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Electronic cigarettes help smokers to quit safely in landmark trial

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3 October 2013

Electronic cigarettes help smokers to quit safely in landmark trial

Alexandra Kirsten

Electronic cigarettes [e-cigarettes, elec-tronic nicotine inhalers/devices] were found to be as effective as nicotine

patches in helping smokers to quit in the first-ever trial of its kind, presented at the recent European Respiratory Society (ERS) Annual Congress in Barcelona, Spain.

“Several withdrawal studies suggest po-tential of [e-cigarettes] as cessation aids but, until now, no adequately-powered random-ized controlled cessation trial has been con-ducted to establish if they assist smokers to quit,” noted lead author Associate Professor Chris Bullen, director of the National Insti-tute for Health Innovation at The University of Auckland in New Zealand.

In the study, 657 smokers wanting to quit were randomized and stratified by ethnic-ity, sex and level of nicotine dependence (>5 or ≤5 Fagerström test). [Lancet 2013; doi:10.1016/S0140-6736(13)61842-5]

After randomization, the researchers di-vided the participants into three groups: 292 smokers received a 13-week supply of com-mercially available e-cigarettes, containing around 16 mg of nicotine. The same number used a 13-week supply of nicotine patches, containing 21 mg of nicotine. Seventy-three participants received placebo e-cigarettes, which contained no nicotine. All smokers were offered behavioral support.

After 13 weeks of using the cessation aids, and 3 months’ further follow-up, the participants were tested through exhaled

breath carbon monoxide measurement to establish whether they had managed to re-main abstinent from cigarettes.

At the end of the 6-month study period, around one in 20 smokers (overall, 5.7 per-cent) had managed to remain completely abstinent. The proportion of participants who successfully quit smoking was highest in the e-cigarettes group with 7.3 percent (21 of 289), compared with 5.8 percent (17 of 295) in the nicotine patches group and 4.1 percent (3 of 73) in the placebo e-cigarette group. Though the differences were not statistically significant, the results suggest that e-cigarettes are comparable to nicotine patches in helping people to quit for at least 6 months.

Additionally, the results found no statis-tically significant difference in any adverse changes to health reported by participants in the e-cigarettes and the nicotine patches group.

E-cigarettes look like normal cigarettes, but are an electronic inhaler run by battery. An atomizer heats a solution of liquid, fla-

Electronic cigarettes are as effective as nicotine patches in smoking cessation, according to the results of a large randomized controlled trial.

4 October 2013

vorings and nicotine, creating a mist that is inhaled. Despite the study’s findings, Bul-len and colleagues said that “uncertainty exists about the place of e-cigarettes in to-

bacco control, and more research is urgent-ly needed to clearly establish their overall benefits and harms at both individual and population levels.”

Modified aspirin may overcome resistance

Saras Ramiya

Chinese researchers have reported the development of a new form of aspirin to cope with ‘aspirin resistance.’

The researchers, from the Capital Medi-cal University in Beijing, combined aspirin to a carrier consisting of a fragment of protein that can transport the drug directly to dam-aged parts of blood vessels where clots form. Experiments with laboratory rats showed that the carrier delivered aspirin to areas of blood vessels where clots were forming. The carrier released aspirin inside the developing clot and stopped the clot-formation process. [ACS Nano 2013 Aug 29. Epub ahead of print]

The clot-targeting aspirin delivery sys-tem selectively inhibits arachidonic acid-in-duced platelet aggregation. The mechanisms of action probably include releasing aspirin,

modifying cyclic oxidase and decreasing the expression of the platelet integrin GPIIb/IIIa, researchers said.

Aspirin is taken daily by about 60 million people in the US alone to reduce the risk of heart attack and stroke. It is believed that aspirin does not work for millions of people, who have to switch to more costly, potent prescription drugs with more serious side effects. Scientists have tried to address aspirin resistance by combining it with other drugs, but the problem remains.

Now, this modified form may extend aspi-rin’s benefits to those who do not respond to the drug.

READ JPOG ANYTIME, ANYWHERE. Download the digital edition today at www.jpog.com

5 October 2013 Forum

Making family planning accessible to every womanForeword by Dr. Margaret Chan, director-general of WHO, at the London Summit on Family Planning in conjunction with World Population Day, 11 July.

Contraception has a wide range of benefits for the health of women and children, and also for socioeconomic

development. In fact, fewer unintended preg-nancies contribute to the achievement of near-ly all Millennium Development Goals, includ-ing the reduction of poverty and hunger.

The impact of family planning on the lives of women is particularly striking in terms of both improved survival and empowerment. The impact on perinatal, infant and child health is also considerable, and could be increased by a sharper focus on contraception to space births.

WHO regards access to modern contracep-tion as the fundamental right of every woman. Hand-in-hand with this right is a need to honor the dignity of women by giving them a range of family planning options and the freedom to make their own personal choices. This right is far from being fulfilled. Worldwide, an estimat-ed 222 million women have an unmet need for contraception. The need is greatest where ma-ternal mortality rates are the highest. In many countries, more than 30 percent of women who want to use contraception are unable to get it. This translates into an unacceptably high num-ber of unintended pregnancies and all the risks they bring.

When advantages of family planning are compared with the magnitude of unmet need, one conclusion is clear: family planning de-serves a much higher place in the international health agenda, especially in countries where

fertility and unmet needs are high.WHO undertakes a number of activities

aimed at expanding access to family planning services and choices so every woman can select a method that suits her lifestyle. WHO is step-

ping up its program for the prequalification of contraceptive products, which gives procure-ment offices a guarantee of quality, increases supplies, and gets prices down through healthy competition.

Women need a choice, programs need safe and effective products, and everyone needs high-quality reproductive health services. WHO supports this need by giving countries evidence-based policy options for strengthen-ing service delivery and by identifying best practices that work well, especially in resource-

Family planning deserves a

much higher place in the

international health agenda

‘‘

6 October 2013 Forumconstrained settings. As part of preparations for the London Family Planning Summit, WHO convened a multidisciplinary group of experts on 26-29 June 2012. Based on a systematic as-sessment of the evidence, the experts articu-lated a set of policy actions that help countries expand access to contraception.

The WHO policy statements reflect the rec-ommendations of the expert consultation focus-ing on key areas of:• Optimizing the health workforce for effective

family services.• Strategies to increase use of long-acting and

permanent contraception.

• Expanding access to contraceptive services for adolescents.

• Strengthening health systems response: no opportunities missed.

WHO will continue to help countries fulfill their commitments to expand access to fam-ily planning for women and men, based on their personal needs and preferences and in keeping with their fundamental rights. Doing so makes a significant contribution to health, but also to many other broad – and broadly beneficial – goals for social and economic progress.

7 Singapore FocusOctober 2013

Community-based wellness program reduces CVD risk

Rajesh Kumar

A community-based heart wellness pro-gram in Singapore has demonstrated clinically significant improvement in

cardiac risk factors.Patients with cardiovascular conditions

are known to benefit from participation in a structured cardiac rehabilitation program, in-cluding weight loss and routine exercise. But no published data has shown its effectiveness in the Asian population, said the National University of Singapore (NUS) researchers.

They recruited 207 Singapore patients, in-cluding those with certain cardiac risk fac-tors and those who had an underlying car-diac disease but were deemed stable by their physicians, in the 12-month program orga-nized in collaboration with the Singapore Heart Foundation.

The participants went through individual-ized exercise programs, nutritional reviews, smoking cessation and psycho-social coun-seling. Baseline vitals such as heart rate and blood pressure and body weight, body fat, and exercise tolerance were measured.

At the end of the program, the participants achieved an overall 0.8 percent reduction in body fat, 12 percent reduction in “bad” cho-lesterol and 4.6 percent improvement in total cholesterol levels. Patients also showed over-all improvement in exercise tolerance and stamina with the ability to walk 10.7m longer than at baseline.

“These results highlight the program’s

potential in improving health and delaying disease progression, which lends support to the need to expand such community-based programs for early cardiovascular interven-tion,” said lead researcher Assistant Profes-sor Joanne Yeh Chang of the Department of Pharmacy at the NUS Faculty of Science, Sin-gapore.

Although similar programs elsewhere have demonstrated significant fat loss, Singapore study participants registered only a modest 0.8 percent reduction in body fat. When asked why, Chang said the number of weekly visits to the program and exercise intensity levels for individuals were not measured and were very much dependent on patients themselves.

A sub-group of patients in the secondary prevention group who had diabetes and high blood pressure experienced more weight loss, but their abdominal circumference went up during the study.

Researchers, however, argued that the study is preliminary and is now being ex-panded into a controlled trial involving 1,000 patients over 5 years, which would provide a more comprehensive picture on the extent of benefit.

They hope that encouraging initial find-ings can serve as a reference for healthcare professionals and administrators in Singa-pore to further support and expand similar programs. They also hope to influence other Asian countries to initiate affordable early cardiovascular intervention programs to pro-mote health.

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Body’s own immune response shows potential in fight against chronic HBV

Radha Chitale

Patients with chronic hepatitis B viral infections (HBV) typically require an-tiviral therapy to keep viral activity

dormant. But new research suggests that the key to eliminating the virus may lie in the pa-tients’ own blood.

“In patients with chronic HBV, large quan-tities of antigens are physiologically taken up and stored by monocytes, which are antigen presenting cells,” said lead researcher Pro-fessor Antonio Bertoletti of the Singapore In-stitute for Clinical Sciences and the National University of Singapore. “With a cocktail of other cytokines, you could activate T-cells as a sort of external vaccine and you don’t need an external vaccination.”

Bertoletti and colleagues compared anti-gens in blood samples from 57 patients with chronic HBV to samples from healthy donors. In vitro analysis demonstrated that while no immune response resulted from exposure to antiviral vaccines, when exposed to inflam-matory stimuli – in this case cytokines – the monocytes activate and begin presenting par-ticles of HBV on their surface for recognition by T-cells in order to activate an immune re-sponse. [J Clin Invest 2013;123:3766-76]

“We’re using the proteins already present in the patients, and so really targeting the virus

that is present in the patient,” Bertoletti said. Mass-produced antivirals and vaccines can

be significantly limited by pathogenic varia-tions and slight mutations. Pathogens them-selves are evolving constantly due to indi-vidual immune response and environmental factors.

Bertoletti’s method bypasses the need for antigen-specific antivirals and vaccines in fa-vor of ramping up the body’s own immune response to existing antigens. This kind of im-munomodulatory treatment is already being used to suppress inflammatory events in au-toimmune diseases, for example.

The researchers used HBV to test this treat-ment method because the virus produces large quantities of viral proteins that are tak-en up by monocytes. But the approach could be useful for other types of chronic infections such as hepatitis C or human immunodefi-ciency virus (HIV).

Bertoletti said testing in human subjects could begin soon.

A patient’s own blood may provide the key to eliminating HBV.


Tailored drug therapy may help reverse long QT syndrome 2Rajesh Kumar

Researchers at the National Heart Cen-tre Singapore (NHCS) have scored a world first by managing to reverse

long QT syndrome 2 in vitro in patient-spe-cific heart cells, using a tailored drug therapy.

Long QT syndrome 2 is a potentially fatal heart rhythm disorder caused by mutation in hERG (human ether-a-go-go-related gene) which helps to control the electrical activity in the heart cells and coordinate its beating rhythm. The syndrome can cause sudden car-diac death even in young patients.

The NHCS team obtained skin cells from a patient clinically diagnosed with long QT syndrome 2 caused by hERG mutation. They used the cells to generate human-induced plu-ripotent stem cells and reprogrammed these into heart cells. They then tested various drug compounds and discovered that one drug, not normally tested in this condition, could reverse the effects of long QT syndrome 2.

The researchers found that the heart cells in a petri dish mirrored the patient’s heart condition outside the body, allowing them to study the disease and test treatments ac-curately and repeatedly on the cells without any risk to the patient. Although achieved in vitro, the breakthrough could accelerate new cures for the condition, compared with con-ventional drug development which takes 10 to 15 years.

“For the first time, we have mimicked a pa-tient’s disease condition in a petri dish, under-stood the mechanism of long QT syndrome 2 on this platform, and successfully tailored a drug that reverses the entire condition,” said

Associate Professor Philip Wong, director of the Research and Development Unit (RDU) at the NHCS.

The development also paves the way for a better understanding of how drugs affect cell and intra-cell disordered function and allows safe testing of new compounds on patients’ own cells, without the risk of side effects to the patients themselves, said the researchers.

“With the efficacy aspect proven, we will now be testing the therapy’s safety profile as it moves towards clinical applications,” said lead investigator Dr. Ashish Mehta, senior re-search scientist at the RDU, NHCS.

Since the drug therapy will be specific to the patient, there is a high chance that it will work on the individual whose skin cells are sampled, added RDU scientific director Dr. Winston Shim.

“We can use similar disease models to in-troduce a gene that will correct that particular mutation in the body…If that is successful, there is a possibility of permanently revers-ing the genetic condition without the need for any long-term medication,” said Shim.

The NHCS research team, l-r: Dr. Ashish Mehta, Associate Professor Philip Wong and Dr. Winston Shim.


Young Scientist Award for Dr. Khor Chiea ChuenRadha Chitale

Novel research on the role of heredity and genetics in eye disease, cancer and drug response earned Dr. Khor

Chiea Chuen a Young Scientist Award during the 2013 Presidential Science and Technology Awards.

“Mostly we are trying to find the herita-ble underpinnings of human diseases,” said Khor, of the Genome Institute of Singapore and the National University of Singapore. “How come many people who are seemingly healthy, with no early predisposition for dis-ease, all of a sudden are prone to illness? We suspect part of the reason could be genetics.”

Khor focuses on Asian-centric disease be-cause genetics plays a significant role in the discrepancies between disease presentation and drug efficacy among Asian populations compared to the pool of trial data, which tends to reflect Western forms of disease.

For example, among Asians, polypoidal choroidal vasculopathy is the dominant form of age-related macular degeneration (AMD) of the retina while choroidal neovasculariza-tion is common in North American and Euro-pean populations.

Because AMD involves abnormal blood vessel proliferation, antivascular growth fac-tors are used to treat it and western popula-tions respond well, Khor said. But Asians

don’t respond similarly. Data to be published later this year by Khor and colleagues shows that the genetic sequence for blood vessel growth factors is located very close to the se-quence for AMD in Europeans but is very far – more than 100,000 base pairs – away from the AMD sequence in Asians, suggesting an underlying genetic reason for the treatment outcome disparity.

Results from another research effort, which Khor also hopes to reveal at the end of the year, is a “totally unexpected” gene linked to epidermal growth factor receptor-positive (EGFR-positive) lung cancer that is so strong, “even if you correct for every base pair and every human being on earth, they would still be linked.”

This gene, identified through genome scans of Singaporean Chinese patients and validated through genome scans of patients in Guangzhou, China, is a surrogate for the disease variant which remains undiscovered but is within reach, comparable to knowing which building on a street to explore, but not the precise room, Khor said.

EGFR status is important to know because its presence or absence dictates the type of chemotherapy required to treat it. EGFR-pos-itive lung cancer comprises just 10 percent of the lung cancer cases among Europeans but up to 50 percent of Asian cases.

Khor’s laboratory group is also examining ways to tailor chemotherapy doses for cancer patients based on their genetic makeup and he said such pharmacogenetic data will be increas-ingly important within the next 5 years.

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underpinnings of human diseases‘‘

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13 October 2013 News

Flu vaccine cuts heart attack risk in middle-aged

Saras Ramiya

The influenza vaccine appears to almost halve the risk of heart attacks in mid-dle-aged people with narrowed arter-

ies, shows a study. The researchers from the School of Public

Health and Community Medicine, University of New South Wales, Sydney, Australia, as-sessed 559 patients over the age of 40 who were referred to a tertiary hospital during consecu-tive winters in 2008-10. Some 275 of these pa-tients had sustained a heart attack. [Heart 2013 Aug 21. doi: 10.1136/heartjnl-2013-304320]

Nose and throat swabs and blood samples taken at admission and 4 to 6 weeks later showed that around one-in-eight (12.4 per-cent; 34) of the heart attack patients had re-cently had influenza, compared with just un-der 7 percent (18) in the comparison group. Half of all the patients had had the influenza vaccination that year.

Influenza had not been diagnosed in around one in 10 of those who had the infec-tion, indicating that it may be missed in hos-pital patients with other clinical problems, the study authors said.

After taking account of other influential factors, such as age, high cholesterol and smoking, influenza did not increase heart at-tack risk. But vaccination against the infection did seem to be protective, decreasing the risk of a heart attack by 45 percent.

The researchers wanted to find out if in-fluenza is an unrecognized, but clinically

important, contributing factor in increased heart attack risk. Published evidence suggests that influenza boosts the risk of death from all causes as well as the risk of admission to hospital for cardiovascular and respiratory problems.

Previous research suggests that infections such as influenza might encourage blood to thicken or prompt an inflammatory response in arteries that are already diseased, so spark-ing the development of a blockage.

