Journal of the Society of PhySicianS of hong Kong · January 2014 Journal of The Society of...

January 2014 • Vol. 6 • no. 1

Journal of the Society of PhySicianS of hong Kong

January 2014 Journal of The Society of Physicians of Hong Kong | 1

gastro-esophageal Reflux Disease: optimizing Proton Pump inhibitor therapy to improve Symptom control

Introduction

Gastro-esophageal reflux disease (GERD) is a chronic disorder of the upper gastrointestinal tract

with associated morbidity and an adverse impact on quality of life.1 GERD is defined as a “condition that develops when the reflux of stomach contents causes troublesome symptoms and/or compli-cations”.2 The current definition is not only symptom-based and patient-driven, but also encompasses esophageal and extra-esophageal manifestations of the disease.3 Psychological well-being ques-tionnaires have found that patients with

GERD can have a worse quality of life than some patients with menopausal symptoms, peptic ulcer disease, angina or congestive heart failure.4

Prevalence estimates show sig-nificant geographical variation, with prevalence rates as high as 28% in North America and up to 33% in the Middle East.5,6 A population-based survey involving 2,209 individuals from Chinese households in Hong Kong found the GERD prevalence rate to be about 8.9%.7

The initial management of GERD includes lifestyle modifications and phar-macologic therapy. The therapeutic goals are to control symptoms, heal esopha-gitis and maintain remission so that mor-bidity is decreased and quality of life is improved.1

According to the recently published ‘Guidelines for the diagnosis and man-agement of GERD’, lifestyle interventions should be part of the management strategy for patients GERD.8 Medical options for patients failing lifestyle inter-ventions include antacids, histamine-receptor antagonists (HRA), or proton pump inhibitor (PPI) therapy.8

Proton pump inhibitors for the management of GERDPPI therapy has been associated with superior healing rates and decreased relapse rates compared with HRAs and placebo for patients with erosive esophagitis.9 However, response rates to PPIs in GERD are highly variable.10 A substantial proportion of GERD patients continue to have symptoms despite optimal PPI therapy.3 Incomplete acid

suppression over the 24-hour post-dose interval is one of the major limitations of once daily PPI therapy.11

The majority of patients with GERD are not optimally managed with existing PPI therapy. In a recent Asia-Pacific survey,12 about 50% of patients were using a PPI more than once daily. However, there appeared to be unsatisfactory control of symptoms, with 94% of PPI-treated patients reporting breakthrough symptoms.12 Similarly, another survey revealed that 38% of GERD patients in the United States also experienced break-through symptoms with PPI therapy.13

A novel treatment option for the management of GERDOnce-daily dexlansoprazole has a dual-delayed release (DDR) formulation, making it attractive for step-down man-agement of patients whose symptoms are well controlled on twice-daily PPIs.14

DDR technology is designed to provide an initial drug release in the proximal small intestine followed by another drug release at more distal regions of the small intestine several hours later.15 For this reason, once-daily dexlansoprazole produces two distinct peaks: the first at 1–2 hours and the second at 4–5 hours, post-dose.11,15 Cur-rently one of the widely used once-daily PPIs, esomeprazole, produces maximum plasma concentrations at approximately 1.6 hours post-dose.16 While dexlanso-prazole may be taken without regard to meals,17,18 esomeprazole should be taken 30 minutes before meals to achieve maximum efficacy.16

Dr Wong Chun Yu, Benjamin (王振宇醫生)

MBBS (HK), DSc(HK), MD(HK), PhD(HK), MRCP (UK), FHKCP, FHKAM (Medicine), FRCP (London), FRCP (Glasgow), FRCP (Edinburgh)Specialist in Gastroenterology & HepatologyHonorary Clinical Professor, The University of Hong Kong

Key words: Gastro-esophageal reflux disease (GERD) (胃食道反流性疾病), proton pump inhibitor (質子泵抑制劑), dexlansoprazole (右蘭索拉唑), symptom control (症狀控制)

2 | Journal of The Society of Physicians of Hong Kong January 2014

EfficacyIn patients with symptomatic GERD, dex-lansoprazole 30 mg was found to be more efficacious than placebo in providing relief from nocturnal heartburn, in reducing GERD-related sleep disturbances and the consequent impairments in work pro-ductivity, and in improving sleep quality/quality of life.19

In a phase I, randomized, open-label, crossover study, the average intragastric pH following a single dose of dexlanso-prazole was higher than that observed following a single dose of esomeprazole (p<0.001).11 In the first 24 hours after a dose, the mean percentage of time patients’ intragastric pH was above 4 for dexlansoprazole and esomeprazole was 58% and 48%, respectively (p=0.003).11

In the 12–24 hour post-dose period, the mean percentage of time patients on dexlansoprazole had an intragastric pH above 4 was 60% (vs 42% with esomeprazole; p<0.001).11 During this 12–24 hour post-dose period, the average mean intragastric pH was 4.5 for dex-lansoprazole, compared with 3.5 for esomeprazole (p<0.001).11 These findings demonstrate that dexlansoprazole may be more effective than once-daily esome-prazole for the control of nighttime symptoms.

Further, a randomized, double-blind trial involving 445 patients showed that 6 months treatment with dexlansoprazole (30 mg or 60 mg) was superior to placebo for maintaining healed erosive esopha-gitis (p<0.0025).20 Superiority to lanso-prazole in healing of erosive esophagitis was also demonstrated in one study, with non-inferiority in another study.21

Adjusted indirect comparisons based on currently available randomized controlled trial data suggested sig-nificantly better control of heartburn in patients with non-erosive reflux disease for dexlansoprazole versus esome-prazole. Dexlansoprazole 30 mg was more effective than esomeprazole 20 mg or 40 mg (RR: 2.01, 95% CI: 1.15–3.51; RR: 2.17, 95% CI: 1.39–3.38).22

SafetyPPI therapy has been associated with adverse effects such as vitamin and mineral deficiencies, hip fractures and osteoporosis, and increased cardio-vascular events in patients using con-comitant clopidogrel therapy.8

In 2009, the FDA issued a warning regarding the potential for increased adverse cardiovascular events in con-comitant users of PPI and clopidogrel therapy, particularly among users of omeprazole, lansoprazole, and esome-prazole.8 The concern arises from the fact that the anti-platelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. This potentially reduces the effectiveness of clopidogrel.23

A randomized, open-label, two-period, crossover study of healthy subjects (N=160) found that the area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dex-lansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reac-tivity index.23 Dexlansoprazole does not attenuate the efficacy of clopidogrel.

Common side effects of dexlan-soprazole include gas, mild diarrhoea, nausea and vomiting.17 Upper respiratory tract infections may also be observed more frequently in dexlansoprazole-treated patients.20

Pooled data from 4,270 patients receiving dexlansoprazole (30 mg, 60 mg or 90 mg), lansoprazole 30 mg, or placebo showed that the number of patients with at least one treatment-emergent adverse event was higher in placebo and lan-soprazole groups than in any dexlanso-prazole group. Fewer patients receiving dexlansoprazole discontinued therapy because of an adverse event (p≤0.05 versus placebo).24

ConclusionPPI is the mainstay of GERD treatment. However, patients report inadequate symptom control with currently available PPIs. Dexlansoprazole, an enantiomer of lansoprazole, is formulated with a unique DDR formulation. It has proven efficacy in symptom control,11 healing of esoph-agitis21 and maintaining remission20. Clinical data also demonstrate superior effects compared with currently available PPIs.11,21,22

Dexlansoprazole is generally well tolerated.24,25 Importantly, dexlanso-prazole may be used concomitantly with clopidogrel without increasing the risk of adverse cardiovascular events.23

References1. Scott M, Gelhot AR. Gastroesophageal reflux disease: diagnosis and

management. Am Fam Physician 1999;59:1161-1169, 1199.2. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal

definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920; quiz 1943.

3. Nwokediuko SC. Current trends in the management of gastroesophageal reflux disease: a review. ISRN Gastroenterol 2012;2012:391631.

4. Fennerty MB. Medical treatment of gastroesophageal reflux disease in the managed care environment. Semin Gastrointest Dis 1997;8:90-99.

5. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2013 Jul 13 [Epub ahead of print].

6. Wu JC. Gastroesophageal reflux disease: an Asian perspective. J Gastroenterol Hepatol 2008;23:1785-1793.

7. Wong WM, Lai KC, Lam KF, Hui WM, Hu WH, et al. Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study. Aliment Pharmacol Ther 2003;18:595-604.

8. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-328.

9. Labenz J, Malfertheiner P. Treatment of uncomplicated reflux disease. World J Gastroenterol 2005;11:4291-4299.

10. Sobrino-Cossio S, Lopez-Alvarenga JC, Remes-Troche JM, Galvis-Garcia ES, Soto-Perez JC, et al. Proton pump inhibitors in gastroesophageal reflux disease: “a custom-tailored therapeutic regimen”. Rev Esp Enferm Dig 2012;104:367-378.

11. Kukulka M, Eisenberg C, Nudurupati S. Comparator pH study to evaluate the single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60 mg and delayed-release esomeprazole 40 mg. Clin Exp Gastroenterol 2011;4:213-220.

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

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

14. Fass R, Inadomi J, Han C, Mody R, O’Neil J, et al. Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release. Clin Gastroenterol Hepatol 2011;10:247-253.

15. Vakily M, Zhang W, Wu J, Atkinson SN, Mulford D. Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials. Curr Med Res Opin 2009;25:627-638.

16. Nexium (esomeprazole magnesium) delayed release capsules [package insert]. Wilminton, DE: AstraZeneca Pharmaceuticals LP; 2011. In.

17. Dexilant (dexlansoprazole) delayed release capsules [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2011. In.

18. Lee RD, Mulford D, Wu J, Atkinson SN. The effect of time-of-day dosing on the pharmacokinetics and pharmacodynamics of dexlansoprazole MR: evidence for dosing flexibility with a Dual Delayed Release proton pump inhibitor. Aliment Pharmacol Ther 2010;31:1001-1011.

19. Fass R, Johnson DA, Orr WC, Han C, Mody R, et al. The effect of dexlansoprazole MR on nocturnal heartburn and GERD-related sleep disturbances in patients with symptomatic GERD. Am J Gastroenterol 2011;106:421-431.

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org


Non-Hodgkin’s lymphoma (NHL) is the eighth most common malignancy in Hong Kong, with

an annual incidence of 800 cases.1 It is amongst the most treatable, with only 300 deaths annually. The peak age of presentation is 70 years. About 70% of cases are aggressive lymphomas (mostly diffuse large B cell lymphoma [B-DLCL]). The rest are indolent lymphomas com-prised of a mixture of entities (follicular lymphoma [FL], marginal zone lymphoma [MZL], mantle cell lymphoma [MCL], small lymphocytic lymphoma [SLL] and mucosa lymphoid tissue associated lymphoma [Maltoma]). About 85% of lymphomas are of B-cell lineage and express the surface marker CD20. The advent of anti-CD20 antibody (rituximab, R) in 1999 vastly improved survivals. For low-risk DLCL, cure rates exceed 90%. For indolent lymphomas, 5-year disease

free survival rates >80% are easily achievable. Similar improvements have also been seen in chronic lymphocytic leukemia (CLL), a blood-based version of SLL. Although CLL and FL are less common in Chinese patients due to genetic factors, lifestyle Westernization have led to a steady increase in cases.2-4

Remarkably, almost no new anti-lymphoma chemotherapy has been approved by the US Food and Drug Administration (FDA) over the past 30 years. Until recently, older drugs including cyclophosphamide (C), vincristine (V or O), prednisolone (P), doxorubicin (H) and fludarabine (F) were the mainstay of anti-lymphoma therapy. A randomized trial of FL patients in Italy showed that there was no difference in outcomes comparing R-CVP, R-CHOP and R-F combinations.5 Hence, there has been an unmet need for a new anti-lymphoma agent, with increased activity and an improved side effect profile, to supplement rituximab for both aggressive and indolent lymphomas.

Forward progress is often achieved by considering lessons from the past. The drug bendamustine represents a remarkable example. After the Second World War, the Soviet Union set up a string of Communist-controlled puppet states in Eastern European nations. On 1 May 1949, a “direct election” of screened worker representatives established East Germany, ironically named the German Democratic Republic (GDR). For a host of reasons, the phobic government com-missioned the overnight construction of the Berlin Wall on 13 August 1961. The Iron Curtain sealed off Eastern Europe from the world, ceasing all medical and academic exchange, leaving Communist technology and science to evolve on its own. From 1953, in the East German

Bendamustine: the gift from Behind the iron curtain

Dr Au Wing Yan (區永仁醫生)

MBBS (Hons) (HK) MD (HK) FRCP (Edin/Lon) FHKAMSpecialist in Hematology / Hematological OncologyCrawford House, Central

Key words: Non-Hodgkin’s lymphoma (非何杰金氏淋巴瘤), bendamustine (苯達莫司汀)

figure 1. Zentralinstitut für Mikrobiologie und experimentelle therapie – ZiMet tower, Jena


industrial and intellectual town of Jena, an ominous building (Figure 1) housed the much revered Central Institute for Microbiology and Experimental Therapy (Zentralinstitut für Mikrobiologie und experimentelle Therapie, ZIMET). Its pre-decessor was the German drug giant Jena Pharm, and its director Hans Knoll, together with its handpicked executive council members, were collectively responsible for classified decisions on scientific experiments. The most famous were the biochemical manipulations of young East German athletes, who were not allowed to fail in open competition. Numerous medical compounds were also conceptualized and tested. These included ZIMET 3393, invented by W. Ozegowaski and D. Krebs, and first described in 1963 in the Journal fur Praktische Chemie. ZIMET 3393 is a member of a family of compounds (amino-benzimidazole deriv-atives) synthesized for anti-cancer, anti-viral and immunosuppressive properties. This unique drug combines chemical parts of three anti-cancer classes: an akylator part, a purine analogue part and a butyric acid part (Figure 2). It was available from 1971 in the GDR under the name Cytostasan and was effective for a wide range of malignancies. It was used in thousands of patients for lymphoma,

leukemia, Hodgkin’s lymphoma, plasma cell myeloma, breast cancer, lung cancer, and sarcomas. Following the iconic year of 1989, which saw the collapse of Com-munism and the fall of the Berlin Wall, ZIMET was rapidly dissolved, and its drug arsenal and research dossiers dis-persed and forgotten. However, in 1992, ZIMET 3393 was remarketed in Germany by Mundipharma under the trade name Ribomustin. Between 1992 and 2003, more than 18,000 German patients with NHL, myeloma and Hodgkin’s lymphoma were treated.6,7

In 2003, the drug was marketed to the rest of the world under the brand name Trenda. In the European Intergroup CLL study, a 2-day infusion of benda-mustine outperformed oral chlorambucil in elderly CLL patients (median age, 65 years) with a response rate of 68% versus 39% (p<0.0001) and a progression-free survival of 21.7 months versus 9 months (p<0.0001). The results led to its FDA approval for frontline CLL on 20 March 2008. In another pivotal study in rituximab-refractory indolent lymphomas, single-agent bendamustine gave a response rate of 84%, which lasted 9 months. Even with these very early phase II results, the FDA approved bendamustine for relapsed indolent B-cell lymphoma on 30 October

2008, highlighting the need for effective new agents.6,8 The decision was vindicated by the results of a phase III trial (STIL-HNL-1 2003), which compared R-bendamustine against R-CHOP standard chemo-therapy.9 Bendamustine was associated with fewer side effects (neutropenia, infection, rash, stomatitis and neuropathy) than CHOP, with no hair loss (p=0.012 to p<0.0001 for various side effects). Addi-tionally, R-bendamustine was superior to R-CHOP for progression free survival in all 10 comparisons (follicular lymphoma, marginal zone B-cell lymphoma, mantel cell lymphoma, high or low stage, age above or below 60, raised or normal lactate dehydrogenase, patients reaching complete or partial response). A new standard of care for first-line treatment of all low-grade lymphomas was thus estab-lished.8 Encouragingly, bendamustine was eventually designated an NCCN- recommended agent for relapsed high-grade lymphoma, Hodgkin’s lymphoma and myeloma, reflecting its broad spectrum of activity as first envisioned by the East Germans.8 Front-line results with B-DLCL are imminent, and it is an accepted alter-native for patients who cannot tolerate multiple chemotherapy combinations or steroid-containing regimens.7

References1. Hospital Authority. Hong Kong Cancer Registry. 2013. Available at:

http://www3.ha.org.hk/cancereg/statistics.html. Accessed 16 October 2013.

