likewise, antiplatelet therapy with aspirin is not recommended for diabetic patients who do not have clinical evidence of CVD. However, aspirin or clopidogrel alone reduces mortality and vascular events in patients after myo-cardial infarction (MI), stroke or peripheral vascular disease. Moreover, antiplatelet agents are essential in the management of acute coronary syndrome (ACS).6 Dual antiplatelet agents clopidogrel and aspirin have been shown to improve outcome in the whole spectrum of ACS including ST elevation MI, non-ST elevation MI, and unstable angina. However, in patients with ACS for whom an early invasive strategy is planned, dual antiplatelet therapy with a P2Y12 inhibitor, ticagrelor7 or prasugrel8 added to aspirin was superior to clopi-

dogrel and aspirin. The benefit was a larger reduction in composite endpoint of vascular death, MI or stroke. There was increased risk of major bleeding with pra-sugrel, but not with ticagrelor. Ticagrelor offers several advantages over currently available antiplatelet agents. It does not require activation, has a shorter half-life with rapid onset of action, and may be used when clopidogrel resistance occurs. However, long-term experience with these new antiplatelet agents is limited.

Conclusions

Atherosclerotic CVD remains the leading cause of premature death worldwide. In apparently healthy individuals, CVD risk is most frequently the result of multiple interacting risk factors. Preventive strategies are effective in reducing cardiovascular mortality and morbidity. Pre-ventive efforts should be lifelong, from birth to old age, as well as comple-mentary, from population-based to tar-geting high-risk individuals. Despite gaps in scientific knowledge and our understanding, there is ample evidence to justify intensive public health and individual preventive efforts.

references1. The Fifth Joint Task Force of the European Society of Cardiology and

Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) Eur Heart J 2012;33:1635-1701.

2. Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009;27:2121-2158.

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.

4. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572.

5. Reiner A, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) 2011;32:1769-1818.

6. The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). ESC guidelines for the management of acute coronary syndrome in patients presenting without persistent ST-segment elevation. Eur Heart J 2011;32:2999-3054.

7. Wallentin L, Becker RC, Budaj A, et al. Ticargrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-1057.

8. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015.

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