Extending the influenza vaccination pro-gram to 50- to 64-year-olds has been mooted before, but not considered to be cost effective, the authors said. However, cardiovascular disease, which causes a great deal of illness and death in older adults, wasn’t taken into consideration in these estimates, they added.

“As such, even a small effect of influenza vaccination in preventing [heart attacks] may have significant population health gains,” they wrote.

They called for the issue to be explored further, and at the very least, said that doc-tors should be aware that influenza is an un-derlying and poorly diagnosed condition in hospital patients and that the influenza vac-cine seems to lessen the risk of a heart attack in susceptible patients.

Currently, those aged 50 to 64 are not routinely included in national influenza vaccination programs in either the UK or Australia. But the findings prompted the authors to suggest that further explora-tion of extending the schedule may be warranted


Rewarding doctors for quality of care improves patient outcomes

Saras Ramiya

Paying doctors for how they perform specific medical procedures and exam-inations yields better health outcomes

than the traditional ‘fee for service’ model, where everyone gets paid a set amount, re-gardless of quality or patient outcomes, shows a new study.

“‘Pay for performance’ programs shift the focus from basic care delivery to high quality care delivery. So they are designed to incen-tivize people to improve care,” said first au-thor Dr. Naomi Bardach, assistant professor, department of pediatrics, University of Cali-fornia San Francisco, US.

In a study published in JAMA, Bardach and colleagues tested a tiered pay for perfor-mance program at physicians’ offices in New York City. The program rewarded physicians who were successful in preventive healthcare to reduce long-term risks of heart attack and stroke – for instance, in blood pressure con-trol, and included patients who had Medic-aid insurance and those who were uninsured. [2013;310(10):1051-9]

The innovative ‘pay for performance’ mod-el they tested rewarded physicians for every single patient who did well, and paid extra for ‘high-risk’ patients who were difficult to treat based on comorbidities such as diabetes, coro-nary artery disease or socioeconomic factors.

In this cluster-randomized study conduct-ed from April 2009 through March 2010, im-provements in the incentivized group com-pared to the control group ranged two-fold to

eight-fold (9.7 percent vs. 4.3 percent, and 9 percent vs. 1.2 percent). With the help of elec-tronic medical record (EMR) data, researchers examined 7,634 patients (4,592 in the incentiv-ized group and 3,042 in the control group) for this study.

“The numbers are meaningful because the rates of blood pressure control were so low to begin with, for instance, only 10 to 16 percent of patients with diabetes had normal blood pressure control, so an improvement of even 5 percent of patients is relatively quite large,” Bardach said. This is a high-risk population for heart attack and stroke and so getting their blood pressure under control will make a dif-ference.”

“The worry about pay for performance programs that pay only if physicians meet the quality target is that the financial incentive discourages physicians from caring for more complicated patients,” said Bardach.

“This program did not penalize physicians for patients they were caring for whose blood pressure might be more difficult to control than others, for medical or for socio-economic reasons. It also recognized, through higher payments, the additional work it might take.”

While the findings are encouraging, Bar-dach said further research is needed to deter-mine whether or not this trend can continue over time since pay for performance programs are intended to remain in place for more than a year.

“The hope is to study this over a longer time period, since the goal of healthcare is to improve long-term outcomes among our patient population,” she said.


High-strength statins not linked to renal damage in ACS patients

Laura Dobberstein

Higher dose statins do not increase the risk of kidney injury in patients after an acute coronary syndrome (ACS),

despite contradictory past reports, accord-ing to preliminary research presented at the American Heart Association’s recent Emerg-ing Science Series Webinar in San Francisco, California, US.

“These findings provide important reas-surance to clinicians that the use of some high-potency statins will not increase the risk of kidney injury,” said the study’s lead author Dr. Amy Sarma of the Brigham and Women’s Hospital in Boston, Massachusetts, US.

By analyzing two separate randomized double-blind trials, the researchers found that patients taking higher dose statins did not have higher levels of creatinine and were not at higher risk of hospitalization with kidney injury than those on lower dose statins.

The trials, PROVE IT-TIMI 22* and the Phase Z portion of the A-to-Z trial, included over 4,000 patients each who received vary-ing doses of statins and were monitored for serum creatinine levels. Participants in the PROVE IT-TIMI 22 trial received either 40 or 80 mg/day of statin to prevent a major ad-verse cardiac event. In the A-to-Z trial, pa-tients received either 40 mg/day of statin for 1 month followed by 80 mg/day thereafter, or placebo for 4 months followed by 20 mg/day to compare early initiation of high-dose statin to delayed initiation of a lower dose treat-ment. Sarma and colleagues evaluated the tri-

als for changes in creatinine and adverse kid-ney events in relation to statin dose.

“This is reassuring, especially in light of the findings from other studies that high-dose statins were associated with cognitive impair-ment and the development of diabetes melli-tus,” said Dr. Tan Kok Soon, Singapore-based cardiologist at The Heart Specialist Clinic at Mount Elizabeth Medical Centre.

According to Tan, doses of more than 80 mg/day of statin are rarely prescribed in Sin-gapore. The few patients he has on this high level of dosage do not have any problems. However, Tan has seen numerous patients who were on statins and worried about the side effects due to negative media coverage.

“I usually explain to my patients that whether they should be on statins and at what dose depend on weighing the risks and ben-efits of them being on the drug. A study like this would help in fine tuning this risk-benefit assessment,” said Tan.

Dr. Ted Tyberg, of the New York Cardiol-ogy group and the New York Presbyterian Hospital in New York City, US, had similar views saying that there is more concern over statins than necessary. “There has never been any serious evidence of renal damage from statins,” said Tyberg. “The rumor stems from trials of [rosuvastatin] given at 2 to 4 times the usual clinical doses. Some patients had pro-teinuria… but no damage.” The moral of the story, according to Tyberg, is to not give drugs at twice the recommended clinical dose.

* PROVE IT-TIMI 22: Pravastatin or Atorvastatin Evaluation and

Infection Therapy –Thrombolysis in Myocardial Infarction 22.


Testosterone gel boosts memory in older women

Laura Dobberstein

Treatment with testosterone gel im-proved verbal learning and memory in postmenopausal women, accord-

ing to data presented at The Endocrine Soci-ety’s 95th Annual Meeting in San Francisco, California, US.

“There is no effective treatment to date to prevent memory decline in women, who are at higher risk of dementia than men,” said principal investigator Dr. Susan Davis of Monash University in Melbourne, Aus-tralia.

In the study, women who received 26 weeks of transdermal testosterone gel treatment scored a small but significantly greater score in short-term verbal learning and memory tests compared with placebo recipients. Cog-nitive performance and general psychologi-cal well-being was the same between groups. Although the treatment enhanced levels of testosterone in the participants, the hormones remained in the normal range for women and no major side effects were reported.

The 0.22 g of testosterone gel or a visibly similar placebo gel was applied daily to the upper arm of 92 postmenopausal women be-tween 55 and 65 years of age. Cognitive func-tion, well-being and testosterone levels were measured at baseline, 12 weeks and 26 weeks. Verbal learning and memory was measured using the International Shopping List task, a

test where the women recalled words on a list. “[This study and our past studies] provide

compelling evidence for the conduct of large-scale clinical studies to further investigate the use of testosterone to prevent memory de-cline in postmenopausal women,” said Davis and colleagues.

Dr. Cornelia Chee, director and senior con-sultant of the Women’s Emotional Health Ser-vice at the National University Hospital in Singapore warned that the results of the study may be too small to be clinically significant and should be weighed against any potential clinical and metabolic side effects in the long term. “While promising, as with many initial studies, it may be too premature to draw con-clusions that testosterone therapy may have a clinical role in being prescribed routinely as a neuroprotective agent in postmenopausal women,” said Chee.

Clinical sexologist Dr. B. Srilatha of the NUH Women’s Centre in Singapore, told the Medical Tribune that there is currently no ap-proved testosterone preparation available for use in women in Singapore, although there is a testosterone patch approved for use in women with hypoactive sexual desire disor-der in Europe. Testosterone preparations for men and tibolone, a synthetic hormone ana-log, are available in Singapore, but Srilatha recommends caution when prescribing medi-cations off-label. “The long-term safety of testosterone use in women is yet to be estab-lished,” she said.


Risk of death persists after hip fracture

Elvira Manzano

Individuals with hip fractures are at in-creased risk of dying from coronary heart disease, pneumonia and urinary tract in-

fection (UTI) within 5 years following an inju-ry, according to an analysis of adult men and women (with or without hip fractures) from the Singapore Chinese Health Study.

All-cause mortality rates were higher among patients with hip fractures than among those without hip fractures (37 percent vs 22 percent). Crude mortality rates were 76.2 per 1,000 person-years and 38.5 per 1,000 person-years, respectively. The increase in risk was highest at 3 months and persisted for up to 5 years of a fracture for both genders. [Osteopo-rosis Int 2012; doi 10.1007/s00198-012-2183-7]

The study included 1,666 hip fracture cases matched with 5,830 controls of the same gen-der and age. Only cases of first hip fractures were included. Incidentally, there were dif-ferences in the risk of cause-specific mortality between genders and over time.

“Men had a higher risk of death from stroke and cancer 1 year post-fracture while women had a higher risk of death from coronary heart disease for up to 5 years post-fracture,” said lead study author Professor Gerald Koh from the Saw Swee Hock School of Public Health, National University of Singapore. “The in-creased risk of death from CHD and stroke may be related to biological mechanisms link-

ing osteoporosis and atherosclerosis.”Similarly, men were more than twice as

likely to die from pneumonia from 3 months onwards, with the difference narrowing 5 years post-fracture, whereas women had a two-fold risk of dying from UTI for up to 5 years. The greater risk of death from pneumo-nia and UTI after a hip fracture is relatively straightforward as these are known conse-quences of immobility which is associated with hip fractures, Koh said.

For mortality rates by types of surgery, there was no difference between patients who underwent hemiarthroplasty and open reduc-tion internal fixation (ORIF) at any time points (3 months, 6 months, 1 year and 5 years).

The findings have several implications with regard to the management and counsel-ing of patients after a hip fracture, Koh said. “The next step is to develop new strategies and interventions targeted to reduce pneu-monia and UTI, and eventually reduce the global burden of osteoporotic hip fractures.”

As a preventive step, Professor Wilson Wang, senior consultant, department of or-thopaedic surgery, National University Hos-pital, suggested that aging women should take vitamin D and calcium, exercise and avoid smoking and alcohol to protect their bones.

“Thinning of the bones is silent and does not hurt until one breaks a hip,” he said. “Cli-nicians on the other hand should screen for osteoporosis.”


Family history of diabetes raises prediabetes risk in non-obeseRajesh Kumar

A family history of diabetes can raise the risk of prediabetes by 26 percent, especially in non-obese individuals, a

large meta-analysis has found. While a family history of type 2 diabetes is

known to increase the risk of full blown dia-betes, the risk of prediabetes is unknown. The knowledge is important for prevention efforts because a fifth of people with prediabetes de-velop full blown diabetes every year, said the researchers. [Diabetologia 2013, doi:10.1007/s00125-013-3002-1]

Prediabetes can either be in the form of im-paired fasting glycemia (IFG), whereby levels of glucose in the fasting state are higher than normal but not high enough to be classed as diabetes, or impaired glucose tolerance (IGT), wherein blood sugar levels are abnormal due to increased insulin resistance.

The researchers analyzed data from 8,106 non-diabetic individuals of European origin who had earlier participated in four cohort studies by the German Center for Diabetes Research (GCDR). Of these, 5,482 persons had normal glucose tolerance, and 2,624 had IFG and/or IGT.

They checked whether having at least one first degree relative with diabetes is associated with prediabetes. A family history of diabetes was found to increase the crude, unadjusted risk for prediabetes (IFG and/or IGT) by 40 percent. This increased risk fell to 26 percent when the analysis took account of age, sex, and body mass index (BMI) of participants.

When different types of prediabetes were

considered, family history increased the risk of isolated IFG by 37 percent, of isolated IGT by 25 percent, and the two combined by 64 percent. Overall, when adjusted for BMI, the association between family history and predi-abetes was seen only in non-obese individu-als (BMI <30 kg/m2).

Given that IGT implies a higher conversion rate to diabetes than IFG, its weaker associa-tion with family history was surprising, the researchers said. Since IFG is predominantly associated with hepatic insulin resistance and IGT is often associated with muscle insulin resistance as well as impaired insulin secre-tion, the researchers speculated that family history of diabetes might have a stronger link to hepatic insulin resistance.

“Our data suggest that a family history of diabetes is associated with prediabetes in non-obese rather than in obese individuals. This might indicate the effect of family his-tory on prediabetes becomes readily measur-able only when not overshadowed by strong risk factors such as obesity,” said researcher Dr. Andreas Fritsche and colleagues from the GCDR in Neuherberg, Germany.

The effect of family history on prediabetes becomes readily measurable only when not overshadowed by strong risk factors such as obesity.


Health test patients can be prompted to follow up on their results

Laura Dobberstein

The simple act of asking a patient to think about why they may avoid receiving medical test results can increase the

chances they will participate in follow-up, ac-cording to new research in the US.

The researchers believe that incorporating this simple theory-based intervention into medical care can reduce the public-health burden of disease.

“When prompted to consider their own cognitive processes, people can switch from intuitive to analytical decision making which allows them to override their gut feelings in fa-vor of quantifiably superior decisions,” wrote study investigators Dr. James Shepperd, pro-fessor of social psychology, and graduate stu-dent Jennifer Howell, both of the University of Florida in Gainesville, Florida, US. [Psychol Sci 2013; doi:10.1177/0956797613478616]

In the first of three trials, 25 percent of a group of college students undergoing a type 2 diabetes risk test after being asked to reflect on the disease, their perception of it, and the consequences of being at risk for it, chose not to learn the results of the test, compared with 44 percent in a control group who were not prompted to reflect, a statistically significant difference [p<0.02].

In another study with a similar design, 28 percent of subjects undergoing a CV risk test who were asked to rate their reasons for why they might choose to seek or avoid the results of the test subsequently avoided learning their results compared with 55 percent of sub-

jects in a control group who were not asked to reflect on those reasons [p<0.01].

A third study distinguished whether those facing an untreatable condition would have comparable rates of test result avoid-ance to those whose condition was treatable. When told that a fictitious disease, thioamine acetylase (TAA), was treatable, 20 percent chose not to learn their test results after con-templation compared with 53 percent in a non-contemplation control group [p=0.003]. However, there was no observed difference in avoidance between the contemplation (40 percent) and control group (55 percent), when study participants believed TAA was untreatable [p=0.19].

“Study 3 demonstrated that contemplation reduces information avoidance only when information seeking is the superior option,” explained Shepperd and Howell.

The first, second and third studies includ-ed 146, 130 and 166 participants, respectively. Control groups were asked to recite facts pri-or to deciding whether to hear their personal-

Contemplation or cognitive shift may help reduce avoidance of crucial health information.

21 October 2013 Newsized test results.

“The authors of this article note that if there is time for patients to answer a sim-ple questionnaire, or to benefit from readily available personalized risk analysis profiles, their attitudes and priorities become clearer and serve as the basis for what might be a better decision,” said Dr. Steven Kussin, patient advocate and author of Doctor, Your

Patient Will See You Now. Kussin explained that doctors often do not have the time, and in many cases the desire, to allow patients to prioritize their medical needs based on their own risk tolerance and personal goals. “This study adds to a growing literature that acknowledges that patients are mov-ing and being pushed far too hastily,” said Kussin.

Soft drink consumption linked to aggression in young kids

Jasmine Teo

A study conducted in the US has found a link between soft drink consump-tion and aggressive behavior among

young children. An analysis of data from 3,000 5-year-old

children in the Fragile Families and Child Wellbeing Study, a prospective birth cohort following mother-child pairs from 20 large US cities, showed that those who drank ≥4 soft drinks per day were more than twice as likely to destroy things belonging to others, get into fights, and physically attack people. They also had increased attention problems, and withdrawal behavior compared with non-soda drinkers. This was despite after adjusting for sociodemographic factors, ma-ternal depression, intimate partner violence and paternal incarceration. [J Ped 2013; doi 10.1016/j.jpeds.2013.06.023]

“We found that the child’s aggressive be-havior score increased with every increase in soft drinks servings per day,” wrote lead

Aggressive behavior in children has been shown to increase with every increment in daily soft drink servings.

22 October 2013 Newsstudy author Dr. Shakira Suglia, Mailman School of Public Health, Columbia University, New York, US, and colleagues.

Overall, 43 percent of the children in the sample studied consumed ≥1 serving of soft drink per day, according to their parent’s re-port, and 4 percent consumed ≥4.

The researchers said the relationship be-

tween soft drinks and child behavior has not been closely examined until now. Although their study was unable to identify the exact reason for why soft drinks cause aggressive behaviors in children, they recommended limiting or eliminating a child’s soft drink consumption to reduce behavioral prob-lems.