2. Au WY, Fung A, Liang R. Molecular epidemiology of follicular lymphoma in Chinese: relationship with bcl-2/IgH translocation and bcl-6 397G/C polymorphism. Annals of Hematology 2005 Aug;84(8):506-509.

3. Au WY, Gascoyne RD, Klasa RD, Connors JM, Gallagher RP, Le ND, et al. Incidence and spectrum of non-Hodgkin lymphoma in Chinese migrants to British Columbia. Br J Haematol 2005 Mar;128(6):792-796.

4. Mak V, Ip D, Mang O, Dalal C, Huang S, Gerrie A, et al. Preservation of lower incidence of chronic lymphocytic leukemia in Chinese residents in British Columbia: a 26-year survey from 1983 to 2008. Leuk Lymphoma 2013 Sep 12 [Epub ahead of print].

5. Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013;20;31:1506-1513.

6. Rummel MJ, Mitrou PS, Hoelzer D. Bendamustine in the treatment of non-Hodgkin’s lymphoma: results and future perspectives. Semin Oncol 2002;29(4 Suppl 13):27-32.

7. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol 2009;27:1492-1501.

8. National Comprehensive Cancer Network. NCCN Clinical Oncology Guidelines. Available at: http://www.nccn.org/professionals/physician_ gls/f_guidelinesasp#site. 2013. Accessed 9 November 2013.

9. Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013;381:1203-1210.

CIH2C

CIH2C

CH3NH2

N

N

O OPNH

N

CI

CI

N

N

N

O

OH

HOCH2

CIN

N

O

OH

COOH

Alkylator/Purine analogue/HDAC inhibitor

Butyric acid

Bendamustine

Carboxylic acid

Benzimidazole ringNitrogen mustard

Cyclophosphamide

Cladribine

figure 2. the structure of bendamustine combines active parts of cyclophosphamide, cladribine and butyric acid

IMET 3393 (4-[5-(bis[2=chloroethyl]amino)-1-methyl-2-benzimidazolyl] butyric acid)


Chronic myeloid leukaemia (CML) is a neoplastic disease of the hema-topoietic stem cells. The Phila-

delphia chromosome, the product of a translocation between chromosomes 9 and 22, is characteristic of CML. The resulting BCR-ABL fusion protein acts as an active kinase and tyrosine kinase inhibitors (TKIs), such as imatinib, can block the tyrosine kinase activity of BCR-ABL.

CML is one of the few malignant diseases triggered by a single oncogene, the BCR-ABL oncogene. This serves as the basis for and efficacy of, molecular targeted therapy in CML. A diagnosis of CML requires evidence of BCR-ABL translocation verified by cytogenetic studies or polymerase chain reaction (PCR) analyses.

The treatment of CML has been revolutionized over the past decade by

the introduction of the TKI, imatinib. Hae-matologic, cytogenetic and molecular techniques are currently used to monitor disease and treatment responses. Achieving a complete cytogenetic response (CCyR) is an important objective of therapy because it is associated with prolonged survival.1-5 In patients who achieved CCyR, the BCR-ABL1 tran-script levels can be measured to assess molecular residual disease. The results are often expressed as the log10 reduction from a standardized value for untreated patients, or more recently using the inter-national scale where 100% is the starting point. It is generally accepted that CCyR corresponds to an approximate 2-log reduction in transcript levels or 1% on the international scale. Major molecular response (MMR) is usually defined as a 3-log reduction in transcript levels or 0.1% on the international scale. Real-time PCR (RT-PCR) is by far the most sensitive method for monitoring BCR-ABL levels during treatment. It can measure the levels of BCR-ABL transcripts in both the peripheral blood and bone marrow. Achieving MMR is regarded as an optimal response to TKI treatment. An optimal treatment response has been asso-ciated with the best long-term outcome, which means the life expectancy of the patient is comparable with that of the general population.6 The quantitative RT-PCR (qRT-PCR) assay reports the actual percentage of BCR-ABL tran-scripts. Another advantage of qRT-PCR is the strong correlation between results from peripheral blood and bone marrow, allowing the monitoring of minimal residual disease without obtaining bone marrow specimens. Once MMR has been achieved, further cytogenetic assessments are not necessary as they

do not provide additional information. The absence of CCyR after 12 months and MMR after 18 months may require switching to a more powerful TKI.6

Second generation TKIs as first-line therapyThe development of second-generation TKIs that are more potent than imatinib could potentially solve some of the problems associated with the latter. These agents have demonstrated efficacy in patients resistant, or intolerant, to imatinib. Increased inhibition of BCR-ABL kinase is associated with improved clinical response. The administration of the second generation TKI as initial therapy for chronic phase CML can improve response and reduce the progression of the disease in newly diagnosed patients. Progression to accelerated phase (AP) or blast crisis (BC) is associated with short survival times.

Second-generation TKIs, nilotinib and dasatinib, have demonstrated efficacy as frontline therapy for chronic phase CML in phase III studies, in which molecular and cytogenetic responses to either agent were found to be superior to imatinib. The rate of progression to AP/BC was also lower with these newer generation TKIs. The 2013 European Leukaemia-Net (ELN) guideline-recommended first, second and subsequent lines of treatment are sum-marized in the Table on the next page.

The ENESTnd trialNilotinib binds to the inactive confor-mation of BCR-ABL1, with a 30–50-fold increased binding affinity compared with imatinib. Nilotinib has demon-strated superior efficacy to imatinib in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials

Update on the treatment of chronic Myeloid Leukaemia

Dr law Man Fai (羅文輝醫生)

MBChB, MRCP, FHKAM, FHKCP Associate ConsultantDepartment of Medicine and TherapeuticsPrince of Wales Hospital

Key words: chronic myeloid leukaemia (慢性骨髓性白血病), tyrosine kinase inhibitor (酪氨酸激酶抑制劑)


-Newly Diagnosed Patients) trial. In this phase III, randomized, open-label, multi-center study, 846 patients with chronic-phase Philadelphia chromosome-positive CML were randomized in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily [BID]) or imatinib (at a dose of 400 mg once daily).

At 12 months, the rates of MMR for nilotinib (44% for the 300 mg dose and 43% for the 400 mg dose) were twice

that for imatinib (22%; p<0.001 for both comparisons). The rates of CCyR by 12 months were also significantly higher for nilotinib (80% for the 300 mg dose and 78% for the 400 mg dose) than for imatinib (65%; p<0.001 for both com-parisons). Significantly longer time to progression to AP or BC were also noted with either the 300 mg or 400 mg of nilotinib BID versus imatinib (p=0.01 and p=0.004, respectively).7

ENESTnd 4-year updateAt the 4-year data cutoff, >86% of patients across the three treatment arms remained in the study. In addition, more patients in the nilotinib arms (76% for the 300 mg dose and 73% for the 400 mg dose) achieved MMR compared with those in the imatinib arm (56%; Figure).

Patients in both nilotinib arms had significantly lower rates of progression to AP/BC on core treatment throughout the study period (including follow-up after discontinuation of treatment) versus patients in the imatinib arm.8 Including clonal evolution, progression occurred in 3 (1.1%), 5 (1.8%), and 17 (6.0%) patients receiving nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib, respectively (p=0.0009 and p=0.0085 for nilotinib 300 mg BID and nilotinib 400 mg BID vs imatinib, respectively).

The estimated overall survival rates were similar across all groups at 4 years (94.3% and 96.7% for nilotinib 300 mg and 400 mg, respectively, and 93.3% for imatinib). However, fewer CML-related deaths occurred with nilotinib 300 mg and 400 mg versus imatinib (n=5, 4 and 13, respectively).

