MICA (P) 127/05/2012

Apr.May.Jun 2012

contents
1 SURGERY FOR FOOT & ANKLE DEFORMITIES 11 TO BARE OR NOT TO BARE 13 BARRIERS TO HEALTH CARE FACED BY FOREIGN WORKERS 17 DABIGATRAN AND RIVAROXABAN: THE EVIDENCE BEHIND THE NEWER ANTICOAGULANTS 25 RADIOLOGY QUIZ 28 ECG QUIZ

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Medical
Apr.May.Jun 2012

From The Editor

I stand by what I wrote in this column in the July-September 2005 issue of Medical Digest. I said that the most important quality of a doctor is his or her ethics and moral character. I shall reveal what I have learnt is the second most important. It is fortitude or persistence under adversity. It is seductive to always take the easy out. We transfer the care of difficult patients (either medically or temperamentally, or both) to other doctors. We order 20 tests and 5 scans to arrive at the diagnosis rather than work through the data from the history and examination. We resign from our work when we encounter difficulty with our colleagues or administrators. We become bitter when we are not happy with the prevailing culture, but we do nothing to make things better, except being a gadfly. Being a doctor is never easy; being a very good doctor is even harder. Being able to work through difficulty, to trust that the solution will reveal itself sooner or later, and to constantly keep our eye on the desired outcome is a great personal strength. I think that we must decide from the outset what we want to achieve as a doctor. This objective may be achieved in public service or private practice. Frittering away our time on picayune or constantly working in our job and not on it are good ways to lose sight of our long-term goals. We should not alter course just because we encounter some hardship. Similarly, we should not game the system and turn our back to it after we have gained what we wanted. Do we speak up constructively when we see that things are wrong? Do we set an example of strength and consistency for our colleagues and juniors? Do we require our staff to take on hardship that we will never bear ourselves? Do we only love patients and colleagues who are lovable? Who will love the ugly and the difficult? When we are old and gray, when we meet former colleagues for coffee and kaya toast, do we regret the opportunities wasted, deeds undone or words unsaid? Or do we triumph over disasters averted, wrongs righted or hypocrisy exposed? Make a difference. Stand up and be prepared to slug it out. Be a good doctor.

digest

ANSWER

The definitive diagnosis is ventricular tachycardia. Lets look at the telemetry strips. There are fusion beats in the top 2 strips (1st, 9th 10th complexes from the left in the top strip, 3rd, 4th, 14th and 15th complexes in the second strip). There is also a capture beat with a P wave preceding a narrow complex QRS in the third strip (8th complex). These features are consistent with ventricular tachycardia. The patients cardiac rhythm reverted to sinus after direct-current cardioversion (above).

Dr Leong Khai Pang EDITOR Medical Digest

Dr David Foo is the Head of the Department of Cardiology, Tan Tock Seng Hospital.

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Surgery for Foot &

Medical Progress

Ankle Deformities
Deformity correction is a complex yet rewarding surgical challenge. Deformities of the foot and ankle pose an even greater challenge to the orthopaedic surgeon given the wide-ranging causes and the progressive nature of some of them. An in-depth understanding of the bony, muscular and ligamentous relationships of the foot and ankle is required to tackle these deformities. With better knowledge of the conditions causing the deformities and with the advent of newer implants, we are now able to achieve very satisfactory surgical results. Patients with foot and ankle deformities may present with pain, difficulty with footwear and walking, ulceration or simply a funny-looking foot. Given the plethora of conditions that can cause deformities of the foot and ankle, we approach the problem by determining the cause of the deformity through a sound history. This is followed by a detailed examination to assess the mobility of the joints, the soft tissue status and the neurovascular status of the foot. I present a few cases that illustrate the commoner conditions that present with deformity of the foot and ankle. CASE 1 This is a 52-year-old bus driver who presented with bilateral feet deformity which has been progressively worsening over the past 3 years (figure 1).

Figure 1. Deformity of the feet of a 52-year-old driver.

Figure 2. Posterior view of the feet, showing hindfoot valgus deformity.

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This patient has adult acquired flatfoot deformity (AFFD).1 Notice that the talus is completely dislocated in the talonavicular joint on the left side (figures 1 and 3). He also has severe hindfoot valgus and subfibular impingement on the lateral aspect of his foot. (figure 2). This is collectively described as pes plano abducto valgus deformity. If left untreated, this patient will develop ankle arthritis and ulcers over the bony prominences of his foot.

Figure 3. Radiographic view of the feet of a 52-year-old driver.

Figure 4. Anterior and medial views of the left foot just after surgery, illustrating the incisions on the medial and lateral aspects.

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Figure 5. X-ray showing the medial view of the left foot after surgery.

He underwent corrective triple arthrodesis of the left foot (figure 4) producing a plantigrade and stable shoeable foot. Plate sand screws were utilized in the surgical reconstruction (figure 5). At the time of writing, one year after surgery, he is able to wear his shoes when he drives his bus. Surgical correction of his right foot will be carried out.

CASE 2 This is a 26-year-old banker who presented with bilateral forefoot deformity. Her main complaints were metatarsalgia (pain over the ball of the feet) and inability to wear her favorite shoes. This patient has bilateral bunion deformity. There is prominence of the first metatarsal head over the medial aspect of the foot (figure 6). Notice that the seasomoids are subluxed laterally out of the metatarsal heads (figure 7).

Figure 6. A 26-year-old banker with bilateral forefoot deformity.

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Figure 7. X-ray of the feet of the 26-year-old banker.

On the right foot, the first metatarsal is a lot shorter and pronated, disrupting the normal parabola of the forefoot, which contributed to her transfer metatarsalgia.2 Clinically, she had callosity over the metatarsal heads of the first and second toes. She was also noted to have calf tightness. Tight gastrocnemius tendon is a very common associated finding in bunion deformity and it contributes to excessive forefoot overload and exacerbates the metatarsalgia.3

Figure 8. Surgical correction of forefeet deformities.

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She underwent bilateral correction of her deformity with an osteotomy of the first metatarsal and of the proximal phalanx of the right foot, a Weils decompression osteotomy of the third metatarsal of the right second toe, medial capsulorraphy and bilateral endoscopic gastrocnemius release (figure 8) Postoperatively, the big toe is well aligned and the lesser toes are symmetrically placed. The endoscopic gastrocnemius release improves dorsiflexion of the foot and relives forefoot overload. She is pain-free and is able to wear her favorite shoes. CASE 3 This is a 66-year-old lady with rheumatoid arthritis. She is wheelchair bound due to her deformity especially that of the left ankle. On examination there was excessive mobility of the left ankle as well as an ulcer over the lateral malleolus. She had good pedal pulses (figure 9).

Figure 9. Ankle deformity with lateral malleolar ulceration.

Figure 10. X-ray of the left foot showing destruction of the ankle joint, talus and calcaneum.

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The radiograph shows complete destruction of the talus and the calcanuem from severe destructive inflammatory arthritis. There is absence of the ankle joint and the foot is subluxed medially away from the tibia (figure 10). In such cases of severe arthropathy, it is important to exclude an infective etiology. A multi-disciplinary approach was adopted and this patient was optimized for surgery in collaboration with the anaesthetist, rheumatologist and the rehabilitation physician.

Figure 11. X-ray showing left hindfoot arthrodesis.

She eventually underwent a hindfoot arthrodesis procedure using an intramedullary device.

Figure 12. Results of left foot surgery.

Figure 12 shows the left ankle of the patient 3 months post-reconstruction of deformity. She has a stable, plantigrade foot and the ulcer over the lateral malleolus has healed. She is able to weight bear and now walks with a walking stick.

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CASE 4 This is a 70-year-old lady with Charcots arthropathy of the hindfoot from diabetes mellitus. She has severe rocker-bottom deformity of both her feet and the heel is not in contact with the ground (figure 13). She presented with pain on both soles and ankle and was unable to stand for prolonged periods of time.

Figure 13. Photographs of the posterior and dorsal views of the feet of a 70-eyar-old lady with diabetes mellitus.

Figure 14. Radiographs of the lateral view of the feet of the 70-year-old lady with diabetes mellitus.