No link shown in laughing gas-CV risk studyLaura Dobberstein

Nitrous oxide (laughing gas) is not as-sociated with a raised risk of cardio-vascular events such as myocardial

infarction when used for anesthesia during surgery, according to the findings of a US study.

“It’s been known for quite a while that laughing gas inactivates vitamin B12 and, by doing so, increases blood levels of the amino acid homocysteine,” said lead study author Assistant Professor Peter Nagele of the Wash-ington University School of Medicine in St. Louis, Missouri, US. “That was thought to raise the risk of a heart attack during and af-ter surgery, but we found no evidence of that in this study.”

Nagele and team monitored troponin lev-els in 500 non-cardiac surgery patients with coronary artery disease, heart failure or other health problems that could lead to heart at-tack after the administration of nitrous oxide anesthesia. [Anesthesiology 2013;119:19-28]

All patients received nitrous oxide and

were randomized to receive additional dou-ble-blind treatment with either vitamin B12 and folic acid supplementation or placebo. Troponin levels were also monitored in a sep-arate 125 surgery patients who did not receive nitrous oxide for comparison.

Troponin levels in the non-nitrous oxide group were similar to those in the initial study and the rate of heart attacks were 2 percent higher than those in the initial study. How-ever, the smaller study was not randomized and subsequently should be interpreted with caution.

“We therefore believe that, based on cur-rent evidence, practitioners who feel that ni-trous oxide could be beneficial for their pa-tients should not refrain from administering it based on concern for acute homocysteine increase or [a predisposed] gene variant,” said the authors.

Dr. Tan Kok Soon, Singapore-based cardi-ologist at The Heart Specialist Clinic at Mount Elizabeth Medical reviewed the study. “High serum homocysteine levels [were] previously thought to be a risk factor or even a cause for coronary heart disease. Recently, a few prospec-

23 October 2013 Newstive studies have shown persuasively that this was not the case and that use of vitamin B12 or folate, which reduce blood homocysteine lev-

els, have no protective effect against coronary heart disease. Hence, the negative results of the study would be expected,” said Tan.

Amount of exercise more important than frequencyLaura Dobberstein

Exercising 150 minutes a few days per week may be just as beneficial for re-ducing diabetes, heart disease and

stroke risk factors as the same amount of ex-ercise spread more frequently throughout the week, according to researchers in Canada.

Their study demonstrated that subjects who exercised less than 150 minutes per week had a 4.43 times higher relative odds of having metabolic syndrome than those who exercised more than 150 minutes a week. Among those who did exercise for 150 minutes or more a week, the relative odds of having metabolic syndrome was not statisti-cally different between those who exercised on 5 to 7 days out of the week and those who exercised on 4 or less days each week. [Ap-plied Physiology, Nutrition, and Metabolism 2013,38:773-778]

“The findings indicate that it does not mat-ter how adults choose to accumulate their 150 weekly minutes of physical activity,” said Dr. Ian Janssen of the School of Kinesiology and Health Studies at Queen’s University, Kings-ton, Ontario, Canada, who recommends that adults get 150 minutes of exercise in any pat-tern that fits their schedule.

Janssen and graduate student Janine

Clarke examined the link between frequency of physical activity and metabolic syndrome in a cross sectional study of 2,324 adults age 18 to 64 years. Study participants wore accel-erometers to measure the quantity of mod-erate to vigorous physical activity (MVPA) experienced over a 7-day period and were ex-amined for signs of metabolic syndrome.

“To our knowledge this is the first study to use accelerometers to investigate the re-lationship between the weekly patterns of MVPA and health in adults,” said Janssen and

The results of a study suggest that adults can employ any pattern or schedule of exercising to achieve the recommended goal of 150 minutes per week.

24 October 2013 NewsClarke. The researchers suggest that future studies better identify patterns of physical ac-tivity within the study participants.

“This is a good study,” said Dr. John Hig-gins, sports cardiologist at Memorial Her-mann, Lyndon B. Johnson General Hospital and The University of Texas Health Science Center in Houston, Texas, US, speaking to Medical Tribune. However, he added, “this is only talking about metabolic syndrome. Ex-ercising 5 to 6 days a week is best for over-all health. You will live longer and have less disease.”

A session of exercise can boosts aspects of a person’s health including metabolic rate, en-dothelial function, bone growth, insulin sen-sitivity and emotional well-being for a period

lasting for up to 24 hours, explained Higgins. Those who exercise more frequently experi-ence that boost more often.

Those that accumulate their weekly exer-cise minutes over only a few days instead of 5 to 7 days are more likely to experience muscle damage, disinterest or fatigue in the activ-ity, and will miss a larger percentage of their weekly total when they must skip an exercise session due to unforeseeable events, Higgins said.

However, he qualified that exercising 1 or 2 days a week is better than not at all. “I will still tell those [who are unable to exercise ev-ery day] that whenever you can is the next best. You are still better off overall to fit it in when you can.”

25 October 2013 Conference Coverage

Prolonged DAPT necessary in all PCI patients?

European Society of Cardiology Annual Congress, 31 August - 4 September, Amsterdam, The Netherlands

Christina Lau

The risk of cardiovascular complica-tions after stopping dual antiplatelet therapy (DAPT) in patients undergo-

ing percutaneous coronary intervention (PCI) is highly variable, with some patients experi-encing none at all, according to the results of a large registry study.

“These findings of a real-world registry challenge existing paradigms for prolong-ing antiplatelet therapy in otherwise stable patients after PCI,” said lead investiga-tor Professor Roxana Mehran of the Icahn School of Medicine at Mount Sinai, New York, US.

In the prospective, observational registry dubbed PARIS (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients), investigators enrolled 5,031 patients with cor-onary artery disease who underwent success-ful PCI with stenting from 15 sites in the US and Europe. [Lancet 2013, doi: 10.1016/S0140-6736(13)61720-1]

The patients were followed for 2 years to determine whether they had discontinued, interrupted or disrupted DAPT, and wheth-er this resulted in any major cardiovascular events (MACE).

DAPT discontinuation was defined as physician-recommended cessation of DAPT for patients believed to no longer need it. In-terruption was defined as physician-guided DAPT cessation for up to 14 days due to sur-

gical necessity, while interruption was due to bleeding or noncompliance.

At 2 years, the cumulative incidence of any DAPT cessation was 57.3 percent. The most common mode of DAPT cessation was dis-continuation (40.8 percent), followed by dis-ruption (14.4 percent) and interruption (10.5 percent).

“The overall 2-year rate of MACE was 11.6 percent, with the majority of events [74 percent] occurring while patients were on DAPT,” Mehran reported.

Compared with patients who remained on DAPT, those with DAPT disruption had a 50 percent increased risk of MACE, while those who discontinued DAPT as per physician rec-ommendation had a 37 percent reduction in risk. Brief interruptions did not increase the

The PARIS study, which involved more than 5,000 patients undergoing PCI, found no increased risk of adverse events following subsequent discontinuation of DAPT in those that were deemed stable.

26 October 2013 Conference Coveragerisk of MACE significantly.

“Our findings show that when physicians recommend DAPT discontinuation, presum-ably because patients are stable, there is no risk of adverse events,” said Mehran. “How-ever, when patients don’t comply or have to stop DAPT due to bleeding, their risk for adverse events is significantly increased. For these patients, the risk of MACE was highest during the first 7 days of disruption, repre-senting a 7-fold increase, and attenuated over time.”

Importantly, sustained DAPT was not as-

sociated with reduced thrombotic risk com-pared with recommended discontinuation.

“In fact, we found a slight, although statis-tically nonsignificant reduction in risk asso-ciated with physician-recommended discon-tinuation. This contrasts with some previous studies that suggested a potential protective effect with prolonged antiplatelet therapy,” she said.

“The overall impact of DAPT cessation on adverse events is modest, and may have been mitigated with the introduction of safer stent platforms,” she added.

End of the road for otamixaban in ACS?

Elvira Manzano

The novel anti-Xa factor anticoagulant otamixaban has been shown to be not superior to current standard of care in

reducing the risk of death or heart attack in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).

In the phase III TAO* trial, which involved 13,229 patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI), those who were given high-dose otamixaban had a comparable rate of death from myo-cardial infarction (MI) at day 7 of treatment as those treated with standard heparin/ep-tifibatide therapy (5.5 versus 5.7 percent, re-spectively).

Patients in the study were randomized to receive either low- (0.10 mg/kg per hour) or high- (0.14 mg/kg per hour) dose otamixa-ban, after an initial 0.08 mg/kg IV bolus, or unfractionated heparin plus eptifibatide, at

the time of PCI. All patients also received aspirin and either clopidogrel, prasugrel or

Negative phase III results have prompted the drug-maker to drop development of the drug.

27 October 2013 Conference Coverageticagrelor.

Bleeding episodes were two-fold higher with high-dose otamixaban (3.1 percent vs 1.5 percent, respectively; p<0.001). Conversely, a reduced dose did not achieve better results. [JAMA 2013; doi: 10.1001/jama.2013.277165]

Given the lack of efficacy benefit and in-creased bleeding rates with otamixaban, drug developer Sanofi decided to discontin-ue further trials with otamixaban.

The findings were clearly disappointing to researchers looking for optimal anticoagula-tion for NSTE-ACS. “These suggest a narrow therapeutic window for acute Xa inhibition and that increasing the intensity of anticoag-ulation via this mechanism will not achieve superior efficacy-safety balance in ACS in the modern era of intervention,” said lead investigator Professor Philippe Gabriel Steg from the Hôpital Bichat, Assistance Publique - Hôpitaux de Paris in Paris, France. “The re-sults do not support the use of otamixaban in NSTE-ACS patients undergoing planned early PCI.”

At 7 days, the rate of death or MI with low-er dose otamixaban was even higher at 6.3

percent. There was no reduction of risk at 30 days. The results were contrary to the phase II dose-ranging trial (SEPIA-ACS1 TIMI 42** study) which showed that otamixaban had a beneficial effect in ACS.

Discussant Dr. Christian Hamm of Ker-chchoff Heart and Thorax Center, Bad Nauheim, Germany, said the investigators shouldn’t be frustrated. “We need to think of other pathways, maybe not anticoagula-tion or antiplatelet drugs to improve the out-comes.”

Dr. Keith Fox from the University of Ed-inburgh, Scotland, said anticoagulation ap-peared to be not so important in the mod-ern era of quick intervention. Several trials of new anticoagulants have failed to show better efficacy but increased bleeding. By comparison, trials of antiplatelet agents with improved antiplatelet activity had shown “more success.”

*TAO: Treatment of Acute Coronary Syndromes with Otamixaban Trial

**SEPIA-ACS1 TIMI 42: Study Program to Evaluate the Prevention of

Ischemia with direct Anti-Xa inhibition-Acute Coronary Syndromes-1-

ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 42

Less bleeding with once-daily edoxaban in VTERajesh Kumar

Aonce-daily dose of edoxaban, a nov-el oral factor Xa inhibitor, has been shown to be as effective as warfarin

in patients with venous thromboembolism (VTE), but with a better safety profile.

In the Hokusai VTE trial, edoxaban was as-sociated with significantly less bleeding than warfarin in a broad spectrum of more than 8,000 VTE patients evaluated, including those with severe pulmonary embolism (PE), who were initially treated with heparin. [N Engl J Med 2013; doi:10.1056/NEJMoa1306638]

The researchers randomized 8,292 symp-

28 October 2013 Conference Coveragetomatic VTE patients from 39 countries to receive double-blind treatment with either edoxaban 60 mg once daily or 30 mg once dai-ly (in those with moderate renal impairment or a body weight of <60 kg), or warfarin, for 3 to 12 months following an initial course of heparin.

The results of the trial revealed edoxaban to be noninferior to warfarin with respect to the primary efficacy endpoint – recurrent symptomatic VTE, which occurred in 130 pa-tients in the edoxaban group (3.2 percent) and 146 patients in the warfarin group (3.5 per-cent) [HR, 0.89; 95% CI, 0.70 to 1.13; p<0.001 for noninferiority].

Major or clinically relevant non-major bleeding, the principal safety outcome, oc-curred in 349 patients (8.5 percent) in the edoxaban group and 423 patients (10.3 per-cent) in the warfarin group (HR 0.81; 95% CI, 0.71 to 0.94; p=0.004 for superiority). The rates of other adverse events were similar in the two groups.

“We set out to show noninferiority (of edoxaban) and hoped for an improvement in safety, and that’s what we got. But what is more important with this new anticoagulant is a different pattern of bleeding,” said the researcher Dr. Harry Buller of the Academic

Medical Center in Amsterdam, The Nether-lands.

Buller drew attention to the observation that only two cases of fatal bleeding occurred in the edoxaban group compared with 10 in the warfarin group. Furthermore, there were five versus 12 cases of non-fatal intracranial bleeding in the two groups, respectively. A to-tal of 938 patients with PE had right ventricu-lar dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent VTE in this sub-group was 3.3 percent in the edoxaban group and 6.2 percent in the warfarin group (HR 0.52; 95% CI, 0.28 to 0.98).

Discussant Dr. Stavros Konstantinides of the Center for Thrombosis and Hemostasis at the University of Mainz Medical Center in Mainz, Germany, said the regimen may be less handy in patients with DVT or “non-severe” PE, especially if early discharge and outpatient treatment was considered.

“Moreover, physicians having concerns about administering a new drug to their pa-tients right away, in the first critical hours, may feel comfortable to start with low molecular weight heparin, and then switch to the new oral anticoagulants as soon as the situation is fully under control. This may particularly be the case if the physician is not certain about the patient’s hemodynamic stability during the first hours or days after admission,” said Konstantinides.

We got…[an] almost 20 percent

reduction in bleeding‘‘

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CRT of no benefit in HF patients with narrow QRS complex


Laura Dobberstein

The use of cardiac-resynchronization therapy (CRT) is not beneficial in sys-tolic heart failure patients with narrow

QRS complexes and was even associated with an increased risk of death, according to the findings of the Echo-CRT trial, a multination-al prospective randomized controlled trial.

“The observed excess mortality with CRT in this trial is of clinical concern,” wrote study presenter Dr. Johannes Holzmeister from the University Hospital Zurich and University of Zurich in Switzerland, and colleagues. [N Engl J Med 2013; doi: 10.1056/NEJMoa1306687]

Overall, CRT was deemed not beneficial for any patient in the study. The trial was stopped prematurely by the data safety monitoring board due to an almost doubled risk of mortality in those receiving CRT compared with the control group. Mortality occurred in 11.1 percent of the CRT group and 6.4 percent of the control group. The higher death rate in the CRT group was driv-en by cardiovascular death. There were 37 deaths from cardiovascular problems in the CRT group compared with 17 in the control group. Worsening heart failure was seen in 17.6 percent of the CRT group and 18.8 per-cent of the control group. When comparing the CRT group to placebo, the CRT group had more complications from the implanta-tion (12.4 percent vs 8.9 percent, respective-ly), more serious adverse events related to the device after implantation (13.6 percent

vs 7.2 percent), and about three times more lead-related serious adverse events.

The trial included 809 patients with New York Heart Association class III or IV heart failure, a left ventricular ejection fraction of 35 percent or less, a QRS duration of less than 130 msec and echocardiographic evi-dence of left ventricular dyssynchrony. The mean duration of QRS in both groups was 105 msec. All patients underwent CRT im-plantation, but 405 patients were random-ized to serve as the control group and had their CRT turned off. The devices were pro-vided by study sponsor Biotronik, Inc. Fol-low up occurred at 1 month, 3 months, and every 3 months thereafter, for a mean follow-up duration of 19.4 months.

“The excess risk of CRT among patients in-cluded in the EchoCRT study who had heart failure and a narrow QRS complex is of partic-ular concern, because it serves as a reminder that the implantation of left ventricular leads and the ongoing care of patients treated with CRT… are not without challenges,” said the study researchers.

The use of CRT was not beneficial in HF patients in a large randomized controlled trial, and was even linked with an increased risk of death.

31 October 2013 Conference CoverageEuropean Society of Cardiology Annual Congress, 31 August - 4 September, Amsterdam, The Netherlands

Optimism surrounds omecamtiv mecarbil despite phase II setback

Laura Dobberstein

Self-assessed dyspnea scores fell in pa-tients with acute heart failure who re-ceived higher-dose infusion of omecam-

tiv mecarbil, but not significantly enough to achieve a pre-defined efficacy endpoint in the phase II ATOMIC-AHF* study.

“Although [the drug] did not meet its pri-mary endpoint in dyspnea relief, it appeared to improve dyspnea within the [higher dose] group as well as demonstrate a trend towards reduction of worsening heart failure,” said Dr. John Teerlink of the University of Califor-nia San Francisco and San Francisco Veterans Affairs Medical Center, US.

Over 600 patients were enrolled in the study within 24 hours of acute heart failure and randomized to receive either omecamtiv mecarbil or placebo administered via intra-venous infusion for 48 hours. Those receiv-ing omecamtiv mecarbil were given one of three different strength dosages of the drug. Patients underwent evaluation of symptoms and clinical events, pharmaceutical sampling and intensive cardiac biomarker evaluations during their hospital stay.