Some commonly reported side effects of nilotinib included skin rash, hyperglycaemia and increased triglyceride levels. Therefore, patients are required to fast for 2 hours before taking nilotinib and 1 hour thereafter.

ConclusionsRecent results from the ENESTnd trial confirm the benefits of nilotinib over imatinib, supporting the role of frontline nilotinib therapy in patients with newly diagnosed chronic phase CML. The updated ELN recommendations also recommend nilotinib 300 mg twice daily as one of the first-line treatment options for chronic phase CML.6

100908070605040302010

00 6 12 18 24 30 36 42 48 54 60

Time since randomization, months

Patie

nts

with

MM

R %

ENESTnd 4-Year dataCumulative Incidence of MMR*

By 1 year55%, p<0.0001

51%,p<0.0001∆ 24–28%

27%

By 4 years76%,p<0.0001

73%,p<0.0001∆ 17–20%

56%

Nilotinib 300 mg BID (n=282)Nilotinib 400 mg BID (n=281)Imatinib 400 mg QD (n=283)

figure. the rates of MMR by 4 years remained significantly higher in both nilotinib arms compared with the imatinib arm

IMET 3393 (4-[5-(bis[2=chloroethyl]amino)-1-methyl-2-benzimidazolyl] butyric acid)

MMR, major molecular response; BID, twice daily; QD, once daily

table. eLn guideline-recommended treatment options for cMLfirst line

Imatinib or nilotinib or dasatinibHLA type patients and siblings only in case of baseline warnings (high risk, major route CCA/Ph+)

Second line, intolerance to the first tKiAny one of the other TKIs approved first line (imatinib, nilotinib, dasatinib)

Second line, failure of imatinib first lineDasatinib or nilotinib or bosutinib or ponatinibHLA type patients and siblings

Second line, failure of nilotinib first lineDasatinib or bosutinib or ponatinibHLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT

Second line, failure of dasatinib first lineNilotinib or bosutinib or ponatinibHLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT

third line, failure of and/or intolerance to 2 tKisAny one of the remaining TKIs; alloSCT recommended in all eligible patients

any line, t315l mutationPonatinibHLA type patients and siblings; search for an unrelated stem cell donor; consider alloSCT

TKI, tyrosine kinase inhibitor; HLA, human leukocycte antigen; SCT, stem cell transplant

A complete list of references can be downloaded from www.SOPHYSICIANSHK.org

MY

C-M

AD

-101

213-

0001

Abbreviated Prescribing InformationActive ingredients: Micafungin sodium. Indication and dosage: 1 Esophageal candidiasis: IV infusion. Adult: 150 mg/day. 2 Prophylaxis of Candida infections undergoing hematopoetic stem cell transplantation: IV infusion. Adult: 50 mg/day. 3 Treatment of patients with candidemia, acute disseminated candidiasis, candida peritonitis and abscesses: IV infusion 100 mg/day. Side effects: Rash. Pruritus. Nausea. Vomiting. Diarrhea. Injection site reactions. Other side effects, please see package insert. Contraindications: Hypersensitivity to any of the components. Precautions: Discontinue in cases of serious hypersensitivity reactions. Monitor for evidence of worsening hepatic and renal function and hemolysis or hemolytic anemia during therapy. Pregnancy. Lactation. Pregnancy (FDA): Cat C.Full prescribing information is available upon request

References1. Pfaller MA, et al. Diagn Microbiol Infect Dis 2011;69:45-50. 2. Lockhart SR, et al. Antimicrob Agents Chemother 2011;55:3944-3946. 3. Espinel-Ingroff A, Cantón E. Enferm Infecc Microbiol Clin 2011;29(Suppl 2):3-9. 4. Kuse ER, et al. Lancet 2007;369:1519-1527. 5. Pappas PG, et al. Clin Infect Dis 2007;45:883-893. 6. Kohno S, et al. J Infect 2010;61:410- 418. 7. Hanadate T, et al. J Infect Chemother 2011;17:622-632. 8. Yamaguchi M, et al. Ann Hematol 2011;90:1209- 1217.

1, 2, 3

4, 5, 6, 7, 8


L ung cancer is the leading cause of cancer death worldwide, including Hong Kong. About 75% of cases

are inoperable upon presentation, largely because of their advanced stage or patients’ poor physical performance status. Systemic therapy is, therefore, the mainstay of treatment for locally advanced or metastatic disease in which surgery is inappropriate. However, the survival rate for inoperable disease is dismal despite platinum-based chemo-therapy, which carries the risk of systemic side effects and poor tolerability.

Epidermal growth factor receptor – tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib are a break-through in the treatment of advanced lung cancer. The landmark study, iPASS, was the first clinical trial to show that oral targeted therapy is both effective and well tolerated in patients harbouring EGFR mutation. Although EGFR mutation is more commonly found in patients who are Asian, female, non-smokers and with adenocarcinoma histology, only 60% of this enriched population carries the EGFR mutation.1 The molecular profiling of the remaining population has yet to be elu-cidated.2

Similar to EGFR mutations, ana-plastic lymphoma kinase (ALK) translo-cations are also predominantly found in patients with adenocarcinoma but are more common in patients with signet rings, never- or light-smokers, and young patients (median age, 50 years).3 Unlike the EGFR mutation, the ALK change is a translocation of the gene. ALK trans-locations are present in approximately 5% of cases of non-small cell lung cancer (NSCLC); notably, they are also found in anaplastic large-cell lymphoma (in which they were originally identified

in the 1990s) as well as pediatric neu-roblastoma.4 The identification of the ALK translocation as a potent oncogenic driver in NSCLC in 2007 resulted in devel-opment of ALK inhibitors. Crizotinib is the first identified oral small-molecule TKI tar-geting ALK, MET, and ROS1.5 In contrast to EGFR status, studies suggest that ALK status is not predictive of chemotherapy response. In the iPASS study, patients harbouring the EGFR mutation showed better response to chemotherapy compared with EGFR mutation-negative patients.

Currently, there are three methods for identification of ALK-positivity: fluo-rescence in situ hybridization (FISH; Figure 1), immunohistochemistry (IHC; Figure 2) and reverse transcriptase poly-merase chain reaction (RT-PCR). Each of these are associated with strengths and weaknesses. FISH is the only test approved by the US Food and Drug Administration (FDA) as the standard method. However, it is labour-intensive (needing interpretation by two qualified personnel) and is associated with false negatives. IHC is widely used, and its detection of ALK-positivity is improving as methods of signal enhancement and more sensitive antibodies are developed. A two-tier screening, comprising an initial IHC screening followed by FISH eval-uation of IHC samples scoring 1 to 2, is commonly adopted.5

Trials with crizotinib have consis-tently reported notably high response rates of prolonged duration, often rapidly achieved. In addition, crizotinib is well tolerated and provides symptomatic relief while maintaining quality of life. Acce-lerated FDA approval of crizotinib was granted based on data from phase I and II trials.6,7 Results of the phase III

egfR-negative: can i Use oral targeted therapy?

Dr Wong King yan, Matthew (黃敬恩醫生)

MBBS (HK), MRCP (UK), FHKCP, FHKAM, FCCP, FRCP (Edin), FRCP RCPS (Glasg)Specialist in Respiratory MedicineHonorary Clinical Assistant Professor, The University of Hong Kong

Key words: anaplastic lymphoma kinase (ALK) (間變性淋巴瘤激酶), crizotinib (克里唑替尼), endobronchial ultrasound guided-transbronchial aspiration (EBUS-TBNA) (支氣管內超聲波導引針吸活檢術)


clinical trial, published in 2013, estab-lished the role of crizotinib as an alter-native first-line treatment of NSCLC. Platinum-based chemotherapy was tra-ditionally standard treatment.8 Patients with locally advanced or metastatic ALK-positive lung cancer assigned to receive crizotinib 250 mg twice daily achieved a median progression-free survival of 7.7 months compared with 3.9 months for those receiving standard chemotherapy (hazard ratio 0.49, p<0.001). The objective response rate was 65% versus 20% favouring crizotinib (p<0.001). Patients also reported greater symptom reduction and greater improvement in quality of life with crizotinib than with chemotherapy.