The radiographs show the abnormal position of the calcaneum with a flexion deformity. The anterior process of the calcaneum is in direct contact with the ground and the patient is essentially walking on a bony prominence with limited dorsiflexion ability. The subtalar joint is not visible and patient has loose bodies in the anterior ankle joint (figure 14). The hindfoot and midfoot show architectural collapse and consolidation consistent with Eichenholtz Stage 3 Charcot arthropathy.4

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Figure 15. X-ray of the right ankle after surgery.

The patient underwent soft-tissue deformity correction with bilateral endoscopic gastrocnemius release, exostectomy (removal of bony prominence) and anterior chilectomy (removal of loose bodies) (figure 15). Note that the calcaneum is in a more anatomical position and the anterior bony loose bodies have been removed. She did not require any rigid internal fixation as she was a stable Charcot arthropathy in the remodeling stage. She is able to enjoy pain-free ambulation with a pair of special orthotic shoes. CASE 5 This 20-year-old national serviceman presented with symptomatic flatfeet (figure 16). He had bilateral medial feet pain which severely limited his participation in military activities. He was also unable to wear his military boots and experienced pain even when walking in normal sports shoes. Note his excessive heel valgus, worse on the right (figure 16).

Figure 16. Photograph of the dorsal and posterior views of feet of a 20-year-old national serviceman.

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Figure 17. Medial view of the right foot showing the most painful spot which was the insertion of the tibialis posterior tendon into the navicular.

The area marked out on the foot represents his most painful spot and corresponds to the tibialis posterior tendon insertion into the navicular bone (figure 17). There is complete absence of an arch over the medial foot. Most cases of painful adolescent flatfoot deformity are due to an unstable accessory navicular and it has to be actively looked for during examination of the foot.

Figure 18. Medial view of the right foot showing the loss of the normal arch The two non-parallel lines show that the axes of the talus and first metatarsus are no longer collinearly aligned.

Figure 19. Radiograph of the right foot after surgery.

The lateral radiograph of the foot displays the midfoot arch collapse and the declination of the talus. The talus and the first metatarsal bone are not collinearly aligned. One can also make out the accessory navicular bone (figure 18).

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He underwent flatfoot reconstruction surgery. He had an endoscopic gastrocnemius recession, modified Kidners procedure (excision of the accessory navicular and reattachment of the posterior tibial tendon), subtalar arthroeriesis screw insertion into the sinus tarsi to correct talar declination and a first metatarsal osteotomy (figure 19). The aim of the reconstruction is to remove the painful source and reestablish the architecture of the foot (figure 20). Figure 21 shows the excised accessory navicular bone.

Figure 20. Immediate post operative photograph showing the re-establishment of the medial arch.

Figure 21. The excised accessory navicular bone.

CONCLUSION The cases illustrate common conditions of the foot and ankle presenting with deformities that are seen in general practice. A systematic approach to elicit the underlying pathology and appropriate counseling of the patient can bring about improved patient satisfaction and outcome. Some of the conditions may require surgical intervention.
References

The Foot and Ankle Division in Tan Tock Seng Hospital is a newly established subspecialty service and is well poised to handle foot and ankle specialist referrals. More information can be found in the TTSH website http://www.ttsh.com.sg/ patient-guide/find-care/clinics/page. aspx?clid=105.

1. Bluman EM, Title CI, Myerson MS. Posterior tibial tendon rupture: A refined classification system. Foot Ankle Clin N Am 2007; 12:233-49. 2. Barouk LS. Forefoot Reconstruction. 2nd Edition. Springer-Verlag. 2006. 3. Di Giovanni CW, Kuo R, Tejwani N, Price R, Hansen S. Isolated gastrocnemius tightness. J Bone Joint Sur 2002; 84A:962-70. 4. Wukich DK, Sung W. Charcot Arthropathy of the foot and ankle: modern concepts and management review. J Diabetes and its Complications 2009; 23:409-26.

Dr Kannan Kaliyaperumal is a Consultant in the Foot and Ankle Service of the Department of Orthopedic Surgery, Tan Tock Seng Hospital.

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To Bare Or

Review

Not To Bare
For an activity that is supposedly second nature to humans, the sport of running seems to be fairly complex, at least judging from the number of possible running styles. The latest of these is barefoot running. I am often asked by my patients whether barefoot running is right for them, whether it will make them faster, and the type of barefoot running shoes they should use (if there is ever a prize for the best oxymoron, barefoot running shoes must be one of the contenders). It really isnt helped by the fact that there is relatively little empirical data on this style of running and most of the pronouncements are based on personal likes and dislikes. Let us have a look at the empirical data and then infer some lessons from them. IS BAREFOOT RUNNING IS MORE EFFICIENT? Intuitively, most runners would agree that having less weight on the feet translates into less effort in running. This is true as there are energy costs incurred in moving this extra weight on your feet repeatedly (this has been tested by hanging weights on the feet of runners).1 The energy cost has been estimated to be twice to thrice that to having an equivalent weight carried by the trunk. Indeed, only some of the studies that compare oxygen consumption (and therefore energy demand) between running barefoot and running with shoes have shown a difference between them; in fact, one found that less metabolic requirement was lower with lightweight running shoes.1 Why this is so is not clear. One conjecture is that while shoes do incur a weight penalty, they help in cushioning and support and this translates into less effort expenditure for the muscles, at least up to the point beyond which the weight of the shoes offset the benefit of shock dampening. Conversely, in studies where running is measured over a short distance (much shorter than most endurance races in practice), comparing net efficiency between barefoot running and running with shoes, the latter is less efficient, as shoes add weight, and though it functions mechanically as a dampener, might also result in less energy transfer to the elastic tissue in the leg or foot, which might be recycled in the next step (but also mean these structures are under less

strain).2 In fact, the studies seem to suggest that as we run without shoes, we tend to change to our running pattern to that with shorter strides and forefoot landing, with pre-contraction of the calf muscles to anticipate the impact of foot strike.3 There are other practical considerations involved. Since empirical data shows that runners change the way they run and tend to activate the muscle on the leg when not wearing shoes (presumably

to account for the change in impact), whether this increased activation leads to earlier fatigue and then a less efficient gait in a the latter part of a long race (hence off-setting the initial benefits of carrying less weight on the foot) is not known at this stage. Does this mean that we would have immediate race improvement if we change to barefoot running based on the current available data? Not necessarily so. For instance, we

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do know that for regular runners, the gait that we adopt are often the most metabolically efficient way of running (that our body can manage) and that in the short term, altering the cadence and stride length actually makes a runner less efficient.4 This is not to say that one cannot change the running pattern to improve but potentially, it takes time to be retrained in the new gait both in turn of the technique and for physical adaptations) in order to be proficient (and also avoid overuse injuries). Conceptually, it is akin, to climbing down one peak (best performance on running with shoes) into the valley (of temporary poorer performance) in the hope that climbing the next peak (running barefoot) is ultimately higher when reaching the top. IS BAREFOOT RUNNING THE PANACEA FOR RUNNING INJURIES? Conceptually, when running barefoot without shoes to cushion impact of foot strike, the work must be done by some other part of the body (when landing on the forefoot, the muscles tendon units of the calf and the tibialis posterior, flexor hallucis longus and the flexor digitorum longus are activated). This runs counter to the assertion by barefoot running proponents that barefoot running decreases running injuries, since the structures would have to work harder. Despite the assertions of barefoot running enthusiasts, there are no good studies to demonstrate this but rather there are case studies associated with the switch to barefoot running (but not barefoot running per se). 5,6 The distinction is important as, in overuse injuries, it is often the pace of change (outstripping the adaptive capacity in response to training), not the absolute volume of training, that leads to injury. The practical implications when advising runners who seek to change to barefoot running are three-fold. First, the switch should be gradual, in terms of the time given to the change and how fast we remove the

running barefoot, so one can might avoid total bareness and save ones soles.7 Secondly, it might be advisable to condition the foot in preparation for the change in loading pattern e.g. through eccentric calf strengthening. Lastly, bearing in mind that barefoot running probably results more transfer of energy to the elastic tissues in the foot and leg, one should take into consideration the presence of pathology in deciding whether to switch. For instance, in the presence of plantar faciitis or Achilles tendinopathy or enthesopathy, it would be advisable switch slowly, if at all.
References