Primary efficacy was defined as minimally improved dyspnea symptom response in the first 6 hours of treatment and moderately or markedly better dyspnea response at both 24 and 48 hours without worsening heart failure or death for any cause by 48 hours. Analysis of omecamtiv mecarbil cohorts who achieved primary efficacy compared with placebo re-vealed a p value of 0.33 and a treatment ef-

fect size of about 23 percent in the high-dose cohort. Rates of achieving primary efficacy endpoint were 51 percent in the highest dose group, 47 percent in the second highest dose group, 42 percent in the lowest dose group and 41 percent in the placebo group. Although these dose-related improvements were seen, the effect across the combined dosage cohorts was statistically too small to be considered successful.

In addition, those receiving omecamtiv mecarbil had a greater decrease in heart rate and less reduction in blood pressure compared with patients receiving placebo. Within a weeks’ time, the risk of death or worsening heart failure was reduced by 45 percent in the two groups receiving the highest doses of the drug. The safety profile of the drug was similar to placebo with no evidence of the drug causing an increase in proarrythmias. A modest increase in tropo-nin was observed in those taking omecamtiv mecarbil, but the researchers were hesitant to credit the slight rise to the drug since the increases in troponins did not vary with peak concentration or total exposure. Phar-macokinetic effects appeared to be similar to those seen with healthy volunteers and stable heart failure patients.

“We are looking forward to seeing [the impact of these findings] predict the future development of the dosage regimens for the phase III program,” said Teerlink.

*ATOMIC-AHF: Acute Treatment with Omecamtiv Mecarbil to Increase

Contractility in Acute Heart Failure.


Another HDL-raising agent fails to impress

Elvira Manzano

RVX-208, a novel oral agent designed to increase HDL cholesterol (HDL-C) levels was no more effective than pla-

cebo in reducing coronary plaque build-up in patients with coronary artery disease (CAD) in the phase II multicenter ASSURE trial in-volving 323 patients with symptomatic CAD and low HDL-C.

Previous studies have linked higher HDL levels with improved cardiovascular out-comes. In the ASSURE study, the researchers sought to determine if increased production of apoliprotein A-1 (apoA-1) with RVX-208, a bromodomain and extra-terminal (BET) pro-tein inhibitor and major component of HDL, would increase HDL-C levels and slow the progression of coronary atherosclerosis or plaque.

However, 26 weeks of treatment with RVX-208 was associated with comparable increases in HDL-C and apo A-1 levels and reductions in LDL-C to those seen with placebo. There were also similar reductions in coronary atheroma volume (-0.4 percent and -0.3 percent, respec-tively; p=0.81). Overall, the trial did not meet its primary endpoint of a -0.6 percent change in percent atheroma volume (PAV) as deter-mined by intravascular ultrasound (IVUS). Change in total atheroma volume (TAV) also did not differ substantially between the two

treatment groups. [Abstract 2755]“RVX-208 turned out to be not as potent as

we had hoped,” said lead investigator Profes-sor Stephen Nicholls of the South Australian Health and Medical Research Institute in Ad-elaide, Australia. “Longer treatment is prob-ably needed to show an effect. The search for an effective HDL-targeted therapy therefore continues.”

In terms of safety, RVX-208 was associated with a significantly higher rate of liver enzyme elevations at triple the normal limit (7.1 per-cent vs 0 percent for placebo; p=0.009) that were resolved when the drug was discontin-ued. Although there were numerically fewer cardiovascular events in the RVX-208 arm (7.4 percent vs 13.8 percent for placebo; p=0.09), the difference did not reach statistical significance.

“This suggests that increasing synthe-sis of apoA-1 does not appear to be a po-tent approach to HDL therapeutics,” said Nicholls.

Commenting on the study, Professor Deep-ak Bhatt of Brigham and Women’s Hospital in Boston, Massachusetts, US, said that with on-going trials of novel cholesteryl ester transfer protein (CETP) inhibitors that can substan-tially raise HDL levels, “it is premature to say that the HDL hypothesis is dead, but it is sort of on life support.”

*ASSURE: ApoA1 Synthesis Stimulation and Intravascular Ultrasound

for Coronary Atheroma Regression Evaluation



No rise in adverse CV events with alogliptin


Radha Chitale

The new selective dipeptidyl pepti-dase-4 (DPP-4) inhibitor alogliptin is not associated with an increase in ad-

verse cardiovascular (CV) events in patients with type 2 diabetes (T2D) and recent acute coronary syndrome (ACS), according to data from EXAMINE,* a large randomized, place-bo-controlled non-inferiority trial.

After a median follow-up period of 18 months (maximum 40 months), a primary endpoint event (CV death, nonfatal myocar-dial infarction or nonfatal stroke) occurred in 11.3 percent of patients randomized to alo-gliptin (n=305) and 11.8 percent of placebo re-cipients (n=316) [hazard ratio 0.96, p<0.001 for non-inferiority]

Although the risk of CV disease is more than doubled for patients with T2D, lead re-searcher Dr. William White of the University of Connecticut School of Medicine in Farm-ington, Connecticut, US, noted that recent studies have not demonstrated much impact on CV events with intensive glycemic con-trol, and that regulatory bodies have insisted on more stringent CV safety assessment over concerns about more adverse CV events with antidiabetic agents.

Alogliptin is approved by the US Food and Drug Administration for treating T2D and in trials has had low background CV risk.

In the EXAMINE trial, patients continued with standard of care for blood sugar control and secondary CV prevention throughout. These included antiplatelet agents such as as-pirin, statins, beta-blockers, and renin-angio-tensin system blockers.

In addition to the primary endpoint, sec-ondary endpoints such as composite of CV death, nonfatal MI, nonfatal stroke, urgent re-vascularization for unstable angina, any CV death and all cause mortality were similar in the alogliptin group compared with placebo.

Glycated hemoglobin was significantly lower for alogliptin than for placebo, a -0.36 percent difference (p<0.001).

Of the adverse events, only acute pancre-atitis showed a significant difference between the alogliptin (n=12, 0.4 percent) and placebo (n=8, 0.3 percent) groups (p=0.50).

While EXAMINE achieved the noninferi-ority objective, White said the results, which did not demonstrate CV benefits, still do not clarify how alogliptin should be used in CV patients with T2D and that metformin should still be used as first-line therapy.

Commenting on the study, Dr. Eugene Braunwald, a cardiologist at Brigham and Women’s Hospital in Boston, Massachusetts, US, noted the ambivalent nature of the data on alogliptin, given that there was no impact on CV events despite being a DPP4 class in-hibitor, which in previous studies have been shown to reduce CV outcomes in diabetics.

A closer look at the concurrent therapies given with alogliptin and placebo might be valuable in the context of whether alogliptin is worth prescribing, he said.

“If equality in outcome can be achieved with the addition of an inexpensive generic drug, it will be appropriate and important to conduct a cost-benefit analysis for alogliptin in this population.”

* EXAMINE: Alogliptin after Acute Coronary Syndrome in Patients with

Type 2 Diabetes

Gastroesophageal reflux disease (GERD) may have complications beyond esophagitis and may occur in the form of laryngitis, cough, asthma, dental caries, and chest pain, thus presenting a therapeutic challenge for clinicians. At a lunch symposium held in Singapore, sponsored by AstraZeneca, eminent speaker Professor David Johnson gave insights on GERD and clarified issues and trends in its management.

Hot topics in acid related diseases

Sponsored as a service to the medical profession by AstraZeneca Singapore Pte Ltd.

Editorial development by MIMS. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever arising is hereby disclaimed.

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Sponsored Symposium Highlight

What do you advise clinicians in managing GERD and erosive esophagitis of patients?Always take a good history, especially asking patients to create a good picture of the GERD burn sensation symptom. Also, make sure there are no alarming complaints, such as trouble in swallowing, or sensation of food being trapped, or nausea and vomiting. If there are alarming complaints, a more urgent evaluation is needed. Bleeding or iron deficiency are also markers of something serious. The importance of patient profiling, particularly in elderly and obese patients who are predicted to have more severe forms of acid reflux, cannot be overemphasized.

As weight gain and obesity have a significant impact on GERD severity, stomach cancer or esophagitis, what is your recommendation to doctors in managing these patients?Certain physiologic changes affecting the lower esophagus render weight gain and obesity as a negative risk factor, but metabolic activity of visceral fat also contributes to the increase in disease severity. Physicians should convey to patients that weight reduction is important not only for GERD or esophageal symptoms, but also other morbidities such as diabetes and hypertension. Small amounts of weight loss, maintained consistently, may be helpful in attenuating reflux symptoms.

How does the GERD theory relate to the level of pH control?

GERD is a function of acid reflux causing signs or symptoms, making pH control necessary in its management. Investigations show that damage to the esophagus occurs at the pH of 4 or less, so the target for pH control is a level of above 4. This level needs to be kept at a longer period of time, to lead to better healing. Once or twice daily dosing of a PPI maximizes optimal pH control, and satisfies the healing threshold phenomenon of beyond 18.5 hours. Data shows that esomeprazole is better in maintaining this pH control, compared with other PPIs.

What is the prevalence of nocturnal GERD symptoms, and how do you think these symptoms affect sleep?

From several studies on GERD patients, around 80% have nocturnal symptoms.21,22 GERD can affect sleep in a profound way. One is that a patient can often stay awake due to heart burn/regurgitation. Some patients may not awaken, but could have fragmented sleep due to interference of normal sleep stage transition. As nocturnal GERD symptoms cause sleep disturbance, they also affect a patient’s next day functioning.

What can be done to minimize sleep disturbance due to GERD?Firstly, patients and doctors should be made aware of the association of nocturnal GERD symptoms and productivity. Secondly, care providers must be more proactive in understanding the symptoms GERD patients can have and be more sensitive in detecting sleep disturbances in subtle symptoms of daily function such as irritability, anxiety and loss of productivity. Concentration problems may be investigated more and clinicians should target not just the nocturnal complaints, but the daytime symptoms that have potential detrimental effects. Lastly, therapeutic use of PPIs, once or twice a day, has shown to also improve sleep disturbance issues due to GERD.

What can you say about the concurrent use of PPIs and clopidogrel?Current evidence by randomized clinical trials has shown that there is no significant signal for cardiovascular harm, while there is substantial benefit in terms of prevention of gastrointestinal (GI) complications.22 The use of clopidogrel, particularly when combined with aspirin, carries significant GI risk. The society consensus recommendations are thus fairly strong that patients receiving clopidogrel plus aspirin should be considered for PPI prophylactic therapy.23

In the clinical setting, physicians and patients should be good communicators, by always asking questions and referring to product labels for answers. Also, patients should be ready to refer to product labels and not be dismissive of any signs or symptoms.

Pittsburgh Sleep Quality Index (PSQI), a validated instrument, was used for the assessment of sleep abnormality and response to therapy. It was observed that 72% of patients had improvement and nearly half of the patients had normalized PSQI, after 4 weeks of esomeprazole, 40 mg every morning.18 Relief of nocturnal heartburn, with the use of PPIs demonstrated a highly significant difference in sleep quality as assessed by the PSQI. It is important to recognize that extremely small changes in the PSQI are significant. A 0.5 change in the PSQI equates to a statistical significance of approximately p<0.05, hence the high significance evident with the PSQI difference between esomeprazole and placebo.19(Figure 1) Approximately 16 work hours were lost due to GERD-related sleep disturbances at baseline. After treatment, a highly significant difference was evident. More work hours were saved in both esomeprazole groups (20 & 40mg/day) compared to placebo. This means that the cost savings realized for those patients receiving active therapy was substantial. Optimal pharmaceutical utilization that reduces productivity loss is of benefit to patients and payors alike.

David A JohnsonProfessor of Medicine Chief, Department of GastroenterologyEastern Virginia School of Medicine Norfolk, VirginiaUSA

GERD: Basic concepts and new therapeutic management issues

Age is a very strong discriminant, in terms of severity of esophagitis in reflux disease patients. In a large compilation of patients enrolled in registry trials for esomeprazole, there was a clear association between age and the proportion of patients diagnosed with severe esophagitis. In this group of untreated patients severe esophagitis was rare in the younger age groups and became progressively more common with aging. Esophagitis as an age-related phenomenon, was however found to be inversely proportional to GERD symptoms, according to baseline data of five prospective, randomized, multicenter, controlled clinical trials.1 Therefore, it must be investigated aggressively, as it also seems to be more likely to cause complications, particularly bleeding.2

Furthermore, a meta-analysis demonstrated that there was a statistically significant risk of GERD symptoms associated with increased BMI (overweight and obese).3 This was also true even for Barrett’s esophagus and esophageal adenocarcinoma. Fat, particularly visceral fat, is implicated with a metabolic mechanism.3-6

Esomeprazole provides superior acid controlControl of pH is important in the management of GERD. In a

cross-over design study comparing pH control of five different proton pump inhibitors (PPIs), esomeprazole was shown to have superior acid control.7 Aside from pH control, difference

in healing erosive esophagitis was also investigated among PPIs. 8-10

The European Metropole Study was a large, 6-month maintenance trial conducted by Dr. Lauritsen and colleagues in patients with healed erosive esophagitis. Patients were treated with either the FDA-approved maintenance dose of esomeprazole (Nexium) 20 mg or lansoprazole 15 mg. This study demonstrated that patients treated with esomeprazole, 20 mg once daily, consistently maintained higher remission rates than those treated with low dose lansoprazole, regardless of baseline disease severity. Moreover, the same dosage of esomeprazole was effective at controlling accompanying GERD symptoms, such as heartburn and acid regurgitation.11

Acid reflux has profound effects on productivityNocturnal symptoms have recently become a common

complaint among individuals with GERD, also appearing to have a negative effect on a patient’s sleep quality. Over 50% of patients with nighttime GERD symptoms report waking up during sleep.12,13 Fifty-seven percent reported nocturnal awakening and 40% of patients reported that night time heartburn’s effect on sleep impacts their ability to function at work the following day.12

Sleep poses a period of risk for reflux-related complications because the protective mechanisms to clear reflux (including gravity, peristalsis, salivation, and intrinsic mucosal defense) are attenuated or eliminated.14,15 This is especially true if the patient is in supine or reclining position.16 These changes in the normal defenses against reflux can result in proximal migration of infused acid and prolonged mucosal contact time.17 Even if nocturnal symptoms may awaken the patient, they are usually not recalled, due to the amnestic effect of sleep. However, the patient will usually complain of poor sleep quality.

In a pilot open label trial among patients with erosive esophagitis with no previously diagnosed sleep abnormality, the

KOL interview with Professor David A. Johnson

References1. Johnson DA, Fennerty MB. Gastroenterology. 2004;126:660-664.2. Zimmerman J, et al. Scand J Gastroenterol. 1997; 32:906-909.3. Hampel H, et al. Ann Intern Med. 2005;143:199-211.4. Aro P, et al. Gut. 2005;54:1377-1383.5. Smith KJ, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:2481-2486. 6. Lagergren J, et al. Ann Intern Med. 1999;130:883-890.7. Miner P Jr, et al. Am J Gastroenterol. 2003; 98:2616-2620.8. Castell DO, et al. Am J Gastroenterol. 2002;97:575-583. 9. Fennerty MB, et al. Aliment Pharmacol Ther. 2005;21:455-463. 10. Labenz J, et al. Aliment Pharmacol Ther. 2005;21:739-746. 11. Lauritsen K, et al. Aliment Pharmacol Ther. 2003;17:333-341.

12. Shaker R, et al Am J Gastroenterol. 2003; 98:1487-1493 13. Farup C et al. Arch Intern Med. 2001;161:45-52.14. Orr WC, et al. Gastroenterolog. 1984;86:814–819.15. Orr WC, et al. Am J Gastroenterol. 2000;95:37–42.16. Orr WC, et al. Am J Gastroenterol. 1994;89:509–512.17. Kjellén G, Tibbling L. Scand J Gastroenterol. 1978;13:283–288. 18. Chand N, et al. Aliment Pharmacol Ther. 2004;20:969-974.19. Johnson DA, et al. Am J Gastroenterol. 2005;100:1914-1922.20. Shaker R, et al. Am J Gastroenterol. 2003;98:1487-1493.21. Farup C, et al. Arch Intern Med. 2001;161:45-52.22. Bhatt DL, et al. N Engl J Med. 2010;363:1909-1917.23. Abraham NS, et al. Am J Gastroenterol. 2010;105:2533-2549.

GERD Related Sleep Disturbance Work Hours Lost Effect of PPI Therapy

0

-5

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-11*

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Per Week

Figure 1. Effect of PPI therapy on GERD-related sleep disturbance19

Esomeprazole 40 mg/dEsomeprazole 20 mg/dPlacebo

* P<0.0001 vs placebo

Fewer Hours Of

Work Lost

ABBREVIATED PRESCRIBING INFORMATIONPlease consult local full prescribing information before prescribing.