Both EGFR mutation and ALK trans-location require the presence of adequate tissue in order to be analyzed by immuno-histochemical staining or FISH test. In the iPASS study, only 36% of tissue retrieved was adequate for EGFR mutation study. This has significant clinical implications: even if the diagnosis of NSCLC is estab-lished by conventional tissue sampling methods, an EGFR TKI cannot be employed as first-line treatment without knowledge of EGFR mutation status.

Recently, endobronchial ultrasound

guided-transbronchial aspiration (EBUS-TBNA) has emerged as a highly diag-nostic and safe tissue sampling modality. Its advantage is that almost all locally advanced or metastatic lung cancer patients have mediastinal lymph nodes involved.9 EBUS-TBNA is a non-surgical technology which can be performed under conscious sedation, and the length-of-stay in hospital can be shortened to one or two days. A tiny ultrasound probe is incorporated at the tip of a designated bronchoscope which allows both endo-scopic and ultrasonic visualization simul-taneously. The target lymph nodes, which may be situated outside the airway and not normally detected by conventional bronchoscopy, are readily revealed by the ultrasound probe. EBUS-TBNA manages tissue sampling under direct visualization, enabling diagnostic yields of 90% with an extremely high safety profile. Our group recently reported that 95% of tissue obtained is suitable for molecular profiling such as EGFR and/or ALK analysis.10

In conclusion, the nomenclature and treatment modalities for lung cancer have evolved over the past 10 years. The previous classification into small cell and non-small cell lung cancer is now con-

sidered an oversimplication. The exact cell type and molecular profile of a lung cancer patient constitutes important components directing personalized man-agement. The detection of EGFR and ALK positivity status allows patients the oppor-tunity to achieve a significantly better response rate, safety profile, quality of life and progression-free survival.

References1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel

in pulmonary adenocarcinoma. N Engl J Med 2009;361(10):947-9572. Shames DS, Wistuba II. The evolving genomic classification of lung

cancer. J Pathol 2013 Sep 30 [Epub ahead of print].3. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and

outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol 2009;27:4247-4253

4. Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994;263:1281-1284

5. Scagliotti G, Stahel RA, Rosell R, Thatcher N, Soria JC. ALK translocation and crizotinib in non-small cell lung cancer: an evolving paradigm in oncology drug development. Eur J Cancer 2012;48(7):961-973.

6. Camidge DR, Bang Y, Kwak EL, et al. Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol 2011;29(suppl.)

7. Crinò L, Kim D-W, Riely G, et al. Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005. J Clin Oncol 2011;29(suppl.)

8. Shaw AT, Kim D-W, Nakagawa K. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-2394

9. Folch E, Yamaguchi N, Vanderlaan PA, et al. Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer. J Thorac Oncol 2013;8:1438-1444

10. Wong MK, Ho JC, Loong F, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer: the first experience in Hong Kong. Hong Kong Med J 2013;19:20-26.

figure 1. aLK-positive non-small cell lung cancer as detected by interphase fiSh using a dual colour break-apart probe system

The arrow shows a tumour cell with the typical split red and green and one wild-type yellow fusion signal pattern.

ALK, anaplastic lymphoma kinase

figure 2. aLK-positive non-small cell lung cancer as detected by immunohischemistry using the 5a4 clone

ALK, anaplastic lymphoma kinase


Introduction

E ver since the late 1950s, with the introduction of amphotericin B-deoxycholate, the development

of safer, more effective systemic anti-fungal agents has been eagerly awaited. The deleterious side effects of ampho-tericin B had earned it the nickname ‘ampho-terrible’. The introduction of flu-conazole in the 1990s and the second-generation triazoles voriconazole and posaconazole in the early-to-mid-2000s were promising developments. The introduction of echinocandins – effective agents with only limited toxicity – repre-sented the fulfillment of this clinical need. This article focuses on one of the echino-candins, micafungin.

Structural characteristics, mechanism of action & pharmacodynamic propertiesEchinocandins are cyclic hexapeptides, with an N-linked fatty acyl side chain. Differences in structure, lipophilicity and geometry of the side chain can lead to reduced toxicity and improved anti-Candida activity.1 Micafungin has a 3,5-diphenyl-substituted isoxazole ring side chain, whereas caspofungin has a fatty acid side chain and anidulafungin, a pentyloxyterphenyl moiety. Irrespective of the side chain, all echinocandins non-competitively inhibit 1,3-beta-D-glucan synthase, an enzyme present in, and essential to, the fungal cell wall.3 The result is the weakening of the cell wall structure and osmotic instability of the cell membrane leading to fungal cell lysis and eventual death.2

Micafungin produces a dose-dependent antifungal effect against all clinical and/or laboratory isolates of Candida spp. Combining micafungin with azoles resulted in negligible effects on antifungal activity, while in immu-

nosuppressed mice with disseminated C. glabrata infection, co-administration of micafungin with amphotericin B or liposomal amphotericin B resulted in significant improvements in antifungal activity.9 Large global surveillance studies have shown that there is a low potential for the emergence of micafungin resistance (≥98.8% of Candida spp. are susceptible). Mutations conferring reduced susceptibility to echinocandins have been mapped to the FKS1 and/or FKS2 genes that encode 1,3-beta-D-glucan synthase.9

Micafungin has shown in vitro activity against Candida biofilms, including those resistant to other anti-fungal agents.

Pharmacokinetic propertiesThe oral bioavailability of micafungin is poor because of its high molecular weight. For this reason, it is admin-istered intravenously. It is extensively protein bound in plasma (>99%), pri-marily to albumin.10 The drug is primarily metabolized in the liver and excreted in the feces. The mean terminal elimination half-life is 10–17 hours.11 The clearance of micafungin in children is affected by age, with younger children clearing the drug more rapidly.10 Micafungin is not dialyzable: continuous haemodiafiltration and continuous venovenous haemo-dialysis had little effect on micafungin pharmacokinetic parameters.11 Mica-fungin has a low potential to cause drug interaction through inhibition of CYP3A4. However, increased side effects may be expected when administered concomi-tantly with itraconazole, nifedipine or sirolimus. Concomitant use of micafungin and amphotericin B was associated with a 30% increase in exposure to the latter and therefore close monitoring for renal toxicity is needed.11

Micafungin: Pros and cons

Dr Tang Siu Fai (鄧兆暉醫生)

MBBS, MRCP (UK), FRCPath (UK), FHKCPath, FHKAM (Path), PDipID (HKU) Honorary Consultant, Clinical Microbiology & Infection, Hong Kong Sanatorium & Hospital

Key words: micafungin (米於芬淨), echinocandins (棘白菌素), antifungals (抗真菌藥物), invasive (入侵性), fungal infection (真菌感染), treatment (治療), prophylaxis (預防)


In vitro activitiesTo date, the European Committee on Anti-microbial Susceptibility Testing (EUCAST) has not proposed clinical breakpoints (CBP) for micafungin or caspofungin against Candida spp.5 The recent 2012 European Society of Clinical Micro-biology and Infectious Diseases (ESCMID) guidelines indicate that EUCAST break-points remain to be established for micafungin and caspofungin. EUCAST susceptibility breakpoints for anidula-fungin against C. albicans, C. glabrata, C. krusei and C. tropicalis are <0.03, <0.06, <0.06 and <0.06 mg/L, respectively.6 The US Clinical and Laboratory Standards Institute (CLSI) has established a suscepti-bility CBP against Candida spp. for echino-candins of ≤2 μg/mL.7 However, evidence indicates that clinical isolates of Candida spp. showing resistance to echinocandins appear to have minimum inhibitory con-centrations (MICs) that are lower than this CLSI CBP and, thus, a lower CBP may be more appropriate.8 A 2011 study indicated that species-specific interpretive criteria for CLSI CBP were generally lower than the initial CLSI CBP for echinocandins of ≤2 mg/mL.4 Against C. albicans, C. tropicalis and C. krusei, proposed CBPs for echinocandins were ≤0.05 (sus-ceptible), 0.50 (intermediate) and ≥1 mg/L (resistant); for C. parapsilosis, respective CBPs for echinocandins were ≤2, 4 and ≥8 mg/L; and against C. glabrata, res-pective CBPs for micafungin were ≤0.06, 0.12 and ≥0.25 mg/L, with those for caspo-fungin and anidulafungin being ≤0.12, 0.25 and ≥0.5 mg/L.4