1) Franz JR, Wierzbinski CM, Kram R. Metabolic Cost of Running Barefoot versus Shod: Is Lighter Better? Med Sci Sports Exerc. 2012 Mar 2. [Epub ahead of print] 2) Divert C, Mornieux G, Freychat P, Baly L, Mayer F, Belli A. Barefoot-shod running differences: shoe or mass effect? Int J Sports Med 2008; 29:512-8. 3) Divert C, Mornieux G, Baur H, Mayer F, Belli A. Mechanical comparison of barefoot and shod running. Int J Sports Med 2005; 26:593-8. 4) Cavanagh PR, Kram R. Stride length in distance running: velocity, body dimensions, and added mass effects. Med Sci Sports Exerc 1989; 21:467-79. 5) Jenkins DW, Cauthon DJ. Barefoot running claims and controversies: a review of the literature. J Am Podiatr Med Assoc 2011; 101:231-46. 6) Giuliani J, Masini B, Alitz C, Owens BD. Barefoot-simulating footwear associated with metatarsal stress injury in 2 runners. J Sports Med Phys Fitness 2011; 51:401-8. 7) Squadrone R, Gallozzi C. Effect of a five-toed minimal protection shoe on static and dynamic ankle position sense. J Sports Med Phys Fitness 2011; 51:401-8.

support from the regular shoes. One might restrict barefoot running to the shorter, slower, recovery runs to begin with, and gradually working it into the longer runs. In addition, there are many degrees of bareness in the minimalist running shoes (sometimes referred to as barefoot running shoes), with different amount of shock absorption, stiffness in the shoes and different degrees of drop (how much the deep is raised above the ground versus the forefoot). One can graduate from a shoe with more cushioning and support to one with less over time. Incidentally, the Vibram five-finger shoes appear to result in a similar running pattern as

Dr Jason Chia is a consultant in the Department of Orthopaedic Surgery, Tan Tock Seng Hospital.

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13:

Barriers to Health Care

Viewpoint

Faced by Foreign Workers

Migrant workers in Singapore face challenges in accessing and navigating our health care system. A greater understanding of their socio-economic concerns can help us provide a higher standard of care. This write-up addresses language, financial, work, societal and legal issues with reference to a Bangladeshi migrant worker diagnosed with extra-pulmonary tuberculosis. Specific suggestions are put forth to address the barriers to health care, some of which are also applicable to patients in general. Every year, 30,000 new Bangladeshi migrant workers enter Singapore, pulled by our construction industrys demand and pushed by the allure of overseas employment. These workers are liable to suffer from occupational injury, food and water borne illnesses and other conditions, yet are disadvantaged in health care access. Their low salaries and non-qualification for Singapores health subsidies pose barriers to health-seeking behavior.

admitted to hospital on 18 February 2012 for fever, arthralgia, myalgia, and cough. The temperature was 37.8C on admission and exceeded 38 C in the ward. No particular febrile pattern was observed. There was no rash, neck stiffness, vomiting, diarrhoea or photophobia. He had frontal headache, general fatigue and nausea. Besides arthalgia and myalgia of nine days duration, he experienced bilateral ankle pain and swelling for seven days duration, which made walking difficult. There was mild cough for four to five days. He lived with 15 other colleagues in a single room. He had seen rats in his dormitory. He was single, and had no sexual contact. He did not smoke or drink. He had not left Singapore for 3 years. One colleague had fever but did not seek treatment. During examination, the temperature was 37.6C, pulse rate 72/min, blood pressure 130/80 mmHg and oxygen saturation 100% on room air. He was alert and comfortable. Tender cervical and inguinal lymph nodes were palpable. There was no icterus, pallor, or thrush. The neurological, cardiovascular, respiratory, and abdominal examinations were unremarkable. The right wrist and both ankles were swollen and tender. The haemoglobin was 14.9 g/dl, total white count 14,000/mm3 and

Inability to speak English, which most of Singapores doctors communicate in, is another handicap. Some diseases evoke disgust among the public in Bangladesh and Singapore, so being labeled with these diagnoses can affect social standing and job security. Finally, certain diseases necessitate a foreign patients repatriation from Singapore, contributing to avoidance of medical services. This paper begins with a case report

of a Bangladeshi migrant who has been hospitalized. Then, issues on language, economics, work policies, stigma and labor law are addressed through literature review and reflections of this patients place in the healthcare system. Practical suggestions involving the health care barriers are also put forth. CASE REPORT Mr R is a 29-year-old Bangladeshi construction worker with no significant medical history. He was

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erythrocyte sedimentation rate 87 mm per hour. The serum sodium was 133 mmol/l, potassium 4.4 mmol/l and creatinine 90 umol/l. The C-reactive protein was 201 mg/l. The glycated haemoglobin was 5.8%. The serum albumin was 35 g/l, bilirubin 21 umol/l, alkaline phosphatase 75 u/l, alanine transaminase 335 u/l and aspartate transaminase 223 u/l. Blood cultures, blood films for malarial parasites, anti-HIV and chikungunya IgM antibodies, rapid plasma regain, syphilis IgG, anti-hepatitis A antibody, hepatitis B surface antigen and antihepatitis B surface antigen antibody were negative. The chest X-ray was normal. CT scan of the thorax, abdomen and pelvis showed enlarged retro-peritoneal and peri-pancreatic lymph nodes, which were possibly necrotic. This finding suggested that infections like tuberculosis and melioidosis and malignancy should be ruled out. Endoscopic ultrasound-guided fine-needle aspiration of the peripancreatic nodes showed necrotic debris with possible granuloma formation. M. tuberculosis PCR was positive. Gram stain, aerobic/ anaerobic culture, AFB smear and fungal smear were negative. Mr R was initially treated for disseminated gonoccocal infection with intravenous ceftriaxone because he presented with fever, arthralgia and myalgia. The revised diagnosis was extra-pulmonary tuberculosis (PCR positive, sputum negative, culture pending). CXR and CT scan showed no lung involvement. Rifampicin, isoniazid, ethambutol and pyrazinamide (RHEZ) with pyridoxine was initiated on 2/3/12. The patient knew that treatment would take 6 months to complete. Other medical problems during admission included facial and shin folliculitis which resolved, and raised LFTs which gradually went down (ALT 335 to 84, AST 223 to 44). He was discharged on 7/3/12, to be followed up by CDCs J Clinic and Tuberculosis Control Unit. HEALTHCARE BARRIER 1: LANGUAGE AND EDUCATION Ong and colleagues studied workrelated injuries in Singapores foreign workers and sought their views on

workplace safety.1 They concluded that interpreters can make safety procedures and training more effective. However, the variety of nationalities, languages, cultural nuances and learning abilities make this difficult. Ding and Hargraves found a caveat to the healthy migrant hypothesis.2 The hypothesis presupposes that migrant workers are initially in good health, being naturally selected from their home countries. The authors found that in the long run, immigrants face disadvantages in health care access, insurance coverage, health service utilization and community support. Language was one key reason. Stress was found to be greatest in the first ten years in a foreign land. Stressors include the immigration process, employment, tight finances and cultural conflicts. These stressors can be caused, and worsened, by language barriers. Billah commented on the teaching of English to teenage students in Bangladesh.3 Recently, many schools teaching English have been established because of the desire to learn the language. However, these institutions are not regulated by the government and the standards of the teachers and teaching material are generally low. My patient, Mr R, had difficulty understanding simple English. His spoke in heavily accented ungrammatical English. The clinical examination was less trying as physical cues could be used. He stated that he had a Bachelor of Arts degree, which suggests that educational attainment is a poor marker of English proficiency in migrant workers. When quizzed on his diagnosis and treatment, R recognized some words like tuberculosis, TB and injection. In my experience, the average HO- or MO-on-call may not be aware that a Tamil-speaking health care colleague will not be able to help them communicate with Bangladeshis as the latter mainly speak Bengali. The language barrier affects the quality of care we can provide our patients. There are three ways to access Bengali translators in Tan Tock Seng Hospital. The first option is