NEXIUM® (esomeprazole magnesium) 20 mg & 40 mg Film-coated tab (MUPS). INDICATIONS: Listed in Dosage. DOSAGE: Adults and adolescents from the age of 12 years Treatment of erosive reflux esophagitis: 40 mg once daily for 4-8 wks. Long-term management of patients with healed esophagitis to prevent relapse: 20 mg once daily. Symptomatic treatment of GERD: 20 mg once daily. If control has not been achieved after 4 wks, the patient should be further investigated. Once symptoms have resolved, subsequent symptom control can be achieved using an on-demand-regimen taking 20 mg once daily, when needed. Adults Healing of H. pylori-associated duodenal ulcer and prevention of relapse of peptic ulcers in patients with H. pylori-associated ulcer disease: 20 mg with 1 g amoxicillin & 500 mg clarithromycin, all bd for 7 days. Healing of gastric ulcers associated with NSAID therapy: 20 mg daily for 4-8 wks. Prevention of gastric and duodenal ulcers associated with NSAID therapy: 20 mg once daily. Prevention of rebleeding of gastric or duodenal ulcers following treatment with Nexium IV solution by infusion: 40 mg once daily for 4 wks. Treatment of Zollinger-Ellison Syndrome: The recommended initial dosage is 40 mg twice daily. The dosage should then be individually adjusted and treatment continued as long as clinically indicated. CONTRAINDICATIONS: Known hypersensitivity to esomeprazole, substituted benzimidazoles or any other constituents of the formulation. PRECAUTIONS: Exclude gastric malignancy prior to treatment. Co-administration with atazanavir and nelfinavir is not recommended. Patients with fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Hypomagnesaemia has been reported rarely in patients treated with PPIs for at least 3 months. Monitor when initiating & ending concomitant treatment with warfarin. Caution in pregnancy and lactation. UNDESIRABLE EFFECTS: Headache, abdominal pain, constipation, diarrhoea, flatulence, nausea, vomiting. 07/AA/SG/GI000-059-920.10 July 2011.

NEXIUM® (esomeprazole) 40 mg powder for solution for injection/infusion. INDICATIONS: Listed in Dosage. DOSAGE: Patients with reflux oesophagitis: 40 mg once daily. Patients treated symptomatically for reflux disease: 20 mg once daily. For healing of gastric ulcers associated with NSAID therapy: 20 mg once daily. For prevention of gastric and duodenal ulcers associated with NSAID therapy: 20 mg once daily. Usually the IV treatment duration is short and transfer to oral treatment should be made as soon as possible. Following therapeutic endoscopy for acute bleeding gastric or duodenal ulcers: 80 mg should be administered as a bolus infusion over 30 minutes, followed by a continuous infusion of 8 mg/hour given over 72 hours. The parenteral treatment period should be followed by oral acid suppression therapy. CONTRAINDICATIONS: Hypersensitivity to esomeprazole or to other substituted benzimidazoles or to any of the excipients of this medicinal product. PRECAUTIONS: Exclude gastric malignancy prior to treatment. Co-administration with atazanavir and nelfinavir is not recommended. Hypomagnesaemia has been reported rarely in patients treated with PPIs for at least 3 months. Monitor when initiating & ending concomitant treatment with warfarin. Caution in pregnancy and lactation. UNDESIRABLE EFFECTS: Headache, abdominal pain, constipation, diarrhoea, flatulence and nausea/vomiting, administration site reactions. 07/AA/SG/GI.000-107-142.6.0 July 2011.

For Healthcare Professionals only.

Further information available on request.

Astrazeneca Singapore Pte Ltd8 Wilkie Road, #06-01 Wilkie Edge, Singapore 228095Tel: +65 6579 6500Fax: +65 6238 7815 PS

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When persistent, recurring GERD disrupts life

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Saxagliptin shows no CV effects in patients with T2D


Radha Chitale

The large multicenter SAVOR-TIMI 53 trial on the antidiabetic agent saxa-gliptin showed neither increases nor

decreases in the rate of cardiovascular (CV) events among high-risk patients with type 2 diabetes (T2D) compared with placebo.

The results support mounting data that the selective dipeptidyl peptidase 4 (DPP-4) inhibitor class of antidiabetic drugs may be a neutral addition in the treatment regimen of heart patients with diabetes, in spite of prior research showing the potentially question-able safety of diabetes medications.

In the trial, a total of 16,492 patients with T2D were randomized to receive either saxa-gliptin or placebo, plus their own doctor-pre-scribed regimen of diabetes and CV risk con-trol medications. Eligible patients had HbA1c levels between 6.5-12 percent and a history of CV disease or multiple CV risk factors (men over 55, women over 60, hypertension, smok-ing, dyslipidemia).

Over a median 2.1 years of follow up, 7.3 percent of saxagliptin patients reached a primary endpoint event (CV death, nonfa-tal myocardial infarction, nonfatal ischemic stroke) compared with 7.2 percent of placebo patients (hazard ratio [HR] 1.00, p<0.001 for noninferiority).

Secondary endpoints, a composite of CV death, MI, stroke and hospitalization for heart failure, unstable angina or coronary revascu-larization, were also similar between groups

– 12.8 percent and 12.4 percent in the saxa-gliptin and placebo arms, respectively (HR 1.02, p=0.66).

Saxagliptin patients achieved better blood sugar control, with 36.2 percent at under 7 percent at follow-up compared with 27.9 per-cent in the placebo group (p<0.001).

However, more patients receiving saxa-gliptin were hospitalized for heart failure (35 percent) compared with placebo recipients (2.8 percent), which the researchers noted was unexpected (HR 1.27, p=0.007).

“The increase in hospitalization for heart failure was not expected and deserves fur-ther study,” said study chairman Dr. Eugene Braunwald of the TIMI Study Group, Cardio-vascular Division at Brigham and Women’s Hospital and Harvard Medical School in Bos-ton, Massachusetts, US.

More saxagliptin recipients also reported at least one hypoglycemic event (15.3 per-cent) compared with placebo (13.4 percent,

Saxagliptin did not influence CV event occurences, positive or negative, in the SAVOR-TIMI 53 study.

37 October 2013 Conference Coveragep<0.001). Rates of other adverse events in-cluding pancreatitis were similar between the treatment arms.

The SAVOR-TIMI 53 trial, supported by AstraZeneca and Bristol-Myers Squibb, who collaborated to develop saxagliptin, was initi-ated following 2009 US Food and Drug Ad-ministration guidelines that new diabetes drugs must go through a CV outcomes study.

In an accompanying comment, FDA advi-sory committee members Dr. William Hiatt, Dr. Sanjay Kaul and Dr. Robert Smith said

that while the performance of antidiabetic agents including saxagliptin is satisfacto-rily safe, and, with saxagliptin, beneficial for blood sugar control, “neither intensive glycemic control nor the use of specific dia-betes medications is associated with any suggestion of cardiovascular benefit. Thus, the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.”

Smart Rx. Every Time.

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Pertussis in Singapore: Taking an Under-diagnosed Disease Seriously

Dr Leong Hoe NamConsultant Infectious

Disease PhysicianRophi Clinic, Mount Elizabeth

Novena Specialist CentreSingapore

Pertussis is a highly contagious respiratory infection and one of the most widespread vaccine-preventable diseases in the world. Studies

suggest, however, that pertussis persists to be an ongoing problem globally, with a rise in the number of reported cases of pertussis in adults and adolescents.1,2 In 2012, a pertussis epidemic was declared in the state of Washington, with a 1,300% increase in reported cases compared to the previous year and racking up the highest number of cases reported in any year since 1942, and this was only midway through the epidemic.3 Highest disease rates were reported among infants aged <1 year and children aged 10 years.3 In Singapore, local data suggest that there is also a resurgence of pertussis in recent years, with high morbidity in paediatric patients.4

Risk Factors and Burden of Disease

The resurgence of pertussis can be attributed to a combination of age-specific contact patterns, vaccine-driven virulence evolution, and

waning immunity in different populations.5-7 Family members were found to be the source of infection in 75% of 212 infants between 0 and 3 months of age.8 Adults usually serve as reservoirs of the causative organism. Without the help of vaccine boosters, immunity tends to wane over time, and the body fails to eradicate mucosal colonisation, leading to infection and transmission.

Following transmission through contact with symptomatic or asymptomatic carriers, its natural course consists of a flu-like catarrhal stage, the classic paroxysmal stage characterised by bursts of coughing followed by an inspiratory “whooping” sound, and a convalescent stage. However, typical symptoms are not observed in the majority of cases. Complications of pertussis include secondary respiratory infections, complications of severe coughing, conjunctivitis, epistaxis, hernias and central nervous system sequalae.9-11 Approximately 87% of deaths occur in infants younger than 1 year.12

Approaches to Management of Pertussis

Childhood VaccinationDespite the effectiveness of antimicrobial therapies, vaccination remains the most effective overall management approach to minimise the burden of disease. According to the latest National Childhood and Adolescent Immunisation Schedule of Singapore, DTaP should be given to all infants at 3, 4, and 5 months of age, followed by an initial DTaP booster at 18 months and Tdap at 10 to 11 years of age.13 In 2011, the Singapore Ministry of Health updated its recommendations to incorporate Tdap as the fifth dose in the immunisation schedule. This is aimed at boosting the herd immunity against pertussis and reducing the likelihood of outbreaks in adolescents and adults.

In Singapore, a combined reduced-antigen vaccine (Tdap) containing diphtheria, tetanus and acellular pertussis antigens is available and is administered as a single 0.5 mL booster dose by school

health nurses to children aged 10 to 11 years old.13 It is suitable for use in children >4 years of age through adulthood.

The need for routine boosters in adults and during adolescence is recommended as immunity wanes over time. In a study that assessed serology positivity in 1,200 Singaporean children aged 1 to 17 years, it was revealed that immunity decreases considerably with increasing age.7 Within a year after vaccination, immunoglobulin G (IgG) seroprevalence was 85% and this decreased to 63% after 2 years and as low as 50% after 4 years.7

Adult vaccinationBecause of the possibility of transmission within the family, vaccination of adults is likewise recommended to provide a continuum of protection throughout life, especially for those who are in close contact with infants.14,15 Furthermore, older patients with inadequate protection can experience a more severe clinical course and face a greater risk of hospitalisation.16

References

1. Forsyth KD, et al. Pediatr Infect Dis J 2005; 24:S93-S97. 2. Celentano LP, et al. Pediatr Infect Dis J 2005;24:761-5. 3. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2012;61(28):517-22. 4. Goh A, et al. Vaccine 2011;29:2503-7. 5. Rohani P, et al. Science 2010;330:982-985. 6. Mooi FR. Infect Genet Evol 2010;10:36-49. 7. Lai FY, et al. Vaccine 2012;30:3566-3571. 8. Bisgard KM, et al. Pediatr Infect Dis J 2004;23:985-989. 9. Trollfors B, Rabo E. Br Med J (Clin Res Ed) 1981;283:696-697. 10. Postels-Multani S, et al. Infection 1995;23:139-142. 11. Skowronski DM, et al. Clin Infect Dis 2003;36:e1-e4. 12. Wortis N, et al. Pediatrics 1996;97:607-12 13. The National Childhood and Adolescent Immunisation Schedule, Singapore. http://www.nir.hpb.gov.sg/nir/sv/eservices/eservicesv?ACTION=DISPLAY_IMMUNSCH. Accessed May 6, 2013. 14. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 2011 21;60:1424-1426. 15. Liu BC, et al. Clin Infect Dis 2012;55:1450-1456. 16. Yih WK, et al. J Infect Dis 2000;182:1409-1416.

Sponsored Symposium Highlights

SG/B

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PERTUSSIS – THE DANGERS OF OVERLOOKING ITS RESURGENCE

At a recent symposium, key opinion leaders discussed the current burden of pertussis infection. Dr Leong Hoe Nam described the role of inadequate vaccination in the resurgence of pertussis in Singapore and worldwide. Associate Professor

Daniel Goh Yam Thiam explained current clinical strategies to achieve disease control, highlighting the benefits of Tdap immunisation for patients of all ages.

The Clinician’s Strategy for the Prevention of Pertussis Today

Associate Professor Daniel YT Goh

Chair, Paediatric Cluster and Head, Department of Paediatrics,

National University Hospital and Yong Loo Lin School of Medicine,

National University of Singapore

Global control of pertussis has been inadequate despite routine childhood immunisation; hence, early recognition and treatment

of cases is important and may help prevent the spread of infection, especially to young children who are most at risk.1 Although approximately 80% to 90% of patients with untreated pertussis will spontaneously recover without antibiotic therapy, untreated and unvaccinated infants can remain culture-positive for over 6 weeks and be a source of spread to other susceptible individuals.2

Treatment early in the course of illness can help patients recover faster and be less contagious to others. Children with pertussis are usually excluded from school or day care until they have been on antibiotics for at least 5 days. In addition, post-exposure prophylaxis can eradicate Bordetella pertussis from the nasopharynx of infected persons and should be provided to close asymptomatic contacts to prevent secondary cases; symptomatic contacts should be treated as primary cases.2

Vaccination continues to play a central role in pertussis prevention strategies both locally and internationally. Childhood vaccination is important and effective but evidence shows that the immunity wanes over time and by adolescence, most are susceptible to the infection. Even more importantly these adolescents and older individuals do not exhibit typical clinical features during infection which makes it harder to identify and treat. Hence, they form a large reservoir of infective source for the rest of the susceptible population.2

Pertussis vaccine for adolescents and adults typically combine the tetanus and diphtheria toxoids with the acellular pertussis component.

These antigens are present in lower titres to reduce the reactogenicity of the vaccine while maintaining its immunogenicity.

The acellular pertussis vaccine has been demonstrated to be protective in adolescents and adults.3-5 One month post-administration of a vaccine consisting of acellular pertussis antigens combined with tetanus toxoid and reduced diphtheria toxoid (Tdap), more than 99% of adolescent subjects were seroprotected against diphtheria and tetanus and ≥98.9% were seropositive against pertussis antigens pertussis toxin, filamentous hemagglutinin, and pertactin.4 The pertussis antibody responses in the adolescents after a single dose of Tdap even exceeded those in infants after a 3-dose primary vaccination series with DTaP [Figure 1].4 Importantly, its immunogenicity, when administered 10 years after a previous booster dose, remained significant, indicating potential benefit of a decennial booster dose.6

Recommendations for Tdap Booster Immunisation

Recommendations on Tdap booster immunisation target all adults 19 years and older who have not previously received a Tdap vaccine; parents, older siblings and other family members in families with infants younger than 12 months (cocoon strategy); medical personnel; day care centre staff; immunocompromised patients and individuals with asthma, cystic fibrosis or cardiopulmonary diseases.7-9

Health care workers of all ages comprise a special high-risk group10 and are recommended to receive a single dose of Tdap vaccine as soon as is feasible if they have not previously received it, regardless of the time since the last tetanus-diphtheria vaccine dose.8 After receiving Tdap, personnel should receive routine booster shots against tetanus and diphtheria, as recommended by existing guidelines.8,11 Hospitals and outpatient clinics should also provide Tdap for health care professionals and take steps to maximise coverage such as education and improved access to vaccines.

The “cocoon” strategy, which has been endorsed by the Advisory Committee on Immunization Practices (ACIP) since 2005, consists of vaccinating mothers immediately postpartum and all other close contacts of infants aged less than 12 months with a single dose of Tdap. Ideally, these adolescents and adults should receive Tdap at least 2 weeks before beginning close contact with the infant.12

Following the review of the epidemiology of pertussis in Singapore and the evidence for waning immunity among adolescents and adults

After DTaP in infants

Before Tdap in adolescents

After Tdap in adolescents

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Figure 1. Comparison of pertussis immune responses after a single dose of Tdap in adolescents with responses after completion of a 3-dose primary immunisation series with DTaP in infants.4

who were vaccinated against pertussis as infants, the recommendation of the Singapore Ministry of Health is to incorporate the combined tetanus, reduced dose of diphtheria toxoid, and acellular pertussis vaccine (Tdap) as the fifth dose in the National Childhood and Adolescent Immunisation Schedule. This is aimed at boosting the herd immunity against pertussis and reducing the likelihood of outbreaks in adolescents and adults.

References

1. Forsyth KD, et al. Pediatr Infect Dis J 2005;24:S93-S97 2. Tiwari T, et al. MMWR Recomm Rep. 2005;54(RR-14):1-16. 3. Ward J, et al. New Engl J Med 2005;353:1555-1563. 4. Pichichero ME, et al. Pediatrics 2006;117:1084-1093. 5. Rank C, et al. Pediatr Infect Dis J 2009;28:152-153. 6. Booy R, et al. Vaccine 2011;29:45-50. 7. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics 2006;117:965-978. 8. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2012;61:468-470. 9. Pertussis (Whooping Cough) - Prevention. http://www.cdc.gov/pertussis/about/prevention.html. Accessed May 21, 2013. 10. Sandora TJ, et al. Clin Microbiol Rev 2008;21:426-434. 11. Healthcare Personnel Vaccination Recommendations. http://www.immunize.org/catg.d/p2017.pdf. Accessed May 6, 2013. 12. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2011;60:1424-1426.