The SENTRY program is the largest study on in vitro susceptibilities of clinical isolates from patients with invasive fungal infections. The latest published study consists of 3,418 clinical isolates collected between 2010 and 2011 from 98 laboratories (34 countries) in North America (1,349 isolates), Europe (1,191 isolates), Latin America (492 isolates) and the Asia-Pacific region (384 isolates).13 All three echinocandins and four azoles (flu-conazole, itraconazole, voriconazole and

posaconazole) were tested using CLSI broth microdilution methods. Resistance to the echinocandins was distinctly uncommon (overall range, 0.0 to 1.2%) among C. albicans (0.0 to 0.6%), C. trop-icalis (0.0%), C. parapsilosis (0.0 to 1.2%), and C. krusei isolates (0.0%) from all four geographic regions, using the new CLSI CBP values. Resistance to anidulafungin (3.8%), caspofungin (1.9%), micafungin (1.9%), and the triazoles (5.8% to 13.5%) was most prominent among isolates of C. glabrata from the Asia-Pacific region, whereas none of the C. glabrata isolates from Latin America were resistant to the echinocandins.13 All echinocandins, as expected, were resistant to Crypto-coccus spp., Fusarium, Scedosporium and Mucorales since they all lack 1,3-beta-D-glucan synthase. Forty strains of Asper-gillus fumigatus were tested in the 2009 SENTRY program and were found to have MIC90 ≤0.008 μg/mL for micafungin, 0.008 μg/mL for anidulafungin and 0.25 μg/mL for caspofungin.14

Clinical effectivenessMultiple large-scale, randomized con-trolled or non-inferiority trials in adults have been performed to compare normal-dose micafungin (100 mg/d) to high-dose micafungin (150 mg/d), liposomal ampho-tericin B, fluconazole and caspofungin for invasive candidiasis and esophageal candidiasis, including neutropenic or HIV-infected patients. All study results showed that micafungin given 100 mg/d was as effective as any comparator.10 In a substudy of a large multinational trial, micafungin 2 mg/kg/d (body weight [BW] ≤40kg) or 100 mg/d (BW >40kg) was compared with liposomal ampho-tericin B 3 mg/kg/d in the treatment of paediatric patients (median age ≤1 year), including neonates, with candidiaemia or other types of invasive candidiasis. Both treatments were shown to be effective without a statistically significant dif-ference.12 Likewise, studies comparing the use of micafungin 50 mg/d and flu-conazole 400 mg/d or itraconazole 5

mg/kg/d as prophylaxis against Candida infections in paediatric and adult popu-lations have found that micafungin is as effective as comparators.2

SummaryMicafungin is one of the three echi-nocandins currently available for the treatment of invasive fungal infection. It has been proven to be safe and effective in adult and paediatric populations. It requires no loading dose and has few drug interactions. When compared to the other two echinocandins, it has com-parable MICs against different Candida species and, perhaps, a lower MIC for Aspergillus fumigatus. Moreover, it has been shown to be active against Candida in biofilms, which may have important implications for the treatment of catheter-related fungal infections. More studies are warranted to see if this feature can be translated into clinical benefits.

References1. Mukherjee PK, Sheehan D, Puzniak L, et al. Echinocandins: are they all

the same? J Chemother 2011; 23:319-325. 2. Boucher HW, Groll AH, Chiou CC, et al. Newer systemic antifungal

agents: pharmacokinetics, safety and efficacy. Drugs 2004;64:1997-2020.

3. Odds FC, Brown AJ, Gow NA. Antifungal agents: mechanisms of action. Trends Microbiol 2003;11:272-279.

4. Pfaller M, Boyken L, Hollis R, et al. Use of epidemiological cutoff values to examine 9-year trends in susceptibility of Candida species to anidulafungin, caspofungin, and micafungin. J Clin Microbiol 2011; 49:624-629.

5. European Committee on Antimicrobial Susceptibility Testing.Antifungal agents: breakpoint tables for the interpretationof MICs version 4.1 [online].

6. Maertens J, Marchetti O, Herbrecht R, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update. Bone Marrow Transplant 2011;46:709-718.

7. Clinical and Laboratory Standards Institute. Reference for yeasts; informational supplement M27-S3. Wayne (PA): Clinical and Laboratory Standards Institute, 2008

8. Pfaller MA, Boyken L, Hollis RJ, et al. Wild-type MIC distributions and epidemiological cutoff values for echinocandins and Candida spp. J Clin Microbiol 2010;48:52-56

9. Scott LJ. Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections. Drugs. 2012; 72:2141-65.

10. Hebert MF, Smith HE, Marbury TC, et al. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol 2005; 45: 1145-52

11. Mycamine 50 mg powder for solution for infusion: summary of product characteristics [online]. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000734/WC500031075.pdf

12. Kuse ER, Chetchotisakd P, da Cunha CA, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007;369:1519-1527

13. Pfaller MA, Messer SA, Woosley LN, et al. Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol 2013;51:2571-2581.

14. Pfaller MA, Castanheira M, Messer SA, et al. Echinocandin and triazole antifungal susceptibility profiles for Candida spp., Cryptococcus neoformans, and Aspergillus fumigatus: application of new CLSI clinical breakpoints and epidemiologic cutoff values to characterize resistance in the SENTRY Antimicrobial Surveillance Program (2009). Diagn Microbiol Infect Dis 2011;69:45-50.


Introduction

The novel oral anticoagulants – including the direct thrombin inhibitor dabigatran and the direct

Xa inhibitors apixaban, edoxaban and rivaroxaban – are increasingly popular for use in prevention of stroke in non-valvular atrial fibrillation (AF) and prevention and treatment of venous thromboembolism (VTE). Advantages of these agents over warfarin include faster onset and offset of action and predictable antico-agulant effect so that routine coagulation monitoring is not required (Table 1).1-3 However, there is increasing concern about managing patients on these novel agents in the perioperative setting. This article aims to give a brief overview of the perioperative management of patients on novel oral anticoagulants.

Bleeding risk of new anticoagulantsIn stroke prevention for patients with non-valvular AF, the rate of overall major bleeding was 3.1–5.6%, which is similar to patients receiving vitamin K antagonists (VKAs).4,5 In the EINSTEIN DVT trial, the rate of major bleeding with rivaroxaban (0.8%) was not significantly different from that observed in the VKA group (1.2%).6 In the EINSTEIN PE study, the rate of major bleeding was 1.1%, which was half that

of the VKA group.7 Data on bleeding rate from 7 days prior until 30 days following invasive procedures for patients receiving dabigatran in the RE-LY study has been recently reported.8 This was based on data from over 4,500 patients and over 7,500 procedures and operations. The procedures included the following: pacemaker/ defibrillator insertion (10.3%), dental procedures (10.0%), cataract removal (9.3%), colonoscopy (8.6%) and joint replacement (6.2%). There were no significant differences in the rates of peri-procedural major bleeding among patients receiving dabigatran 110 mg (3.8%), dabigatran 150 mg (5.1%) and warfarin (4.6%). Among patients undergoing urgent surgery, major bleeding occurred in 17.8%, 17.7% and 21.6% in the three groups, respectively. No increase was observed in the risk of thromboembolic or bleeding complications among dabigatran-treated compared with warfarin-treated patients, among those who required major or urgent surgical procedures. To date, there are no published data on peri-operative outcomes in patients receiving rivaroxaban or apixaban who require surgery or procedures.