to request a translator from the High Commission for the Peoples Republic of Bangladesh. However, in a telephone conversation (30 March 2012), the Labor and Welfare Department stated that it was not sufficiently resourced to provide this service, and had not done so for years. Second, there is one Enrolled Nurse in Ang Mo Kio Hospital who speaks Bengali, but she has to travel here upon activation. Third, external translation companies can provide translators for a fee. The hourly rate ranges from $100 to $300, with a mean of $175. None of these three ways are ideal. HEALTHCARE BARRIER 2: ECONOMIC CONSTRAINTS Was health care affordable for R? As a foreigner, his 19-day stay costs $3800 (=$200x19). With invasive ultrasound and needle aspiration, a conservative estimate of Rs total hospital bill is around $7,000 excluding 7% GST. Employers must buy medical insurance of $15,000 per year per Work Permit holder, covering inpatient care and day surgery. The cost of insurance is not borne by the worker, unless he agrees to co-pay.4 In this case, Rs bill can be covered by insurance. For a foreign worker, the current mandatory $15,000 insurance appears adequate for a moderately long stay. However, the fees will rise quickly if intensive care or surgical intervention are needed. Beyond $15,000, R will have to pay the balance in cash, without the benefit of Medisave, Medishield or MediFund, payment mechanisms which Singaporeans enjoy. HEALTHCARE BARRIER 3: WORK ISSUES Some non-profit organizations issue reports on the experiences of foreign workers in Singapore. Though these are unverified and not peer-reviewed, they offer a glimpse of the plight of these workers. Transient Workers Count Too (TWC2) aims to raise awareness of exploited migrant workers through means such as investigative journalism.5,6 One of their articles published in 2011 reported that migrant construction workers without specific skills can expect only $700 to $900 a month,

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for working from 8am to 7pm. They allege that some companies, both small firms and large multinationals, pay no bonus, skimp on overtime pay, do not provide medical benefits and restrict medical leave. Humanitarian Organization for Migration Economics (HOME) also fights for migrant worker rights. Its 2011 paper reviewed the literature on exploited migrant Chinese workers.7 The issues include food, living conditions, fatigue, salary and medical leave. The report cited examples of workers made to work 24 hours without rest, of unfair pay with exorbitant fines for sick days, and of one worker who was allowed only two days medical leave for an amputated finger. The quoted working hours and salary are in agreement with Rahmans rigorous analysis, who studied actual cases and journal articles from 1966 to 2003.8 He found that 95.24% of Bangladeshi migrants work 1118 hours on weekdays, 61.12% work 8-14 hours on Sundays and the average monthly salary was S$712. Contrary to the belief that the remittance of unskilled Bangladeshi migrants can support purchases of land and luxuries at home, the vast majority return home in debt from the high cost of migration. HEALTHCARE BARRIER 4: STIGMA Karim and colleagues compiled interviews of non-patients (i.e. public) in rural Bangladesh regarding their views on tuberculosis (TB).9 It was reported that the stigma of TB causes patients to hide symptoms and diagnosis, and to feel guilt and shame. Women with TB find it difficult to get married. Some men do not send a TB-infected wife for treatment because her death enables him to re-marry and collect more dowries. Women believe men contract TB because of sinful activities like smoking cigarettes and extramarital affairs. Men and women believe that stepping over the sputum of a person infected with TB can transmit disease. For fear of transmission, family members shun an infected person. His utensils and bed are separated. He cannot talk to neighbors unless he covers his mouth. To reduce stigma, people conflate respiratory illnesses with milder

status of TB in Singapore.11 They place the incidence of TB in Singapore (under 40 cases per 100,000 resident population) as the lowest in Southeast Asia but several-fold that of the United States or Western Europe. The perception that TB belongs to the less developed countries in Asia and Africa, or to historical Singapore, can blind residents with chronic cough to the possibility that they may be suffering from TB. Due to the fear of losing their jobs, patients seldom inform colleagues and supervisors that they have TB. This stigma has been officially recognized by the Ministry of Health.12 The articles suggest that cultural sensitivity and high index of suspicion are needed during history taking. For example, a patient speaking of a family member who has TB may refer to the condition as cough instead of the Bengali term jokkha. Stigmatized illnesses in various countries could be referred to by different euphemisms. The sense of community and family is very strong in Bangladesh. Rahman explains that working overseas is seen as honorable; a migrant worker raises his status and his familys.9 Some families even sell houses and jewelry to finance the overseas stint in pursuit of this. A worker who is repatriated because he is found to have TB faces many difficulties. Inability to repay his family loan, the loss of status from losing an overseas job, fear of transmission and the view that he is now too weak for farm work add up to cause immense shame and stigma. It would be understandable for a Bangladeshi migrant to shun doctors for fear of receiving stigmatizing diagnoses. It may be of public health relevance to examine the stigma and beliefs of the residents of Singapore with regard to TB. Such a study should compare the stigma experienced by citizens with TB against that experienced by migrants with TB. The findings could guide TB public education in Singapore, determine the extent that stigma at work and at home is a risk factor for defaulting treatment, and assess the relative stigma of TB, HIV and other diseases. HEALTHCARE BARRIER 5: LEGAL ISSUES The Ministry of Manpowers official

symptoms. The word for cough can mean anything from the common cold and asthma, to whooping cough and TB. Alternatively, women with TB will claim that their cough is due to pneumonia, heart disease or gasteroenteritis; men with TB explain their cough as malaria-induced. Somma et al used standardized questions to find the level of TBrelated stigma in four sites.10 This summary focuses on their findings in Bangladesh. TB stigma includes what society does to the sufferer (social exclusion) as well as what the patient thinks he will receive (felt stigma). Women were more likely to experience impaired selfesteem, shame/embarrassment and perceived low regard of others. In men with TB, the stigma of weakness is due to inability to work. They may stop working for social reasons or due to disability. Weakness in agrarian Bangladesh limits the patients usefulness in farm work, affecting their social status within the community. Cutter and Wang commented on the

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website explains Work Permit in detail.13 The foreign worker has to pass a medical examination by a Singapore-registered doctor within 14 days of arrival in Singapore. The medical examination screens for general fitness for work, and four infectious diseases of public health concern: active pulmonary tuberculosis, HIV, syphilis and malaria. A work permit is not issued unless the medical examination is passed. Those who do not pass will have to be repatriated. Employers who wish to know the results of the medical examination may obtain a copy of the completed report from the examining doctor. If a work permit holder is found to have HIV or TB during his tenure, he will be repatriated unless the employer is willing to intervene on his behalf. Because the employer is charged with ensuring that the worker is fit for work, he is allowed to access the workers medical examination results. Though this is operationally convenient, it remains ethically debatable. The same website cautions employers that the worker may still have other diseases not routinely screened for, and allows the employer to request for additional tests. The charitable organization HealthServe which offers subsidized healthcare ($5 per visit) to migrant workers. HealthServe also offers counseling services for anxiety, depression, financial issues and worries regarding HIV screening. However, this organization does not give legal advice or handle legal issues.
References
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

It is almost a knee-jerk reaction to think that if foreign workers could be repatriated for various diagnoses, then they would want to avoid health care. However, with legal aid and compassionate employers, it is possible that access to health care can be less daunting. SUGGESTIONS FOR CLINICAL PRACTICE The migrant workers employers contact details should be obtained early so that the employer or a fellow worker can be present to translate, if necessary. The Emergency Department commonly obtains this information via a paramedics clerking sheet. Prepare graphical aids for asking questions and other communication, and place them in the hospitals intranet. The 10-point pain score is one example currently in use, and can be paired with a verbal How painful? in the patients native language. We should be aware of the diseases that are prevalent based on the patients demographics and occupation. For a migrant construction worker, this can include chikungunya, dengue, murine typhus, occupational lung disease, malnutrition and dehydration. We should educate employers about diseases like tuberculosis. This may reduce stigma, engender tolerance of TB sufferers with regard to time off for treatment and convalescence, and induce them to think of redeployment of affected migrant employees instead of repatriation.