For Medical /Healthcare Professionals Only This reprint is made possible through an educational grant from GSK.Editorial development by MIMS. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage however so arising is hereby disclaimed. © 2013 MIMS. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher.

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MT-GSK Boostrix_Aug_Sym Ht_FINAL_1.indd 1 10/8/13 12:21 PM


Rajesh Kumar

Low and middle income countries have a higher rate of cardiovascular disease (CVD) mortality despite a much lower

burden of CVD risks when compared with high income countries, a large global study has revealed.

Over 80 percent of the CVD mortality oc-curs in low and middle income countries, but it is not known whether this is due to higher risk factor levels, variations in CVD incidence, or differences in CVD mortality, said the re-searchers of the global Prospective Urban Ru-ral Epidemiologic (PURE) study.

They found that countries with the highest CVD mortality did not have the correspond-ingly high burden of risks.

This burden is actually the highest in high income countries (HIC), moderate in the mid-dle income countries (MIC) and the lowest in the low income countries (LIC), said research-er Dr. Salim Yusuf, professor of medicine at the McMaster University Faculty of Health Sciences in Hamilton, Ontario, Canada.

The study enrolled more than 155,000 in-dividuals from 628 urban and rural commu-nities in 17 countries and assessed their CVD risk using the inter-heart risk score (IHRS), and prevention practices (hypertension control, smoking cessation, use of lipid lowering drugs and secondary prevention). Participants were followed for a mean duration of 3.5 years and their incident CVD events were documented.

HICs included Canada, Sweden and the

United Arab Emirates, MICs included Co-lumbia, Brazil, Chile, Argentina, Poland, Tur-key, China, Iran and Malaysia, and LICs were India, Bangladesh, Pakistan and Zimbabwe.

Mean IHRS was significantly higher in HICs compared with LICs (13 vs 8, respec-tively; p<0.001). Fatal CVD occurred in about 3.7 people per 1,000 person-years in LICs, compared with about 0.5 per 1,000 person-years in HICs. Fatal myocardial infarctions were far more common in LICs and MICs – 17 per 1,000 person-years, compared with 4 per 1,000 person-years in HICs (p=0.0203).

However, the incidence of less severe CVD was higher in HICs, and so were hypertension control, smoking cessation and secondary prevention. It is possible that the high burden of CVD risks in HICs is being offset by better risk factor control, more aggressive manage-ment of less severe CVD, and better outcomes in those experiencing major CVD, leading to much lower CVD mortality, said Yusuf.

“We need to think about improving case management, early detection and primary and secondary prevention in middle and low income countries. These are essential if we want to control [the] CVD epidemic,” he said.

Discussant Professor Joep Perk of the De-partment of Health and Caring Sciences at Linnaeus University in Storken, Sweden, said: “The PURE study should inspire to broaden political action promoting cardiovascular health, such as tobacco legislation and public health campaigns combating adiposity and promoting physical activity.”

Higher CVD mortality in poorer nations despite lower risk burdens



More effective, less toxic meds needed for SLE

Elvira Manzano

The standard of care for systemic lu-pus erythematosus (SLE) is not work-ing in some patients, requiring new

and more effective but less toxic therapies for refractory cases, said Dr. Chi Chiu Mok, a rheumatologist at the Tuen Mun Hospital, Hong Kong.

“SLE is a heterogenous disease, with a wide spectrum of manifestations. There is no specific biological marker and no single outcome measure for disease improve-ment,” he said. “Treatment is difficult as no two patients are alike in their manifesta-tions.”

Up to 30 percent of SLE patients with major organ manifestations do not respond optimally to conventional immunotherapies (corticosteroids, azathioprine and cyclophos-phamide), resulting in persistent inflamma-tion. Prolonged use of these drugs may also cause damage to organ functions, Mok said. Treatment is essentially decided on an indi-vidual basis.

“There are three principles – establish if disease is inflammatory or thrombotic, re-versible or irreversible, and mild or mod-erate to guide treatment decision,” he said. “Other factors such as age, comorbidities, white cell count and drug interaction should be considered, as well as patient desire for

pregnancy, compliance and ability to tolerate medications.”

Cyclophosphamide is the gold standard for first-line treatment of severe and life-threatening SLE which is supported by long track record and clinical experience from physicians, Mok said. For refractory cases, treatment should be balanced between medi-cal evidence and adverse effects of addition-al treatment modalities.

Intravenous immunoglobulin G has been used successfully in hematological, neu-ropsychiatric and renal lupus when other drugs are ineffective or contraindicated but is associated with some side effects including anaphylaxis, allergy, and thrombosis. Treat-ment with plasmapheresis did not show any benefit for severe lupus nephritis. [N Eng J Med 1992;326;1373-1379]

The introduction of new biological drugs brings hope for the management of severe lu-

Symposium of the Asia Pacific League of Associations for Rheumatology 2013, August 29 – September 1, Bali, Indonesia

43 October 2013 Conference Coveragepus. “However, trials of novel agents usually exclude patients with severe lupus manifes-tations... there is also lack of evidence with newer agents (mycophenolate mofetil, tacro-limus and biological agents) in this popula-

tion group,” Mok said.Trials of experimental therapies will only

be successful if combined with more rigor-ous and comprehensive disease outcome measures, he added.

Starting with low-dose allopurinol may reduce risk of hypersensitivity in patients with goutElvira Manzano

Higher starting doses of allopurinol to treat gout may increase the risk of allopurinol hypersensitivity syn-

drome (AHS), a rare but potentially fatal ad-verse reaction to allopurinol therapy, a rheu-matology expert has warned.

“Starting allopurinol at a dose of 1.5mg/unit of eGFR is appropriate to minimize the risk,” said Professor Lisa Stamp from the University of Otago Christchurch in Christ-church, New Zealand.

The relationship between allopurinol dose and AHS is controversial. Current allo-purinol dosing guidelines do not differenti-ate between starting dose and maintenance dose. Dose reduction in renally-impaired patients is based on a reported relationship between “full dose” allopurinol (≥300 mg/day) and development of AHS. This obser-vation, along with recognition that excre-tion of oxypurinol is reduced in patients with impaired renal function, led to the sug-gestion that allopurinol should be dosed ac-cording to creatinine clearance, said Stamp.

“However, such dosing is frequently associ-ated with failure to reach the target serum urate.”

Findings from Stamp’s study showed that starting dose of allopurinol is a risk factor for AHS in gout patients. In a retrospective case-controlled study, there was a significant increase in the percentage of patients devel-oping AHS as the starting dose of allopurinol increased. For the highest quintile of start-ing dose per estimated glomerular filtration rate (eGFR), the odds ratio was 23.2 (p<0.01) [Arthritis Rheum 2012;64:2529-2536]

The study involved 54 cases with AHS and 157 without AHS (controls) matched for age, sex, diuretic use at the time of initiating allo-

An understanding of the relationship between allopurinol starting dose and AHS may improve long-term management of gout.

44 October 2013 Conference Coveragepurinol and renal function. The median time from starting allopurinol to AHS was 30 days.

Patients who developed AHS started al-lopurinol at a significantly higher dose com-pared with controls (p<0.001). They were also more likely to start allopurinol at doses higher than the creatinine-clearance based dose than were controls (p<0.001).

“However, in patients who tolerate allo-purinol, the dose can be uptitrated gradually with appropriate safety monitoring to achieve the target serum urate [6mg/dL], even in those

with renal impairment,” Stamp said.Successful long-term management of gout

requires a sustained reduction in serum urate. There is good evidence that achieving urate levels of 6mg/dL results in fewer acute flares and regression of chronic tophi.

Treatment with allopurinol is effective when optimal urate levels are achieved dur-ing treatment. Similarly, an understanding of the relationship between allopurinol starting dose and AHS may improve long-term man-agement of gout, said Stamp.

00

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Dr Tham Kwang Wei Senior Consultant, Department of Endocrinology Obesity and Metabolic Unit, LIFE Centre Singapore General Hospital Singapore

Data from the Ministry of Health’s 2010 National Health

Survey showed that there was an alarming increase in

the prevalence of diabetes & obesity in Singaporeans

aged 18 – 69 years compared to 2004. Survey results

found that 14.4% of the population has impaired glucose

New Paradigms in Type 2 Diabetes

Professor Donald J. Chisholm Garvan Institute of Medical Research

Sydney, Australia

Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with type 2 diabetes, accounting for two thirds of patient deaths.8 As many as 80% of patients with T2DM will develop and possibly die of macrovascular disease.9 Furthermore, diabetic patients without previous myocardial infarction have as high a risk of myocardial infarction as non-diabetic patients with previous myocardial infarction. Adults with diabetes are 2 to 4 times more likely to have a stroke than those without diabetes.

T2DM and CHD may have common antecedents

An increased risk of coronary heart disease (CHD) is not necessarily a consequence of the development of diabetes. Rather, diabetes may develop in individuals who already possess characteristics (possibly genetic)

Managing diabetes and cardiovascular disease: Current evidence and issues to consider

Sponsored as a service to the medical profession by Astra Zeneca & Bristol-Myers SquibbEditorial development by MIMS Pte Ltd. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever arising is hereby disclaimed.© 2013 MIMS. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher. MIMS Pte Ltd No 6 Shenton Way, Tower 2, #15-08, Singapore 068809 Tel: (65) 6290 7400 Fax (65) 6290 7401 E-mail: [email protected] Website: www.mims.com

Figure 1: The kidneys filter and reabsorb 180 g of glucose per day

References:1. Adapted from National Health Survey 1998, 2004 & 2010, MOH, Singapore. 2. Tuomilehto J et al. N Engl J Med 2001; 344: 1343-50. 3. DPP N Engl J Med. 2002; 346: 393-403. 4. Chiasson J-L et al. Lancet 2002; 359: 2072-77. 5. Norris Sl et al. Arch Intern Med. 2004; 164:1395-1404. 6. Wadden TA et al. Obesity 2011;19:1987-98. 7. Adams TD et al. N Engl J Med 2007;357:753-61. 8. Duckworth W, et al. N Engl J Med. 2009;360:129-139; 9. Buse JB, et al. Circulation. 2007;115:114-126. 10. Jarrett RJ, Shipley MJ. Diabetologia. 1988; 31:737-740. 11. Jarrett RJ. Diabetologia. 1984;26:99-102; 12. Kyler JS et al. Circulation. 2009; 119:351-357; 13. UKPDS Group. Lancet 1998;352:837–853. 14. Holman R, et al. N Engl J Med 2008; 359:1577–1589. 15. Nissen SE et al. N Engl J Med. 2007;356:2457-2471; 16. Tzoulaki I et al. BMJ. 2009;339: b4731. 17. Frederich R et al.Postgrad Med 2010;122:16-27. 18. Stratton IM, et al. BMJ. 2000;321(7258):405-412. 19. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107. 20. Williamson DF, et al. Diabetes Care. 2000;23(10):1499-1504. 21. Patel A. Lancet. 2007;370(9590):829-840. 22. Pyǒrälä K, et al. Diabetes Care. 1997;20(4):614-620. 23. Tahrani AA, et al. Lancet 2011;378182-97. 24. DeFronzo RA. Med Clin N Am 2004;88:787-835. 25. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8. 26. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35. 27. Brown GK. J Inherit Metab Dis 2000; 23:237–246. 28. Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; 29. Marsenic O. Am J Kidney Dis 2009;53:875-883. 30. Nairs S, et al. J Clin Endocrinol Metab 2010;95:34-42. 31. Santer R, et al. Clin J Am Soc Nephrol 2010;5:133-141vc.

Figure 2: Continued glucose reabsorption even at high glucose levels induces sustained hyperglycaemia in diabetics

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SGLT290%

Diabetes is a growing global epidemic. Nearly 400 million people live with diabetes with this figure set to rise to 500 million by 2030. At a recently held symposium in Singapore, sponsored by AstraZeneca and Bristol-Myers Squibb, Dr. Tham Kwang Wei gave an overview on the prevalence of diabetes & obesity in Singapore. Prof. Donald Chisholm then provided insights on managing diabetes and CVD and the role kidneys play in glucose homeostasis.

The role of the kidney in glucose homeostasis

that increase CHD risk in addition to diabetes risk (i.e. common antecedent risk factors like central adiposity, abdominal obesity and dyslipidemia).10,11

Evidence regarding the association between intensive anti-diabetic therapy and a reduction in the risk of major CV events in patients with T2DM have been inconsistent, although metformin may generate a modest benefit.12

UKPDS: legacy effect of earlier glucose control

Analysis of long-term data leans in favour of a strategy that introduces intense glucose control early in the course of T2DM. The UK Prospective Diabetes Study (UKPDS) was a landmark randomised, multicentre trial of glycaemic therapies in 5,102 patients with newly diagnosed type 2 diabetes. 10-year post-trial follow-up data from the trial demonstrated that early intensive glucose control with either sulphonylureas or insulin not only continued to reduce microvascular complications, but also reduced risk for MI, any diabetes-related endpoint and all-cause mortality compared to conventional treatment. The benefits of earlier metformin therapy were

tolerance, while 11.3% have diabetes (compared with 12% & 8.2% respectively in 2004). Obesity was also becoming more prevalent, with the last report showing 10.8% of Singaporeans having a BMI of > 30kg/m2 and 16.9% of adults with abdominal fatness as measured by a raised waist-hip ratio. In 2004, the corresponding figures stood at 6.9% and 11.9% respectively. This trend was found to be similar across Asia.1

Abdominal fat distribution increases the risk of coronary heart disease. While obesity is an independent risk factor for diabetes, it is also the most important modifiable factor. It is essential to treat obesity before the development of

disease, even better if patients are treated before the risk factors develop.

Weight loss has been shown to be an effective means of reducing the progression to Type 2 diabetes mellitus (T2DM) in obese individuals.2-4 A 2-3% drop in body weight can reduce fasting plasma glucose, triglycerides and blood pressure.5 There is no real evidence that weight loss will reduce cardiovascular events as depicted in the LOOK AHEAD study.6 If there is dramatic weight loss as seen in bariatric surgery, then a reduction in mortality especially diabetes related, has been reported for people with T2DM.7

also sustained. Hence, cardiovascular benefit of better glycemic control may require initiation early in the disease process and long duration of therapy.13,14

Certain anti-diabetics, such as sulfonylureas and thiazolidinediones have negative CV effects.15,16 Sulfonylureas in particular have been associated with an increased risk of CV events and mortality in T2DM patients. In one such United Kingdom retrospective cohort study of 91,521 patients, monotherapy with a first- or second-generation sulfonylurea was associated with an increased risk of all-cause mortality, CHF, and MI.16

Cardiovascular Outcomes with Saxagliptin

A pooled analysis was performed to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin (a dipeptidyl peptidase-4 inhibitor) in patients with T2DM. Pooled analysis of all 8 trials comprising the saxagliptin clinical program with 4,607 patients and multiple comparators found that saxagliptin was not associated with an increased risk of CV events: acute CV events on saxagliptin 1.1% versus comparator 1.8% (Cox RR, 0.59 [0.35-1.00]).17

The kidneys play an important part in glucose balance

The kidneys’ contributions to maintaining glucose homeostasis are significant and include functions such as release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy their energy needs, and reabsorption of glucose at the level of the proximal tubule. They also offer an insulin-independent pathway for glucose removal.24 Each day, the kidneys filter and reabsorb about 180 g of glucose per day in the nephrons by active transport.

An insulin-independent pathway in diabetes- Renal SGLT2

Glucose reabsorption in the kidney is mediated by a

class of specific glucose transport proteins, the sodium glucose cotransporters (SGLTs). The SGLT pathway in the kidney plays an important insulin-independent role in glucose balance. One member of this family, SGLT 2, is a low-affinity, high capacity co-transporter which is responsible for the majority of total renal glucose reabsorption in the S1 segment of the proximal tubule. The remaining glucose is reabsorbed in the S3 segment, where the high-affinity, low capacity SGLT1 co-transporters are located. (Figure 1)25-27 It is important to note here however that the movement of glucose is not directly dependent on insulin.

The capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose

concentrations exceed a threshold, glucose appears in the urine (glucosuria). Paradoxically, SGLT2 is upregulated in type 2 diabetes (Figure 2).28-30 Continued glucose reabsorption even at high glucose levels induces sustained hyperglycaemia in diabetics. Furthermore, in patients with familial renal glucosuria, up to 134 g glucose/day may be excreted, mostly with no major clinical impact.31

Patients with T2DM often have co-morbid conditions such as obesity, hypertension, and dyslipidemia that further contribute to the development of CV complications. Hence, incremental reductions sustained over time in glycemic control (HbA1c) and other parameters such as weight, blood pressure and lipids can benefit the physical health of patients with T2DM.18-22 Lowering the HbA1c can also reduce serious risk for macro- and microvascular complications.