Preoperative assessmentThe patient’s risk of thromboembolism must be weighed against the risk of peri-

Perioperative Management of Patients on novel oral anticoagulants

Dr Chan Man Hong, Helen (陳敏航醫生)MBChB (CUHK), MRCP (UK), FHKCP, FHKAM (Medicine)Specialist in Haematology and Haematological Oncology

Dr Ma Shiu Kwan, Edmond (馬紹鈞醫生)MD (HK), FRCP (Edin, Glasg & Lond), FRCPath, FRCPA, FHKCPath, FHKAM (Pathology)Specialist in Haematology Director of Clinical & Molecular Pathology, Hong Kong Sanatorium & Hospital

Key words: novel oral anticoagulants (新型口服抗凝血藥), perioperative management (手術前後的處理), laboratory monitoring (實驗室監察), reversal of bleeding (逆轉出血)

table 1. Pharmacological characteristics of direct thrombin inhibitors and direct Xa inhibitors

Dabigatran Rivaroxaban apixaban edoxabanTarget Thrombin XaTime to peak effect 1 hr 2.5–4 hr 3h 1–2 hrHalf-life 12–14 hrs 7–11 hrs 12 hrs 8–10 hrsPlasma protein binding 34–35% 92–95% 87% 40–59%Metabolism Inhibitors of

P-glycoproteintransporter

Inhibitors of CYP3A4 and P-glycoprotein transporter

Renal elimination 80% 35% 25% 40%


operative bleeding. To assess thrombo-embolic risk, the clinician should consider both patient characteristics and the surgical procedure. Patient characteristics are summarized in the commonly adopted CHADS2 score (Congestive heart failure 1 point, hypertension 1 point, age >75 years 1 point, diabetes 1 point, and prior stroke or transient ischemic attack 2 points) for patients with AF, and by underlying throm-bophilia severity in patients with VTE. CHADS2 score of 5 or 6, recent stroke, TIA, VTE within 3 months and severe thrombophilia (eg, protein C or protein S deficiency, antiphospholipid antibodies, or multiple abnormalities) are considered high-risk strata. The risk of bleeding can be determined by considering previous bleeding history, advanced age, and liver and renal function of the patient. It should be appreciated that patients with a high risk of thromboembolism often have an increased bleeding risk.

Perioperative management issues

Timing of discontinuation of anticoagulants

As there is no specific antidote for immediate reversal of the new antico-agulants, planning ahead of the elective surgery or procedure is the rule. If the surgery cannot be delayed, there may be an increased risk of bleeding. The risk of bleeding should be weighed against the urgency of the surgical operation. For urgent surgery, administer oral activated charcoal if dabigatran is ingested within the last 2 hours. Since dabigatran excretion is primarily renal, the time of interruption of dabigatran before elective surgery or invasive procedures depends on the creatinine clearance (CrCl) and the risk of bleeding associated with the surgery (Table 2).9 The Cockcroft-Gault formula is recommended for calculation of CrCl:

1.23 x (140 - age [years]) x weight (kg) (x 0.85 if female)

serum creatinine (μmol/L)

For normal renal function and low bleeding risk surgery (including dental surgery10,11), discontinue dabigatran 24 hours (~2 half-lives) before surgery, at which point around 25% of the drug remains active. Rivaroxaban, which is

cleared to a lesser degree by the kidneys compared to dabigatran, should be stopped within 1–2 days before the pro-cedure. Some authorities recommend a longer period of discontinuation (eg, 3–4 half-lives).12,13

resumption of new anticoagulants after surgeryThe key factor is whether good hemo-stasis is achieved postoperatively. Peri-operative deterioration of liver and renal function should be considered for either continued usage or need of dose reduction. Do not restart dabigatran if CrCl <30 mL/min and rivaroxaban, if CrCl <15 mL/min. In surgery where haemostasis is satisfactory, it is suggested that dabi-gatran or rivaroxaban is restarted 24–72 hours post-op depending on the bleeding risk of the surgery (Table 3).14 For patients at high risk of thromboembolism after high bleeding risk surgery, it is suggested to consider starting a reduced dose of anticoagulant (dabigatran 150 mg once daily, rivaroxaban 10 mg QD and apixaban 2.5 mg BID) on the evening after surgery and on the following postoperative day.14

Bridging anticoagulationThe rapid onset and offset of the new oral anticoagulants (Table 1) should obviate the need for perioperative bridging antico-agulation unless the patient is unable to take oral medications, or has undergone gastric resection or is with prolonged ileus, when drug bioavailability is in doubt.

laboratory monitoringFor emergency surgery, it is useful to determine any residual anticoagulant effect in patients taking dabigatran or rivaroxaban. PT/ International Normalized Ratio (INR) is relatively insensitive to the activity of dabigatran. An APTT >80 seconds at trough is associated with a higher risk of bleeding but it is less sen-sitive at supra-therapeutic dabigatran levels. The Hemoclot Thrombin Inhibitor assay, which is a dilute thrombin test, allows for quantitative measurement of

table 2. timing of discontinuation of dabigatran or rivaroxaban before invasive or surgical proceduresRenal function (crcl, mL/min)

estimated half-life (hours)

Withholding time prior to surgery before last doseStandard bleeding risk* high bleeding risk#

Dabigatran≥80 13 (11–22) 24 hours 2 days≥50–≤80 15 (12–34) 24 hours 2 days≥30–≤50 18 (13–23) 2 days 4 days≤30 27 (22–35) 4 days 6 daysRivaroxaban>30 12 (11–13) 24 hours 2 days≤30 unknown 2 days 4 days

*Examples: cardiac catheterization, ablation therapy, colonoscopy without removal of large polyps, uncomplicated laparoscopic procedures such as cholecystectomy

#Examples: major cardiac surgery, insertion of pacemakers or defibrillators (risk of pocket hematoma), neurosurgery, large hernia surgery, major cancer, urologic or vascular surgery

table 3. Postoperative resumption of novel oral anticoagulants14

Drug and dosage Surgery of low bleeding risk Surgery of high bleeding risk Dabigatran: 150 mg BID Resume 24 hours

post-operativelyResume 48-72 hours post-operativelyRivaroxaban: 20 mg QD

Apixaban: 5 mg BIDBID, twice daily; QD, daily


dabigatran activity with a reportable range of 50–500 ng/mL.15 The effect of riva-roxaban on PT is reagent-dependent and it shows an even weaker effect on APTT. With the use of rivaroxaban calibrators and controls, chromogenic anti-Xa assay provides peak concentration and trough concentration ranges for clinical use.

Anaesthetic issuesSpinal anaesthesia may require complete hemostatic function. The risk of spinal or epidural hematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. The European Society of Anaesthesiology suggested the time elapsed from the last dose of antico-agulant to performing a central neuraxial block or catheter removal should be at least 2 half-lives of the drug, ie, 24 hours for dabigatran, 22–26 hours for rivar-oxaban and 26–30 hours for apixaban.16 Anticoagulants should not be recom-menced in patients with an epidural or spinal catheter in place. After removal of neuraxial catheters, an interval of at least 4–6 hours should elapse before resuming the first dose of the new oral antico-agulant. Vigilant monitoring for spinal or epidural haematoma is essential in the post-op recovery period and after catheter removal to allow for early detection of neurological deterioration and prompt intervention.

Acute reversal of bleedingTo date, direct thrombin inhibitors and Xa inhibitors have no specific antidote. Sup-portive measures, including fluid resusci-tation, blood transfusion, maintenance of diuresis, identification of bleeding source and surgical haemostasis, are essential. For dabigatran, hemofiltration and hemo-dialysis could be considered because of its relatively low (35%) plasma protein binding.17 Concerning hemostatic agents, human data are scarce. Reversal of the new oral anticoagulants requires over-riding the drug effects on factor IIa or Xa

and not just standard factor repletion. Fresh frozen plasma is not likely to be helpful. Efficacy of activated factor VIIa is unclear. Administration of pro-thrombin complex concentrates (PCC) may reverse the effect of dabigatran18 and rivaroxaban.19 Lower doses of Factor VIII inhibitor bypass activity (FEIBA) may potentially reverse the effects of dabi-gatran and rivaroxaban.20 Administration of 4-factor PCC or FEIBA appears to be a reasonable approach in emergency situations. A catalytically inactive recom-binant factor Xa neutralizing direct Xa inhibitors has been recently proposed as a potential antidote.21 An antibody Fab fragment that binds dabigatran and reverses its anticoagulant activity has also been developed.22 Further clinical studies are needed to clarify if there is any effective reversal agent for these new anticoagulants.