Doctors who are keen to understand migrant workers should volunteer at migrant-targeted clinics like HealthServe. This allows doctors to gain experience while furthering a humanitarian cause. HealthServe requires volunteer doctors to work at least once a month at its Geylang or Little India clinic. CONCLUSION I have reviewed articles on the language, economic, work, stigma and legal issues of foreign workers in Singapore, based on a discussion of a TB-infected Bangladeshi construction worker. The barriers to health care such workers face are many, and I hope that doctors adopt a more nuanced and compassionate approach when they encounter them. ACKNOWLEDGEMENTS The author thanks A/Prof Lim Poh Lian and Dr Lee Cheng Chuan for their help in the preparation of this manuscript.

Mr Yeang Xian Wei is a fourth-year medical student of the Yong Loo Lin School of Medicine.

Ong VY, Habibah AK, Lee FC. Safety among foreign workers and impact on emergency medicine services in Singapore. Singapore Med J 2006; 47:121-8. Ding H, Hargraves L. Stress-associated poor health among adult immigrants with a language barrier in the United States. J Immigr Minor Health 2009; 11:446-52. Billah MM. Articles on Education of Bangladesh. Bangladesh: BD Edu; c2008-2011. How English Version Education going on? 2011 Apr 29. Available from: http://www.bdeduarticle.com/education-policy/37-uncatagorized/172-how-english-version-education-going-on. Accessed 29 March 2012. Ministry of Manpower, Singapore: Government of Singapore; c2012. Work Permit - Before you apply; 2012 Feb 17. Available from: http://www.mom.gov. sg/foreign-manpower/passes-visas/work-permit-fw/before-you-apply/Pages/overview.aspx. Accessed 29 March 2012. Transient Workers Count Too. Singapore: TWC2; c2011-2012. Employer underpaid me $21,000, says worker; 2011 Sep 30. Available from: http://twc2.org. sg/2011/09/30/employer-underpaid-me-21000-says-worker/. Accessed 29 March 2012. Transient Workers Count Too. Singapore: TWC2; c2011-2012. How low can a salary go?; 2012 Jan 25. Available from: http://twc2.org.sg/2012/01/25/ how-low-can-a-salary-go/. Accessed 29 March 2012. HOME Research. The Exploitation of Migrant Chinese Construction Workers in Singapore. 2011. Available from: http://home.org.sg/downloads/PRC_ MCW_Report_final_2011.pdf. Accessed 29 March 2012. Rahman M. Bangladeshi Workers in Singapore: A Sociological Study of Temporary Labor Migration. 2003. 318 p. Located at: Scholarbank@NUS Electronic Ph.D Theses. Available from: http://scholarbank.nus.edu.sg/handle/10635/14050. Accessed 29 March 2012. Karim F, Johansson E, Diwan VK, Kulane A. Community perceptions of tuberculosis: A qualitative exploration from a gender perspective. Public Health 2011; 125:84-9. Somma D, Thomas BE, Karim F, Kemp J, Arias N, Auer C, Gosoniu GD, Abouihia A, Weiss MG. Gender and socio-cultural determinants of TB-related stigma in Bangladesh, India, Malawi and Colombia. Int J Tuberc Lung Dis 2008; 12:856-66. Cutter J, Wang YT. Tuberculosis - an under-appreciated disease. Ann Acad Med Singapore 2010; 39:261-2. Ministry of Health, Singapore: Government of Singapore; c2011. TB Statistics - Update on the Tuberculosis (TB) Situation in Singapore; 2010 Nov 11. Available from: http://www.moh.gov.sg/content/moh_web/home/statistics/infectiousDiseasesStatistics/Tuberculosis_TB_Stats.html. Accessed 29 March 2012. Ministry of Manpower. Singapore: Government of Singapore; c2012. Work Permit (Foreign Worker) - After you apply; 2011 Nov 29. Available from: http:// www.mom.gov.sg/foreign-manpower/passes-visas/work-permit-fw/after-you-apply/Pages/default.aspx. Accessed 29 March 2012.

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Dabigatran and Rivaroxaban: The Evidence behind the Newer Anticoagulants

Pharmaceutical Update

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE). Anticoagulation is required for patients with VTE. For more than 60 years, vitamin K antagonists (VKA) are the only oral anticoagulant agents available in market, with warfarin being the standard therapy. Although warfarin has been effective in preventing recurrence of VTE, it has many disadvantages. First, it has a slow onset of action, which is why a concurrent bridging parenteral anticoagulant such as heparin is necessary at the onset of treatment. This poses a challenge to outpatient treatment immediately after diagnosis. Secondly, warfarin requires frequent international normalized ratio (INR) monitoring in view of its narrow therapeutic window. Warfarin targets multiple coagulation factors (factors II, VII, IX, X) but the extent of action on each coagulation factor is different, making it difficult to predict its effect. Potential drug and food interactions with warfarin also complicate its use. In view of all these limitations and the fear of bleeding, warfarin is often under-utilised. Therefore development of new effective and safe oral anticoagulants is welcomed. Dabigatran (Pradaxa) and rivaroxaban (Xarelto) are two new oral anticoagulants available in the market for the past five years. Dabigatran has been approved by FDA for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This indication and the primary prophylaxis against VTE post-totalknee or -hip replacement surgery were also accepted by the Health Sciences Authority of Singapore (HSA). Rivaroxaban was approved by FDA in 2011 for prophylaxis against VTE post-total-knee or hip replacement surgery, and reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In March 2012, HSA approved both of these indications as well as the treatment of DVT and the prevention of recurrent DVT and PE following an acute DVT in adults. Both anticoagulants, unlike warfarin, interrupt the coagulation cascade directly to prevent clot formation. The coagulation cascade is made up of two pathways, the intrinsic and extrinsic, which converge in the common pathway (figure 1). The intrinsic pathway is activated when blood comes into contact with subendothelial connective tissues or when there is tissue damage. The intrinsic pathway will finally activate factor X which is the first coagulant factor in the common pathway. The extrinsic pathway is also triggered when there is trauma to tissue. The common pathway leads to thrombin and fibrin formation for clot synthesis. Dabigatran is a potent, competitive and reversible direct thrombin (factor IIa) inhibitor. It is presented as dabigatran etexilate which is a prodrug that does not exhibit any pharmacological activity (figure 2). After absorption, it is converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver.1 Thrombin facilitates the conversion of fibrinogen to fibrin for thrombosis, inducing platelet aggregation, and activation of factors V, VIII, XI, XIII.

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Figure 1. The coagulation cascade (adapted from the Anaesthesia UK website http://www.anaesthesiauk.com/article.aspx?articleid=100096).

O O N H Dabigatran etexilate

NH H2C N N H N

N O

NH Dabigatran H2N N H H2C N N

OH

Rivaroxaban

N O

Figure 2. Chemical structures of dabigatran etexilate, dabigatran and rivaroxaban.

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Since dabigatran inhibits both free and fibrin-bound thrombin, it prevents clot formation by blocking the thrombin-mediated effects.1 Rivaroxaban is a direct, selective and reversible inhibitor of factor Xa which is higher in the coagulation cascade than factor IIa (figure 2). Thus, it inhibits platelet activation and fibrin clot formation.1 INDICATIONS OF THE NEW ORAL ANTICOAGULANTS Prevention of VTE VTE occurs in 10 to 40% of medical

and general surgical patients and in 40to 60% of those who undergo major orthopaedic surgery without VTE prophylaxis.2 Pulmonary embolism causes around 10% of hospital deaths.2 NICE guideline recommends heparin or fondaparinux for the prevention of VTE.3 Both rivaroxaban and dabigatran were approved by HSA in 2008 and 2009 respectively for the prevention of VTE after total knee (TKR) or hip replacement (THR) surgery. Table 1 summarizes all the trials performed to compare the efficacy and safety of

dabigatran and rivaroxaban that led to their approvals. DABIGATRAN In the RE-MODEL and RE-NOVATE studies, dabigatran 220 mg or 150 mg once daily was shown to be equivalent to enoxaparin for prophylaxis against VTE post-TKR and -THR respectively.8,10 However, in RE-MOBILIZE trial, non-inferiority was not shown when compared with the gold standard of prophylaxis. Enoxaparin 30mg twice daily was superior compared to both doses of dabigatran for post-TKR prophylaxis

Trial

Trial design

Drug

Comparator Indication

Patients (N)