To date, both research and development for type 2 diabetes have focused primarily on insulin-dependent mechanisms.23 New research has provided a greater understanding of the role of insulin-independent versus insulin-dependent pathways in glucose balance. A pathway that acts independently of insulin has the potential to provide benefits.

Diabetes & Obesity in Singapore

Sponsored Symposium Highlights


Cord blood infusion may have some benefits in cerebral palsy

Singapore International Congress of Obstetrics and Gynaecology 2013, August 21-24, Singapore

Elvira Manzano

Obstetricians should encourage par-ents to bank their babies’ umbilical cord blood (UCB) whenever feasible

in light of studies that show UCB infusions improved neurologic function in children with cerebral palsy.

“Stem cells from cord blood offer exciting promise in regenerative medicine, including cerebral palsy,” said Dr. Keith Goh, consul-tant neurosurgeon, Mount Elizabeth Hospi-tal, Singapore. “We should start to push for collection of cord blood shortly after delivery as it poses hardly any risk to the mother and the baby.”

Cerebral palsy is a disorder of movement, muscle tone or posture that is caused by brain damage, most often before birth. There is no cure, said Goh. The goal of treatment is to help children optimize their motor and cogni-tive potential.

Chloe Levine from Denver, Colorado, US, was one of the first to undergo an experimen-tal stem cell infusion from her own stored cord blood at age two after a diagnosis of ce-rebral palsy. Now, she can play and ride a bi-cycle and has started school.

Stories like Chloe’s have prompted further research on the potential use of stem cell ther-apy for cerebral palsy. Goh noted two recent studies which showed that cord blood infu-sion have some benefits.

The first study, although limited to 20 pa-tients with cerebral palsy, showed that autolo-gous cord blood infusion was safe and resulted

in partial improvements in neurological func-tions in 25 percent of these patients. Research-ers attributed this to the migration of stem cells into the brain and the ensuing cellular and neurotrophic effects. The improvement was more pronounced in diplegics and hemiple-gics rather than in quadriplegics. [J Transl Med 2012;10:58; doi: 10.1186/1479-5876-10-58]

A recent randomized controlled trial con-ducted in Korea, involving 96 children with cerebral palsy, also showed that allogeneic cord blood transfusion plus recombinant hu-man erythropoietin (rhEPO) improved the children’s motor and cognitive performance at 6 months. An effect on daily living was ob-served 3 months post-treatment, with marked improvement in social cognition score. There were no serious adverse events observed. [Stem Cells 2013; 31:581-591]

“The Korean study showed we can use al-logenic cord blood to treat cerebral palsy... it doesn’t have to be autologous,” said Goh.

A Korean study has shown that allogenic cord blood can be used to treat cerebral palsy.

47 October 2013 Conference CoverageResearch continues on the use of cord blood not only for cerebral palsy, but for hypoxic-ischemic brain injury, spinal cord injury and autism, among other diseases. “This exciting development makes cord blood banking even more promising.”

Cord blood contains stem cells that are known to reduce apoptosis, stimulate repair

of damaged cells, encourage angiogenesis, and promote the release of growth and tro-phic factors, all of which have been used suc-cessfully to treat many disorders, and without the ethical concerns surrounding embryonic and fetal stem cells. They have less risk of rejection and do not require perfect HLA-type matching.

Metformin a rising standard in gestational diabetes

Radha Chitale

Metformin can be a viable option for treating gestational diabetes mel-litus (GDM) in pregnant women,

said Dr. Tan Lay Kok, a consultant obstetri-cian gynecologist at Singapore General Hos-pital.

“The evidence shows that, although met-formin crosses the placenta, most of the ob-servational studies show that it has no terato-genic effects,” he said.

In the past, objections towards the use of metformin in pregnant women have been the risk of congenital anomalies and possibly compromising the fetus, particularly the risk of hypoglycemic episodes due to fetal pancre-atic stimulation.

However, Tan noted that a number of tri-als in the past decade have demonstrated that metformin is comparable or preferable to in-sulin without adverse effects to the fetus.

A 2008 trial comparing metformin and in-sulin therapy among women 20-33 weeks pregnant who had GDM showed that metfor-

Metformin has been shown in several trials to have comparable efficacy and safety to insulin in pregnant women with diabetes.

48 October 2013 Conference Coveragemin was not associated with more perinatal complications compared to insulin, including neonatal hypoglycemia, respiratory distress, birth trauma and premature birth. Women randomized to metformin required less sup-plemental insulin therapy for hyperglycemia and preferred to take metformin. [N Engl J Med 2008;358:2003-2015]

A meta-analysis of pregnancy outcomes after metformin treatment for GDM in the first trimester, though limited to eight stud-ies, similarly showed no increased fetal risk – malformations in this study – among children whose mothers used metformin to control their GDM. The researchers reported a sta-tistically significant protective effect of met-formin use of 57 percent after adjusting for publication bias. A pooled analysis showed the malformation rate was lower in the met-formin group (1.7 percent) compared with disease-matched controls (7.2 percent). [Fertil Steril 2006;86:658-663]

A follow up of the 2008 metformin vs in-

sulin trial showed that children exposed to metformin had more subcutaneous body fat compared with unexposed children, though total body fat remained the same, which Tan said may have some yet-to-be-proven benefits in terms of future insulin resistance. [Diabetes Care 2011;34:2279-2284]

Supportive data for metformin are not nec-essarily reflected in clinical guidelines for dia-betes in pregnancy. Some, like those from the UK, specifically advise avoiding metformin, or to obtain informed consent before admin-istering metformin.

But Tan noted that a healthy mother is still the most critical factor in delivering a healthy child.

“It is far more important to maintain [gly-cemic control] as a measure against fetal anomaly rather than whether you use oral an-tidiabetic drugs or not,” he said.

A number of metformin trials are ongoing to address further questions related to metfor-min used during pregnancy, as it still crosses the placenta.

Industry Update brings you updates on disease management and advances in phar-macotherapy based on reports from symposia, conferences and interviews, as well as latest clinical data. This month’s updates are made possible through unrestricted educational grants from Takeda.

Early BMD treatment can slow osteoporosis • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •P44

Industry UPDATE

49 Industry Update

The selective estrogen receptor modulator raloxifene (Evista®, Takeda), used for treating osteoporosis, is particularly effective in early stages of disease. For women, this can translate to reduced risks of advanced osteoporosis and fractures after menopause.

Early BMD treatment can slow osteoporosis

Osteoporosis is a progressive disease in which bones become weaker and more prone to fractures. This con-

tinuum of bone loss happens in both gen-ders but accelerates during women’s meno-pausal transition. Identifying women in the early stages of bone loss, when they begin to have low bone mass – often referred to as osteopenia – and treating them with drugs like raloxifene, could significantly reduce the amount of bone lost before, during and after menopause and consequently reduce their risk of fractures and osteoporosis.

“To wait for a theoretical osteoporosis threshold to start treatment doesn’t make a lot of clinical sense,” said Professor Mone Zaidi, director of the Mount Sinai Bone Pro-gram at Mount Sinai School of Medicine in New York, New York, US. “There is evidence that drugs work and you can prevent that bone loss.”

There can be two extremes of osteopenia, Zaidi said. At one end are the older woman who may have received treatment for bone loss around menopause but whose bone mineral density (BMD) has been slowly de-clining. Now, at 70, she would be osteopenic with a T-score† of -1.8.

At the other end is a younger perimeno-pausal woman with a T-score of 1.8, indi-cating osteopenia. If her bone loss remains

unattended, she is likely to be in a more pre-carious position than the osteopenic 70-year-old, with a worse T-score and a higher risk of fracture.

Bones are broken down by osteoclasts and repaired by osteoblasts constantly. Os-teoporosis simply occurs when the net effect of this process is bone loss. In early meno-pause, more new osteoclasts are being pro-duced.

In fact, Zaidi said, the most bone loss oc-curs in the 3 years prior to a woman’s final menses; it continues rapidly over 10 or so years, and finally slows.

Tools like FRAX® can evaluate fracture risk based on clinical risk factors and capture women at high risk for fracture. Mature os-teoclasts can then be targeted with drugs like bisphosphonates to prevent them from latching onto and leeching away bone.

However, raloxifene is most effective in the early stages of bone loss. This selective estrogen receptor modulator (SERM) reduc-es the birth of osteoclasts as an estrogen agonist and prevents them from maturing at precisely the moment when they are pro-duced at high volume.

“You can treat patients with low bone density with raloxifene starting very early and continue,” Zaidi said.

Raloxifene maintained BMD in healthy

50 Industry Update

postmenopausal women and significantly reduced the risk of new vertebral fractures in post menopausal women in the multicenter MORE* trial. [J Musculoskelet Neuronal Inter-act 2000;1:127-32]

The MORE research group evaluated 7,705 postmenopausal women, mean age 66.5 years, with osteoporosis who had T-scores less than -2.5. The women were randomized to placebo or 60 mg of raloxifene for 3 years.

At follow-up, raloxifene reduced the risk of new vertebral fractures in women with-out prevalent vertebral fractures at baseline by 55 percent (p<0.001) compared with pla-cebo. In women who had prevalent vertebral fractures at baseline, raloxifene reduced the risk of new vertebral fractures by 31 percent (p<0.001) compared with placebo.

BMD increased in the femoral neck and spine by 2.1 percent and 2.6 percent, respec-tively, in the 60 mg raloxifene group, and by 2.4 percent and 2.7 percent, respectively, in the 120 mg raloxifene group, compared with placebo after 3 years.

The MORE results demonstrated that women could be kept from losing as much bone density as they might have without treatment, likely positioning them for a low-er fracture risk later in life.

Zaidi noted that patients can be con-cerned about the length of treatment, which, with several osteoporosis drugs is continu-ously, and the concomitant side effects, such as gastrointestinal, cardiovascular and skel-etal complications.

“But if you start treatment early, you nor-malize bone density and in a few years you can stop,” he said. “The reason women lose bone is not that individual osteoclasts get ac-tivated but because more osteoclasts are be-ing produced. When bone resorption starts rising, you can put patients back on therapy

again.” Although data on raloxifene does not

show benefits for reducing hip fractures, Zai-di said that point is less critical because the younger population of women for whom ral-oxifene would be most useful are not at high risk for hip fractures. They tend to be more at risk for vertebral fractures, which is where bone is lost in early menopause, and where raloxifene has been shown to help.

Identifying good candidates for treatment can be done by using bone turnover markers in urine to determine if a woman is actively losing bone. BMD can be measured at two different time points to determine if there has been decline.

Raloxifene has the added property of treating breast cancer due to its unique es-trogen receptor modulating properties. While the drug acts as an estrogen agonist in bone tissue, it has anti-estrogenic effects in breast and uterine tissue. The MORE trial demonstrated that 3 years of raloxifene re-duced the risk of in situ and invasive breast cancer in postmenopausal women with os-teoporosis by 65 percent compared with pla-cebo (p<0.001).

Including results from the CORE** trial to examine how 4 additional years of raloxifene therapy affects incidence of invasive breast cancer among women in the MORE trial, the incidences of invasive breast cancer and es-trogen receptor-positive breast cancer were reduced by 66 percent and 76 percent, re-spectively, compared with placebo after 8 years, with no new safety issues. [J Natl Can-cer Inst 2004;96:1751-1761]

Zaidi said women with a family history of breast cancer would certainly be a candidate for raloxifene. Women with a history or pre-disposition for deep vein thrombosis would not be good candidates, however, as both

51 Industry Update

the MORE and CORE trials reported a nearly three-fold increase in the rates of DVT and pulmonary embolus compared with placebo. [J Musculoskelet Neuronal Interact 2000;1:127-132; J Natl Cancer Inst 2004;96:1751-1761]

There are no official guidelines for treat-ing osteopenia but Zaidi and colleagues have proposed “aggressive, likely short-term therapy” in the early stages of osteoporosis. [Curr Osteoporos Rep 2009;7:118-126]

He noted that such a course would not be characterized as prevention but as treatment for active bone loss, during which bone den-sity may stabilize and microarchitectural de-terioration could be prevented.

“As you get older, the requirement of a lower T-score to produce increased fracture risk diminishes, and you get fractures at more normal T-scores,” Zaidi said. “I think we’ve got to decide when to start treating or at least capturing women who are in the active phase of bone loss… Raloxifene works best early on when the phenomenon is very active.”

† T-scores indicate deviations from a normal reference

mean. For BMD, that is a healthy 30-year-old. Normal T-

score is -1.0. Osteopenia is between -1.0 and -2.5. Osteo-

porosis is -2.5 or lower.

* MORE: Multiple Outcomes of Raloxifene Evaluation

** CORE: Continuing Outcomes Relevant to Evista

52 October 2013 Obstetrics

Birth preparation program reduces urinary incontinence, encourages exercise during pregnancy

Lianne Cowie

Antenatal preparation programs were developed to promote healthy preg-nancies, communicate ways to reduce

discomfort associated with pregnancy and labor, and to reduce anxiety. However, few studies have assessed the effects of such pro-grams on perinatal outcomes. Now, research-ers in Brazil have determined that a birth preparation program significantly reduced the incidence of urinary incontinence and en-couraged exercise during pregnancy, but had no marked effect on lumbopelvic pain or peri-natal outcomes.

The study was conducted between June 2009 and September 2011, and involved 197 nulliparous women aged 16–40 who pre-sented at the Women’s Integral Health Care Hospital at the University of Campinas, São Paulo, Brazil, and at four primary health care centers in the region, when the gestational age of their fetus was 18–24 weeks. The wom-en were randomly assigned either to a pro-gram of physical exercises and educational activities designed to minimize lumbopelvic pain, urinary incontinence, and anxiety, and increase physical activity during pregnancy (n=97), or to a control group who received routine prenatal care (n=100). [BMC Pregnan-cy Childbirth 2013;13:154]

The number of complaints of urinary in-continence was significantly lower among participants in the birth preparation program compared with the control group at 28–30 weeks (42.7 percent vs 62.2 percent; relative

risk [RR], 0.69; 95% CI, 0.51–0.93) and at 36–38 weeks (41.2 percent vs 68.4 percent; RR, 0.6; 95% CI, 0.45–0.81). Women who participated in the program also exercised significantly more during their pregnancy; but, interest-ingly, the mean duration of delivery was sig-nificantly longer among these women com-pared with the control group (29.2 vs 19.7 minutes). However, no significant between-group differences in the prevalence or inten-sity of lumbopelvic pain, anxiety level, type of delivery, or weight and vitality of the infant were detected.

The researchers concluded that the pro-gram was effective at reducing urinary in-continence and encouraging exercise during pregnancy but that further studies are re-quired to determine the means of reducing lumbopelvic pain during pregnancy.

Exercise can help reduce pain and incontinence during pregnancy.


Smoking throughout pregnancy increases risk of SGA birth

Lianne Cowie

Researchers from the Kyushu Okinawa Maternal and Child Health Study re-port for the first time that smoking

throughout pregnancy is associated with an increased risk of a small-for-gestational-age (SGA) birth, but not smoking during the first trimester or during the second and/or third trimester.

In the prebirth cohort study, 1,565 moth-ers with a single fetus completed two self-administered questionnaires, one before and one after the birth of their child. The ques-tionnaires were returned by mail. Data col-lected included active maternal smoking during the first (≤15 weeks’ gestation), sec-ond (16–27 weeks’ gestation), and third (≥28 weeks’ gestation) trimesters, exposure to to-bacco smoke at home and at work, gestation-al age, birth weight, sex of the baby, maternal age, region of residence, number of children, family structure, maternal education, mater-nal employment status, dietary habits, and body weight and height. [BMC Pregnancy Childbirth 2013;13:157]

The mean birth weight of the 1,565 new-borns was 3,006.3 g; 120 (7.7 percent) were classified as low birth weight (<2,500 g), 62 (4 percent) as preterm (birth at gestational age <37 weeks), and 122 (7.8 percent) as SGA (birth weight below the 10th percentile of Japanese neonatal anthropometric norms). Compared with women who never smoked

during pregnancy, women who smoked throughout had a significantly increased risk of a SGA birth (adjusted odds ratio 2.87; 95% CI, 1.11–6.56), particularly if their new-born was male. A significant association was also noted between active maternal smok-ing throughout pregnancy and birth weight, with smoking leading to an adjusted mean reduction of 169.6 g.

There was no significant risk of active smok-ing leading to preterm birth; however, the positive linear trend between preterm birth and increased exposure to tobacco smoke was significant (p=0.048). Active maternal smok-ing and exposure to tobacco smoke at home or at work had no significant effect on birth weight.

The authors suggest that women who smoke should quit as soon as possible after conception.

Smoking during pregnancy was linked to a higher risk of small size at birth.


Excessive gestational weight gain can be prevented by lifestyle counseling

Lianne Cowie

Excessive weight gain during preg-nancy is an independent risk factor for adverse outcomes such as gesta-

tional diabetes and accelerated fetal growth. A number of interventions aimed at reducing excessive weight gain have been trialed, but with variable success. Now, researchers from the FeLIPO (Feasibility of a Lifestyle Inter-vention in Pregnancy to Optimize maternal weight development) study report that life-style counseling sessions effectively reduce the proportion of pregnancies with excessive weight gain.