ConclusionThe perioperative management of patients on novel oral anticoagulants is an increasingly common clinical challenge to clinicians. The pharmacokinetics of the new anticoagulants, the thrombosis risk, and the bleeding risk related to both the patient and the surgical procedure, are crucial factors to consider for optimal perioperative care. There is, as yet, no consensus on a standardized protocol of perioperative management. Large multi-national registries and further clinical data are required for the development of better evidence-based recommendations.

References1. Granger CB, Armaganijan LV. Newer oral anticoagulants should be used

as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012;125:159-164.

2. Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010;50:743-753.

3. Miesbach W, Seifried E. New direct oral anticoagulants-current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012;108.4:1-8.

4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139-1151.

5. Patel MR, Mahaffey KW, Jyotsna G, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891.

6. Bauersachs R, Berkowitz SD, Brenner E, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510.

7. Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297.

8. Healey JS, Eikelboom J, Douketis JD, et al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 2012;126(3):343-348.

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11. Davis C, Robertson C, Shivakumar S, et al. Implications of dabigatran, a direct thrombin inhibitor, for oral surgery practice. J Can Dent Assoc 2013;79:d74.

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13. Queensland Health: Guideline for managing patients on rivaroxaban, May 2013. Available at: http://www.health.qld.gov.au/qhcss/mapsu/documents/rivaroxaban-guideline.pdf. Accessed: 28 Oct 2013.

14. Spyropoulos AC, Douketis JD. How I treat anticogulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954-2962.

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18. Diaz MQ, Borobia AM, Nunez Ma, et al. Use of prothrombin complex concentrates for urgent reversal of dabigatran in the emergency department. Haematologica 2013;98:e143-e144.

19. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-1579.

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Sunday Symposium • February 23, 2014 The Langham Hotel, 8 Peking Road, TST, Kowloon

Free admission for all medical doctorsPre-registration is required

Sponsor: a. Menarini Hong Kong limited

Please visit the following web site for more details:www.SoPHySICIanSHK.org

JSPHK Jan 2014 issue Page 1 – Gastro-‐Esophageal Reflux Disease: Optimizing Proton Pump Inhibitor Therapy to Improve Symptom Control Dr Wong Chun Yu, Benjamin (王振宇醫生)

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1999;59:1161-‐1169, 1199. 2. Vakil N , van Zanten SV , Kahrilas P , Dent J , Jones R. The Montreal definition and classification of

gastroesophageal reflux disease: a global evidence-‐based consensus. Am J Gastroenterol 2006;101:1900-‐1920; quiz 1943.

3. Nwokediuko SC. Current trends in the management of gastroesophageal reflux disease: a review. ISRN Gastroenterol 2012;2012:391631.

4. Fennerty MB. Medical treatment of gastroesophageal reflux disease in the managed care environment. Semin Gastrointest Dis 1997;8:90-‐99.

5. El-‐Serag HB , Sweet S , Winchester CC , Dent J. Update on the epidemiology of gastro-‐oesophageal reflux disease: a systematic review. Gut 2013 Jul 13 [Epub ahead of print];

6. Wu JC. Gastroesophageal reflux disease: an Asian perspective. J Gastroenterol Hepatol 2008;23:1785-‐1793. 7. Wong WM , Lai KC , Lam KF , Hui WM , Hu WH, et al. Prevalence, clinical spectrum and health care utilization

of gastro-‐oesophageal reflux disease in a Chinese population: a population-‐based study. Aliment Pharmacol Ther 2003;18:595-‐604.

8. Katz PO , Gerson LB , Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-‐328.

9. Labenz J , Malfertheiner P. Treatment of uncomplicated reflux disease. World J Gastroenterol 2005;11:4291-‐4299.

10. Sobrino-‐Cossio S , Lopez-‐Alvarenga JC , Remes-‐Troche JM , Galvis-‐Garcia ES , Soto-‐Perez JC, et al. Proton pump inhibitors in gastroesophageal reflux disease: "a custom-‐tailored therapeutic regimen". Rev Esp Enferm Dig 2012;104:367-‐378.

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15. Vakily M , Zhang W , Wu J , Atkinson SN , Mulford D. Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials. Curr Med Res Opin 2009;25:627-‐638.

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20. Metz DC , Howden CW , Perez MC , Larsen L , O'Neil J, et al. Clinical trial: dexlansoprazole MR, a proton pump inhibitor with dual delayed-‐release technology, effectively controls symptoms and prevents relapse in patients with healed erosive oesophagitis. Aliment Pharmacol Ther 2009;29:742-‐754.

JSPHK Jan 2014 issue Page 1 – Gastro-‐Esophageal Reflux Disease: Optimizing Proton Pump Inhibitor Therapy to Improve Symptom Control Dr Wong Chun Yu, Benjamin (王振宇醫生)

21. Sharma P , Shaheen NJ , Perez MC , Pilmer BL , Lee M, et al. Clinical trials: healing of erosive oesophagitis with dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed-‐release formulation-‐-‐results from two randomized controlled studies. Aliment Pharmacol Ther 2009;29:731-‐741.

22. Wu MS , Tan SC , Xiong T. Indirect comparison of randomised controlled trials: comparative efficacy of dexlansoprazole vs. esomeprazole in the treatment of gastro-‐oesophageal reflux disease. Aliment Pharmacol Ther 2013;38:190-‐201.

23. Frelinger AL, 3rd , Lee RD , Mulford DJ , Wu J , Nudurupati S, et al. A randomized, 2-‐period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-‐state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol 2012;59:1304-‐1311.

24. Peura DA , Metz DC , Dabholkar AH , Paris MM , Yu P, et al. Safety profile of dexlansoprazole MR, a proton pump inhibitor with a novel dual delayed release formulation: global clinical trial experience. Aliment Pharmacol Ther 2009;30:1010-‐1021.

25. Howden CW , Larsen LM , Perez MC , Palmer R , Atkinson SN. Clinical trial: efficacy and safety of dexlansoprazole MR 60 and 90 mg in healed erosive oesophagitis -‐ maintenance of healing and symptom relief. Aliment Pharmacol Ther 2009;30:895-‐907.

JSPHK Jan 2014 issue Page 7 – Update on the Treatment of Chronic Myeloid Leukaemia Dr Law Man Fai (羅文輝醫生)

References: 1. Druker B, Guilhot F, O’Brien S, et al. Five-‐year follow-‐up of imatinib therapy for newly diagnosed chronic

myelogenous leukemia in chronic-‐phase shows sustained responses and high overall survival. N Engl J Med. 2006; 355: 2408-‐2417.

2. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukaemia: incidence of sustained responses in an intention-‐to-‐treat analysis. J Clin Oncol 2008; 26: 3358-‐3363.

3. Ibrahim AR, Clark RE, Holyoake TL, et al. Second generation tyrosine kinase inhibitors improve the survival of patients with chronic myeloid leukemia who have failed imatinib therapy. Haematologica 2011; 96: 779-‐1782.

4. Milojkovic D, Apperley JF, Gerrard G, et al. Responses to second line tyrosine kinase inhibitors are durable: an intention to treat analysis in chronic myeloid leukemia patients. Blood. 2012; 119: 1838-‐1843.

5. Jabbour E, Kantarjian H, O’Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood 2011; 118: 4541-‐4546.

6. Baccarani M, Deininger MW, Rosti G et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013; 122: 872-‐884.

7. Saglio G, Kim DW, Issaragrisil S et al. ENESTnd Investigators: Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 2010, 362:2251-‐2259.

8. Hochhaus A, Saglio G, Larson R et al. Nilotinib shows sustained benefit compared with imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-‐CP): ENESTnd 4-‐year follow-‐up Haematologica. 2013; 98 (Suppl 1):298 (Abstract P712).

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