Primary Major outcome Bleeding Drug % vs comparator %, p value

1.1% vs 3.7%, p<0.001 (superiority) 2.0% vs 9.3%, p<0.001 (superiority) 9.6% vs 18.9%, p<0.001 6.9% vs 10.1%, p=0.0118 0.3% vs 0.1%, p=0.18

RECORD 1

Double blind, double dummy Double blind, double dummy Double blind, double dummy Double blind, double dummy Double blind, double dummy

Rivaroxaban 10mg OD x 5/52 Rivaroxaban 10mg OD x 5/52 Rivaroxaban 10mg OD x 10-14/7 Rivaroxaban 10mg OD x 10-14/7 Dabigatran 220mg or 150mg OD x 6-10/7

Enoxaparin 40mg OD x 5/52 Enoxaparin 40mg OD x 10-14/7 Enoxaparin 40mg OD x 10-14/7 Enoxaparin 30mg BD x 10-14/7 Enoxaparin 40mg OD x 6-10/7

THR

4541

RECORD 2

THR

2509

<0.1% vs <0.1%

RECORD 3

TKR

2531

0.6% vs 0.5% p=0.77 0.7% vs 0.3% p=0.1096

RECORD 4

TKR

3148

RE-MODEL

TKR

2101 included; 1541 evaluated for efficacy 2596 included; 1896 evaluated for efficacy

1.5% vs 1.3% 36.4% vs 40.5% vs vs 1.3% 37.7% P=1.0; p=0.82 p=0.0003; p=0.017 (noninferiority) 31.1% vs 33.7% vs 25.3% p=0.0234; p=0.0009 (noninferiority) 6.0% vs 8.6% vs 6.7% p<0.0001; p<0.0001 (noninferiority) 0.6% vs 0.6% vs 1.4% p>0.05

RE-MOBILIZE Double blind, double dummy

Dabigatran 220mg or 150mg OD x 12-15/7

Enoxaparin 30mg BD x 12-15/7

TKR

RE-NOVATE

Double blind, double dummy

Dabigatran 220mg or 150mg OD x 28-35/7

Enoxaparin 40mg OD x 28-35/7

THR

3494 included; 2651 evaluated for efficacy 2055 included; 1577 evaluated for efficacy

1.3% vs 1.3% vs 1.6% p=0.44; p=0.60

RE-NOVATE II Double blind, double dummy

Dabigatran 220mg OD x 28-35/7

Enoxaparin 40mg OD x 28-35/7

THR

7.7% vs 8.8% 1.4% vs 0.9% p<0.0001 p=0.40 (noninferiority)

Table 1. Summary of trials on prevention of venous thromboembolism for dabigatran and rivaroxaban.4-12

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against VTE.8 All primary efficacy outcomes are similar in all trials. There was a recent meta-analysis study that pooled all the results from the above 3 trials and concluded that dabigatran is non-inferior to enoxaparin in patients who underwent major orthopaedic surgeries in both efficacy and safety profiles.13 RE-NOVATE II was carried out to further evaluate the efficacy and safety of dabigatran in more diverse population. Enoxaparin 40mg once daily was compared with dabigatran 220 mg once daily for duration of 28 to 35 days in patients who underwent THR. It was shown that dabigatran was not inferior to enoxaparin for VTE prophylaxis.11 RIVAROXABAN AAll RECORD studies concluded that rivaroxaban was superior to enoxaparin for VTE prophylaxis in patients who underwent TKR or THR (table 1).4-7 Rivaroxaban also had comparable bleeding risk as enoxaparin. There was a pooled analysis of the four RECORD studies to evaluate the efficacy of rivaroxaban in reducing symptomatic VTE and all-cause mortality. This was done to account for the different study duration of the trials. There were three different pools of analysis - active treatment pool (122 days), total treatment pool (2 weeks for TKR, 5 weeks for THR) and total study duration (65 days for THR and 42 days for TKR). The primary Trial Drug RE-LY

efficacy outcome was significantly reduced in the rivaroxaban arm in active treatment period (0.5% vs 1.0%; p=0.001).14 Risk of major or any bleeding was similar between both groups in the active treatment period. Results were also consistent in the subgroup analysis. Superiority of rivaroxaban was seen across different patient populations with differences in weight, age, gender, and creatinine clearance. ATRIAL FIBRILLATION Atrial fibrillation (AF) is the most common cardiac arrhythmia and its prevalence increases with age.17 AF confers a five-fold risk of cardioembolic stroke and 20% of strokes are caused by this arrhythmia.16,18 Guidelines recommend the use of vitamin K antagonists (warfarin) for patients with AF at high risk for stroke or systemic embolism (in patients with CHADS2 score of 2). However, there are a lot of challenges in the management of this drug. They include the need for frequent INR monitoring, food and drug interactions, and bleeding risk.18 DABIGATRAN The recent phase III trial, RE-LY, led to the FDA approval of dabigatran for prevention of stroke and systemic embolism in patients with nonvalvular AF (table 2). It was designed to compare two fixed doses of dabigatran (110mg or 150mg twice daily) which were administered in blinded fashion with open-label use of warfarin in the rest of the

trial participants. A total of 18,113 patients were enrolled in the trial. The mean age was 71 years old, 63.6% were men, about 50% of the patients received long-term vitamin K antagonists and the mean CHADS2 score was 2.1 with about 1/3 of the patients having CHADS2 score 1, about 1/3 of them having CHADS2 score 2 and rest of them having CHADS2 score 3. Warfarin was within therapeutic range of 2 to 3 for 64% of the time.15 Both dabigatran doses, 110mg or 150mg twice daily, were non-inferior to warfarin (p<0.001) in prevention of stroke or systemic embolism. Only the 150-mg dabigatran dose was superior to warfarin (RR 0.66, CI 0.53 to 0.82, p<0.001). Both doses were significant in reducing number of hemorrhagic strokes (p<0.001). The rate of myocardial infarction was found to be higher for dabigatran than warfarin; the relative risk was significant for dabigatran 150mg only (p<0.048). However, it was no longer significant (p=0.12) after adding the newly identified events from locked database when the data was checked again.15 Dabigatran in general caused significantly less life-threatening bleeding (110mg: RR 0.68, CI 0.550.83, p<0.001; 150mg: RR 0.81, CI 0.66-0.99, p 0.04) and intracranial bleeding (110mg: RR 0.31, CI 0.200.47, p<0.001; 150mg: RR 0.40, CI 0.27-0.60, p<0.001) than warfarin. However, there was significantly ROCKET-AF Rivaroxaban 20mg once daily or 15mg once daily for CrCl 30-49ml/ min Warfarin (INR 2-3) Double-Blinded 14, 264 3.5 Stroke or systemic embolism of the myelin sheath and helps protect nerve cells from oxidative damage)

Dabigatran 110mg or 150mg twice daily

Comparator Trial Design Patients (N) Mean CHADS2 score Primary outcome

Warfarin (INR 2-3) Blinded for the 2 strengths of dabigatran used, open labelled for warfarin 18,113 2.1 Stroke or systemic embolism

Table 2. Characteristics of RE-LY and ROCKET-AF trials.15,16

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more gastrointestinal (GI) bleeding for dabigatran 150mg dose than warfarin (RR 1.50, CI 1.19-1.89, p<0.001).15 More patients who received dabigatran experienced GI symptoms such as pain, vomiting and diarrhea, compared to the warfarin-treated group (2.2%, 2.1% and 0.6% for 110mg, 150mg dabigatran and warfarin respectively). There were also significantly more patients who experienced dyspepsia in the dabigatran treatment groups (p<0.001 for both doses). Dabigatran requires an environment with low pH for better absorption. Therefore, dabigatran capsules contain dabigatrancoated pellets with a tartaric acid core to facilitate absorption. This may explain the increase incidence of GI side effects and GI bleed for Trial Trial design Drug

150mg dabigatran and may increase intolerance to dabigatran.15 Ximelagatran, also a direct thrombin inhibitor, did not receive FDA approval and was withdrawn from the European market due to its hepatotoxic side effects.19,20 Thus, similar concern is extended to dabigatran which belongs to the same class. In RE-LY, no significant difference in liver function has been observed between the 2 doses of dabigatran and warfarin.15 While both 110-mg and 150-mg dabigatran dosing regimens have been approved by some countries for the prevention of stroke and systemic embolism, FDA has only approved the 150-mg dose for this indication. FDA opined that the lower dose Comparator Indication

does not improve the benefit-risk profile of dabigatran in any patient subgroup, thus we should avoid the use of less effective regimen.21 The 75-mg regimen was approved for patients with severe renal impairment based on pharmacokinetic and pharmacodynamic data.22 RIVAROXABAN ROCKET-AF was a multicentre, randomized, double-blind, doubledummy trial. Participants were randomly assigned to receive either warfarin, rivaroxaban 20 mg once daily or 15 mg once daily if creatinine clearance lies between 30 to 49 ml/ min. 14,264 patients participated in the trial. The median age was 73 years, 60.3% were male, about 62% of them have received vitamin K antagonist, and mean and median Primary Major outcome Bleeding Drug % vs comparator %, p value 2.4% vs 2.1%, 1.6% vs 1.9% p<0.001 (noninferiority) 0.9% vs 1.8% vs 1.8%, 1.3%, p=0.03 (non- p=0.058 inferiority) 0.4% vs 5.6%, p<0.001 2.1% vs 3.0%, p<0.001 (noninferiority) 2.1% vs 1.8%, p=0.003 (noninferiority) 0.3% vs 0.0%, p=0.996 0.8% vs 1.2%, p= 0.21

Patients (N)

RECOVER

Double blind, double dummy Double blind, double dummy Double blind, double dummy Open label

Dabigatran Warfarin 150mg BD x 6/12 Dabigatran Warfarin 150mg BD x 6-36/12 Dabigatran Placebo 150mg BD x 6/12 Rivaroxaban SC 15mg BD x enoxaparin then VKA 3/53 then 20mg OD for 3, 6 or 12 months Rivaroxaban SC 15mg BD x enoxaparin then VKA 3/53 then 20mg OD for 3, 6 or 12 months Rivaroxaban Placebo 20mg OD x 6-12 months

VTE

2539

REMEDY

VTE

2856

RESONATE

VTE

1343

EINSTEIN DVT

DVT

3449

EINSTEIN PE

Open label

PE

4832

1.1% vs 2.2%, p=0.003

EINSTEIN Extension

Double blind, double dummy

DVT

1196

1.3% vs 7.1%, p<0.001

0.7% vs 0.0%, p=0.11

Table 3. Summary of trials on treatment of VTE for dabigatran and rivaroxaban.12, 24-29

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CHADS2 score were 3.0 and 3.5 respectively. Warfarin was within therapeutic range of two to three 55% of the time.16 Rivaroxaban was shown to be non-inferior to warfarin for the prevention of stroke or systemic embolism in both intention-totreat (ITT) population and treated population (per-protocol) (HR 0.88, CI 0.74-1.03, p<0.001; HR 0.79, CI 0.660.96, p<0.001). Rivaroxaban was also shown to be superior to warfarin when ITT analysis was limited to the treated (HR 0.79, CI 0.66-0.96, p= 0.02). Similarly, rivaroxaban also resulted in less intracranial hemorrhage than warfarin (HR 0.67, CI 0.47-0.93, p=0.02) as compared to dabigatran. However, as compared to dabigatran, rate of myocardial infarction was similar between rivaroxaban and warfarin (HR 0.81, CI 0.63-1.06, p=0.12).16 Incidence of major bleeding episodes was similar for warfarin and rivaroxaban. However, warfarin caused significantly more fatal bleeding episodes than rivaroxaban (HR 0.50, CI 0.31-0.79, p=0.003). Major bleeding from GI site was also more common in rivaroxaban treatment group than warfarin (p<0.001).16 TREATMENT OF VENOUS THROMBOEMBOLISM According to ACCP guidelines in 2008, short term treatment with heparin and fondaparinux is recommended for treatment of DVT and PE to achieve rapid onset of anticoagulation while waiting for onset of action of vitamin K antagonists.23 Duration of treatment will depend on whether it is an initial episode or a recurrent of event. For the initial episode, anticoagulants will be needed for at least 3 months; for subsequent episodes, lifelong treatment would be recommended unless there are other concerns.23 Rivaroxaban and dabigatran are currently under evaluation in phase III trials for treatment of VTE. They have not been licensed for this indication yet. Table 3 is a summary of the recent studies. DABIGATRAN In RECOVER, efficacy and safety of dabigatran was compared with warfarin for treatment of patients with acute VTE. Patients in both arms were initially given parenteral anticoagulation therapy (heparin) for a median of 9 days while they started on the oral anticoagulants. Primary outcome was six-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Dabigatran was found to be non-inferior to warfarin at the end of 6 months study. Superiority was tested but not significant.24 There was no significant difference between the two arms for incidence of major bleeding. Patients in the dabigatran treatment arm significantly experienced more dyspepsia than the warfarin arm, which was also observed in RE-LY. Two other recent studies examined the efficacy and safety of dabigatran for extended duration of treatment of VTE. Results have recently been presented. In REMEDY, 2856 patients were treated with for 6 months with VKA then randomized to either receive dabigatran or warfarin for 6 to 36 months for the prevention of recurrent VTE. Dabigatran was shown to be non-inferior to warfarin with similar major bleeding risks.25 In RESONATE, 1343 patients who received 6 to 18 months of anticoagulant therapy were randomized to either dabigatran or placebo treatment groups for another 6 months. Dabigatran resulted in a 92% relative risk reduction in recurrence of VTE. Major bleeding was not significantly different between the two groups.26 RIVAROXABAN EINSTEIN-DVT was an open label, non-inferiority study that compared the efficacy and safety of rivaroxaban (patients were first treated with 15mg two times a day for 3 weeks then 20mg per day) with subcutaneous enoxaparin and VKA

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for the treatment of patients with acute DVT. It was then followed by an extended study (EINSTEIN extension) that compared rivaroxaban 20mg daily with placebo for an additional 6 to 12 months to prevent recurrent VTE.27 Being an open-label trial, biases were minimized by having a central adjudication committee whose members were blinded to treatment assignments and by having objective end points.30 Rivaroxaban, as a single oral anticoagulant agent, was non-inferior to the standard therapy group but was not shown to be superior to the standard therapy (p=0.08). Both treatment arms had similar risk for major or clinically significant bleeding (p=0.77).27 No significant difference was observed in liver dysfunction between warfarin and rivaroxaban. There was also no difference in rates of myocardial infarction between the 2 groups.27 EINSTEIN PE study had a similar

trial design as EINSTEIN DVT but included patients with PE. 2.1% of patients had recurrence of VTE in the rivaroxaban treatment group and 1.8% of them had recurrence in standard therapy group. Rivaroxaban was non-inferior to standard therapy (p=0.003), however, superiority was not shown (p=0.57). First major or clinically-relevant non major bleeding was similar in both groups but more major bleeding episodes occurred in standard therapy group (p=0.003).28 EINSTEIN extension study was a double-blind, superiority study. Results showed that rivaroxaban 20mg per day was superior to placebo in the prevention of recurrence of VTE in extended period with no significant difference in major bleeding events.27 CONCLUSION There are no head-to-head studies comparing these new agents (table 4). However, these oral anticoagulants provide options for those patients who require treatment with anticoagulants as they are easier to manage with fewer drug and food interactions. More trials and post marketing surveillance data will be

Warfarin Target Vitamin K epoxide reductase (reduces levels of Factor II, XII, IX, X) No

Dabigatran Factor IIa (thrombin)

Rivaroxaban Factor Xa

Prodrug

Yes; presented as dabigatran etexilate Oral Once or twice daily; fixed dose ~6.5% 0.5-2hrs 11hrs; 14-17hrs for elderly

No

Route Dosing frequency

Oral Once daily; dose adjusted by INR ~100% ~4hrs 40hrs

Oral Once or twice daily; fixed dose ~100% 2-4hrs 5-9 hrs; 11-13hrs for elderly After first dose No CYP 3A4 and P-glycoprotein inhibitors

Bioavailability Tpeak T1/2

Time to reach steady state Routine monitoring Potential drug interactions

5-7 days Yes CYP 2C9, 2C19, 3A4, 1A2

3 days No P-glycoprotein inhibitors

Table 4. Comparison of dabigatran and rivaroxaban with warfarin

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required in the evaluation of the safety of these new agents in the long run. All the trials excluded patients with severe liver disease or severe renal impairment (creatinine clearance <30ml/min). Therefore, use of these new agents should be avoided until dose adjustments have been determined in these groups of patients. There is also no evidence for the use of these new agents in other populations who require anticoagulation, such as patients with mechanical heart valves, the antiphospholipid syndrome, cancer or pregnancy. Warfarin or heparin should still be used in above-mentioned patients, when indicated.31,19 Although the half-lives of these new oral anticoagulants are short, agents to reverse their activity quickly are still desired in cases of acute major
References

bleeding or surgical emergencies. Specific antidotes for the thrombin and factor Xa inhibitors are still absent. There is a recent study that suggests prothrombinase complex concentrates (PCC) may be used to neutralize the effect of rivaroxaban.32 PCC use for reversal of coagulopathy in dabigatran is still controversial. Recombinant activated factor VII may be considered to reverse the activity of dabigatran.28 Around 60% of dabigatran can be removed by hemodialysis and may be considered in cases of overdose or toxicity.33 Rivaroxaban is highly protein bound and will not be removed by hemodialysis.32 The new oral anticoagulants are very expensive; they cost ten times more than warfarin. Prescribers should be aware of their patients financial status before deciding to

use the newer anticoagulants. For existing patients who are compliant with warfarin treatment and remain within their target INRs, the benefit of switching to the newer agents may be small.

Ms Tan Sock Hoon is a pharmacist in the Department of Pharmacy, Tan Tock Seng Hospital.

1. Drug Information Handbook 2009-2010. 18th edition. 2. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of Venous Thromboembolism: The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3 Suppl): 338S-400S. 3. NICE clinical guideline. Venous thromboembolism: reducing the risk. January 2010. From http://www.nice.org.uk/nicemedia/pdf/CG92QuickRefGuide%20LR%20 FINAL.pdf. 4. Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358:2765-75. 5. Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2003; 372:31-39. 6. Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358:2776-86. 7. Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373:1673-80. 8. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5:2178-85. 9. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009; 24:1-9. 10. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for the prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370:949-56. 11. Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105:721-9. 12. Becattini C, Vedovati MC, Agnelli G. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: A review of the literature. Thromb Res 2012; 129:392-400. 13. Friedman RJ, Dahl OE, Rosencher N, Caprini JA, Kurth AA, Francis CW, et aI; RE-MOBILIZE, RE-MODEL, RE-NOVATE Steering Committees. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res 2010; 126:175-82. 14. Turpie AG, Lassen MR, Eriksson BI, Gent M, Berkowitz SD, Misselwitz F, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 1105:444-53. 15. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine 2009; 361: 1139-51. 16. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883-91. 17. Fuster V, Rydn LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation: Executive Summary. Circulation 2001; 104: 2118-50. 18. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31:2369-429. 19. Weitz JI. Factor Xa or thrombin: Is thrombin a better target? J Thromb Haemost 2007; 5 (S1):65-7. 20. Bauer KA. Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa. J Thromb Haemost 2011;9(S1): 12-19. 21. Beasley BN, Unger EF, Temple R. Anticoagulant options - why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med 2011; 364:1788-90. 22. Prasad V, Kaplan RM, Passman RS. New frontiers for stroke prevention in atrial fibrillation. Cerebrovasc Dis 2012; 33:199-208. 23. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ; American College of Chest Physicians. Antithrombotic Therapy for Venous Thromboembolic Disease: ACCP evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133:454S-545S. 24. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342-52. 25. Schulman S, Baanstra D, Eriksson H, Goldhaber S, Kakkar A, Kearon C, et al; RE-SONATE Study Group. Dabigatran versus placebo for extended maintenance therapy of venous thromboembolism (abstr). J Thromb Haemost 2011; 9(s2):22. 26. Schulman S, Eriksson H, Goldhaber SZ, Kakkar AKL, Kearon C, Kvamme AM, et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism (abstr). J Thromb Haemost 2011; 9(s2):731. 27. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-510. 28. EINSTEINPE Investigators, Bller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287-97. 29. Montoya RC, Gajra A. Current status of new anticoagulants in the management of venous thromboembolism. Adv Hematol 2012; 2012:856341. Epub 2012 Mar 8. 30. Beyer-Westendorf J, Bller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different. J Thromb Haemost 2011; 9:2153-8. 31. Van Es J, Eerenberg ES, Kamphuisen PW, Bller HR. How to prevent, treat, and overcome current clinical challenges of VTE. J Thromb Haemost 2011; 9(S1):265-74. 32. Eerenberg et al. Reversal of Rivaroxaban and dabigatran by prothrombin complex concentrate. A randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1-7. 33. van Ryn et al. Dabigatran etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thrombosis and Hemostasis 2010; 103:1116-27.

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RADIOLOGY Quiz
A previously healthy 73-year-old Chinese female presented to the Emergency Department with breathlessness and cough over the past one week. The patient is a non-smoker and has no past medical history of note. A chest x-ray was performed (figure 1).

Figure 1. Chest X-ray of a 73-year-old lady complaining of breathlessness.

QUESTION 1:

What are the findings? What are the differential diagnoses? What other imaging procedure can be considered to confirm the findings?

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In view of the chest x-ray findings, a CT thorax was performed for further evaluation (figures 2 and 3).

Figure 2. Coronal sections of the CT of the thorax

Figure 3. Axial sections of the CT of the thorax.

QUESTION 2

What is the abnormal structure that is seen in these CT images?

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ANSWERS

Answer 1 There is significant widening of the right paratracheal stripe, suspicious for a mass. There is also mild consolidation at the right upper and lower zones, likely representing early infection. Answer 2 There is a multinodular goiter. The enlarged and nodular right thyroid lobe shows intra-thoracic extension, causing compression and leftward displacement of the trachea. There is also patchy consolidation in the right upper lobe. The patient was treated with intravenous antibiotics for the right upper lobe pneumonia, with symptomatic improvement. Although there was compression of the trachea, the patients breathing was not compromised. Thyroid function tests revealed that the patient was euthyroid. The decision was made for conservative management of the multinodular goitre.

Discussion

Figure 4. Illustration of the location and constituents of the right paratracheal stripe. Note the proximity of the reflection of the pleura of the right upper lobe and the lateral border of the trachea. The right paratracheal stripe is indicated by markers in the chest X-ray (right).

When the visceral and parietal pleura of the right upper lobe comes in contact with the right lateral border of the trachea and the intervening mediastinal fat, air within the right lung and trachea outlines these entities to form the right paratracheal stripe. The right paratracheal stripe begins superiorly at the level of the clavicles and extends inferiorly to the right tracheobronchial angle at the level of the azygous arch. The normal thickness should not exceed 4 mm (figure 4). The right paratracheal stripe is one of the most common mediastinal lines and stripes seen in a frontal chest radiograph. Others include: Anterior junctional line Posterior junctional line Left paratracheal stripe Aorto-pulmonary window Aorto-pulmonary stripe

Right and left paraspinal lines Azygos-oesophageal recess It is extremely useful to be able to recognize the displacement or deformation of one of these mediastinal lines and stripes as this could be due to an underlying lesion. Differential diagnoses of a widened right paratracheal stripe are: Pleural disease (most common): effusion or thickening Paratracheal lymphadenopathy Thyroid goitre or neoplasm Parathyroid neoplasms Tracheal carcinoma or stenosis

Dr Lim Mei Chin is a Resident in the Department of Diagnostic Radiology, Tan Tock Seng Hospital.

References 1. Gibbs JM, Chitra A. Chandrasekhar. Lines and Stripes Where Did They Go? From Conventional Radiography to CT. Radiographics 2007; 27: 33-48. 2. Marano R, Liguori C. Cardiac Silhouette Findings and Mediastinal Lines and Stripes. Chest 2011; 139:1186-96.

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ECG Quiz
QUESTION
A 50-year-old man presented with palpitations and the above 12-lead ECG was recorded. What do you think is the likely diagnosis? Subsequently, the rhythm strips were captured on the telemetry. What is the definitive diagnosis now?