The cluster-randomized, controlled, in-tervention trial involved 250 healthy preg-nant women recruited from eight gyneco-logical practices between February 2010 and August 2011. [BMC Pregnancy Childbirth 2013; 13:151]

Each practice was randomly assigned to the control or intervention group. The wom-en were all older than 18 with one live fetus, had not passed week 18 of gestation, and had a body mass index ≥18.5 kg/m2 as well as sufficient German language skills. Wom-en in the intervention group participated in two counseling sessions at weeks 20 and 30 of gestation. During these sessions, they were given information on how to maintain a healthy lifestyle during pregnancy and ad-vice on how to self-monitor diet, physical activity, and gestational weight gain. They also set behavioral goals tailored to their

circumstances. The control group received routine clinical care, including a leaflet with ten statements about maintaining a healthy lifestyle during pregnancy.

Fewer women in the intervention group exceeded Institute of Medicine recommen-dations for weight gain compared with the control group (38 percent vs 60 percent; odds ratio [OR], 0.5; 95% CI, 0.3–0.9). Moreover, there was no increase in the number of preg-nancies with suboptimal weight gain (19 percent vs 21 percent; OR, 1; 95% CI, 0.5–2.1). The women in the intervention group gained significantly less weight than those in the control group, and only 17 percent retained >5 kg at 4 months’ post partum compared with 31 percent of the controls (OR, 0.5; 95% CI, 0.2–0.9). No significant between-group differences in obstetric and neonatal out-comes were noted.

Diet and exercise counselling kept expectant mothers from gaining excessive weight.


TNF inhibitors for treating IBD found to be safe when used in pregnant women

Lianne Cowie

Tumor necrosis factor (TNF)-α inhibitors are commonly used in the treatment of inflammatory bowel disease (IBD),

but the effects of these agents on pregnancy outcomes remain unclear. Now, a systematic review of the English literature has indicated that they pose little risk to the mother or her infant, even if use is continued through the third trimester.

The researchers searched the Medline, EMBASE, and Cochrane Library databases as well as the Food and Drug Administration and European Medicines Agency homep-ages using combinations of the following search terms: inflammatory bowel disease, inflammatory bowel diseases, Crohn’s dis-ease, or ulcerative colitis and biologics, biologic products, infliximab, adalimum-ab, golimumab, or certolizumab as well as pregnancy, newborn, lactation, breast feed-ing, or infant. The date range was January 1998 to May 2013. [BMC Med 2013;11:174]

The search identified 58 studies (33 case reports, 21 case series, 4 prospective stud-ies with or without a control group) that met the inclusion criteria, and at least 1,533 pregnant women with IBD who were ex-posed to TNF-α inhibitors. There were more than 1,426 live births, 128 miscarriages, 81 elected abortions, 12 stillbirths, and 33 pre-term births. TNF-α inhibitors were not as-

sociated with any of these outcomes aside from a slightly increased risk of congenital abnormalities among women exposed to the biologics compared with those who were not. The researchers suggest that the latter result be viewed with caution as only four studies included a control group, only three of these reported odds ratios, and the con-fidence intervals for these ratios were very broad. Moreover, most case reports did not report any such association.

Use of TNF-α inhibitors during pregnan-cy does not appear to be associated with ad-verse pregnancy outcomes such as sponta-neous abortion, preterm delivery, stillbirth, low birth weight, congenital abnormalities, or risk of infections among offspring. How-ever, inoculation with live vaccines is pro-hibited until there is no trace of these agents in the child’s circulation as there is a risk of fatal infections.

Use of TNF-α inhibitors during pregnancy does not appear to be associated with adverse pregnancy outcomes.


High BP during pregnancy linked to future CVD

Lianne Cowie

Women with hypertensive disorders of pregnancy (HDP) may have a greater risk of future cardiovascu-

lar disease than women with normotensive pregnancies, according to new research, but it remains unclear whether HDP is indepen-dently associated with cardiovascular dis-ease. An observational cohort study of 71,819 women showed that HDP is significantly as-sociated with future stroke and high blood pressure, and that the risk is exacerbated by a high body mass index (BMI), particularly among women younger than 58 years. [BMJ Open 2013;3:e002964]

The study analyzed data from 71,819 women from the 45 and Up Study, Australia. The women were ≥45 years of age, had given birth between ages 18 and 45, had not had a hysterectomy or both ovaries removed, and had not been diagnosed with high blood pressure before their first pregnancy. A total of 7,706 (10.7 percent) of the women reported having had a HDP. Logistic regression analy-ses were performed to determine whether there were any associations between HDP, lifestyle characteristics, and high blood pres-sure and stroke in later life. The women were stratified by age (<58 years or ≥58 years) to ac-

count for the known association between high blood pressure and age.

HDP was found to be associated with higher odds of future high blood pressure (<58 years: adjusted odds ratio [AOR] 3.79, 99% CI, 3.38–4.24; p<0.01) and stroke (<58 years: AOR 1.69, 99% CI 1.02–2.82; p<0.01). Compared with women with normotensive pregnancies, women with HDP were also younger at the onset of high blood pressure and stroke. Women with a current BMI ≥25 and HDP had significantly increased odds of having high blood pressure (<58 years: odds ratio [OR], 12.48; 99% CI, 10.63–14.66; p<0.001) and stroke (<58 years: OR, 2.24; 99% CI, 1.14–4.42; p=0.002) compared with those who had not had a HDP and who had a BMI <25.

A study has found that women with hypertensive disorders of pregnancy are at higher risk of future stroke and high BP.

57 October 2013 In Practice

Improving early recognition of sepsis in pregnancy

Sepsis, a full-body inflammation that can be fatal, is the leading cause of death in intensive care units and the tenth most

common cause of death in the developed world overall. It’s a more common cause of death in a hospital than heart attack, stroke and lung cancer.

We often think that antibiotics and good obstetric care in the modern world have made sepsis less common. Because of that, we might also get casual about infections without remembering that some infections can turn in a bad direction very quickly.

Worldwide, one in 100 pregnant women will die of sepsis. It is not as common in the developed world but is certainly a problem in resource-constrained parts of the world.

Early intervention is keyThe strategy for sepsis in pregnancy

should be to try to intervene early before the infection has progressed through the initial stages of infection to sepsis, severe sepsis and septic shock because mortality rates increase as the infection grows worse – from 7 percent for the initial Systemic In-flammatory Response Syndrome (SIRS), to 16 percent for sepsis, 20 percent for severe sepsis, and 46 percent for septic shock.

Incidentally, pregnant women have a better chance at survival (up to 50 percent mortality rate) compared with non-preg-

nant patients (up to 80 percent mortality rate), because they tend to be young and healthy with infection at readily treatable sites. An infection of the uterus is easier to calm down than pneumonia, for example, or intra-abdominal sepsis.

SIRS can be identified when a patient has any two of the following symptoms: fever, elevated heart rate, elevated respiratory rate, low blood pressure, a white blood cell count that is too high or too low, or signs of inflammation.

SIRS can still be difficult to identify in the early stages in pregnant women be-cause inflammation is already increased during pregnancy, as well as heart rate and white blood cell count. This makes it hard-er to distinguish between normal pregnan-cy-related inflammation and abnormal in-flammation.

Septic shock can affect many organs, giving rise to altered mental status, pulmo-nary edema, shock liver, hypotension, re-nal failure and coagulopathy. Furthermore, the sources of sepsis are numerous. It can originate in a variety of areas including the upper or lower respiratory tract, urinary and genital tracts, from wounds, gastro-intestinal fauna, and the intra-abdominal cavity.

Escherichia coli accounts for a high pro-portion of sepsis infections in pregnant

Excerpted from a lecture by Dr. Raymond Powrie, Professor of Medicine and Obstetrics and Gynecology at The Warren Alpert Medical School of Brown University in Providence, Rhode Island, US, during the 2013 Singapore International Congress of Obstetrics and Gynaecology (SICOG).

Dr. Raymond Powrie

58 October 2013 In Practicewomen (60-80 percent).

Diagnostic challenges The challenges of identifying sepsis and

the reason it gets treated late in obstetric patients is the high level of medical com-fort with high heart rates and low blood pressures that we attribute to the normal physiology of pregnancy. We fail to mea-sure the pulse and monitor respiratory rate adequately, even though elevated respira-tion is one of the earliest signs of sepsis.

As sepsis is now relatively rare, doctors often fail to order the right laboratory tests. There is a reluctance to treat infection un-til the source is identified although this is changing. The original mentality was to wait to treat a young and healthy patient until they were sicker, but now we know to treat early and hard because young healthy patients can look very well until they are almost dead, and then they collapse very quickly. Often doctors fail to appreciate how quickly the condition of a septic wom-an can deteriorate.

The non-specific nature of sepsis pre-sentation among obstetric patients can also keep doctors from early identification.

Measures to enhance careSome solutions to these challenges in-

clude standardized, codified care struc-tures, and we have done this in my hospi-tal. We have changed the SIRS definition to make it more specific based on the physiol-ogy of pregnancy. In particular, the heart rate should be elevated above 110 beats per minute while the systolic blood pressure should be below 85 mmHg.

These measures enable us to look more closely at a potentially septic patient ear-lier, take appropriate laboratory tests, get a complete set of vital data at frequent inter-

vals, and early review by medical person-nel.

One of the key factors in ‘heading off’ sepsis is to give fluids early to increase tissue perfusion and follow by antibiotics specific to the source of infection, if it is known. The sepsis cascade begins because not enough blood is getting to the tissues due to sepsis-related physiological chang-es. Increasing the blood volume helps im-prove cardiac output and, rather than be-ing overly careful about pulmonary edema, which can be treated later, it is better to get the blood pressure up and increase perfu-sion.

If the cause of sepsis is surgical, then it is necessary to operate and drain. It is a mis-take to want to stabilize a patient before taking on an operation because waiting for sepsis to stabilize means sitting on a pro-gressing infection. It is the same as waiting for someone who is hemorrhaging to stabi-lize. Patients with a surgical cause of sepsis need surgical intervention.

With all these measures, at our hospital, the optimal procedure is to treat and ad-minister antibiotics within 3 hours of pre-sentation with septic symptoms. However, we are usually able to deal with such cases within 1 hour and the outcomes for many patients are surely different from what they might have been.

59 October 2013 CalendarOCTOBER

Asia Pacific Association of Pediatric Allergy, Respirology & Immunology (APAPARI 2013)2/10/2013 to 4/10/2013Location: Bangkok, ThailandInfo: APAPARI 2013 Organizing Committee Tel: (662) 714 2590Email: [email protected]: www.apapari2013.com

Taiwan Digestive Disease Week 20134/10/2013 to 6/10/2013Location: Taipei, TaiwanInfo: Congress SecretariatEmail: [email protected] Website: www.tddw.org

7th International Congress of the Asian Society Against Dementia (ASAD) 10/10/2013 to 12/10/2013Location: Cebu, PhilippinesInfo: Dementia Society of the PhilippinesTel: (632) 749 9707 Fax: (632) 740 9725Email: [email protected]: www.dementia.org.ph

23rd Asian and Oceanic Congress of Obstetrics and Gynaecology 201320/10/2013 to 24/10/2013Location: Bangkok, ThailandInfo: AOCOG 2013 SecretariatTel : (66) 2 748 7881 Fax : (66) 2 748 7880E-Mail: [email protected] Website: www.aocog2013.org/

31th World Congress of Endourology and SWL 22/10/2013 to 26/10/2013Location: New Orleans, Louisiana, USAInfo: Endourological Society Tel: (1) 8009089414 Fax: (1) 410 689 3912E-Mail: [email protected] Website: www.endourology.org

6th World Conference on Regenerative Medicine 201323/10/2013 to 25/102013Location: Leipzig, GermanyInfo: Conference CommitteeTel: (49) 341 240596-51Fax: (49) 341 240596-51Email: [email protected]: www.wcrm-leipzig.com

151st OMICS Group Conference International Conference on HIV/AIDS, STDs, & STIs24/10/2013 to 25/10/2013Location: Orlando, USAInfo: STD-AIDS-2013 Organizing CommitteeTel: (1) 650-353-4497Fax: (1) 650-618-1417Email: [email protected]: www.omicsgroup.com/conferences/hiv-aids-std-sti-2013/

13th International Workshop on Cardiac Arrhythmias - Venice Arrhythmias 201327/10/2013 to 29/10/2013Location: Venice, ItalyInfo: VeniceArrhythmias 2013 Organizing SecretariatTel: (39) 0541 305830Fax: (39) 0541 305842Email: [email protected]: www.venicearrhythmias.org

60 October 2013 CalendarNOVEMBER

2013 International Conference on Diabetes and Metabolism/Asian Association for the Study of Diabetes 6/11/2013 to 9/11/2013Location: Seoul, Korea Info: Korean Diabetes AssociationTel: (82) 2-714-9064Fax : (82) 2-714-9084E-Mail: [email protected]: http://icdm2013.diabetes.or.kr/

18th Congress of the Asia Pacific Society of Respirology (APSR) 11/11/2013 to 14/11/2013Location: Yokohama, JapanInfo: Congress SecretariatTel: (81) 3 5805 5261 Fax : (81) 3 3815 2028 E-Mail: [email protected]: www.apsr2013.jp/

UPCOMING

9th International Symposium on Respiratory Diseases8/11/2013 to 10/11/2013 Location: Shanghai, China Info: MIMS, China Email: [email protected] Website: www.isrd.org

18th Congress of the Asian Pacific Society of Respirology11/11/2013 to 14/11/2013Location: Yokohama, JapanInfo: APSR 2013 SecretariatEmail: [email protected]: www.apsr2013.jp

8th World Congress on Developmental Origins of Health and Disease (DOHaD 2013)17/11/2013 to 20/11/2013Location: SingaporeInfo: DOHaD 2013 Congress SecretariatTel: (65) 6411 6692Fax: (65) 6496 5599Email: [email protected]: www.dohad2013.org

61 October 2013 After Hours

Not many people realize that Spain is home to some of the world’s greatest artists. But mention Picasso and the

lot, and you realize that these folks worked their magic in this very diverse land. I had the opportunity to visit the Del Prado and Reina Sofia museums, and it was one that I could not miss.

The Del Prado is the main Spanish national art museum, located in the heart of Madrid. It features one of the world’s finest collections of European art, from the 12th to the early 19th century, and was part of the former Spanish Royal Collection. The Del Pra-do was constructed during the reign of King Charles

III (Carlos III) as part of a grandiose build-ing scheme designed as a monumental urban space. The building that houses the museum was conceived by José Moñino y Redondo and commissioned in 1785 by Charles III for the urbanization of Paseo del Prado (roughly translated as del Prado Promenade/Drive).

You can choose to turn up like most tour-ists do, in the mornings, and pay the entrance

fee or you can choose to do what a lot of locals do and turn up at 6 pm and enter for free (until it closes at 8). The museum is nestled between tree-lined avenues and

is a good place to hang out and watch people. It is highly unlikely that you

M U S I N G T H E M U S E U M S O F

MadridMuseo Nacional del Prado and Museo Nacional Centro de Arte Reina Sofía hold some of the finest art pieces the world has ever seen. Those that have heard of Picasso, Dali, Goya, etc would have their tongues wagging at the thought of being able to gawk at these masterpieces in real life. Leonard Yap writes.

62 October 2013 After Hours

will finish the museum in a day: arguably, it would take close to a week to see everything.

I chose to pay attention to the Spanish masters, Goya, Velasquez and El Greco. It was a sight to behold. I was particularly moved by Velasquez’s depiction of the cru-cifixion of Jesus. It almost felt like you were at the cross and you could see the gore and blood, hear the sounds and feel the suffer-ing. It really felt alive. As for Goya, it is good to keep an eye out for his ‘The Third of May 1808’ and ‘The Nude Maja,’ a contro-versial nude painting during the time of the Inquisition.

The Reina Sofia is Spain’s national museum of 20th century art. It was officially inaugu-rated on 10 September 1992, and is named af-ter Queen Sofia. It is located near the Atocha train and metro stations and its building is a conversation piece of its own. For those keen on saving Euros, join the locals who turn up before 7 pm for free entrance. It closes at 9.

But I was here for two reasons: one of them was Salvador Dali but, more importantly, to see Pablo Picasso’s ‘Guernica.’ Dali’s works border on the surreal and the odd, which is probably why I have an interest. Dali famous-ly said, “Come into my brain.” I think you will do just that with a whole floor devoted

to the artist. I first heard about ‘Guernica’ years ago,

but I never imagined that I would live to see it. Studying art appreciation all those years ago did not go to waste after all. To embark to describe it would be a disservice, for one should be there to see it. All I can do is give you an account of what the masterpiece ‘said’ to me. ‘Guernica’ was painted in re-sponse to the bombing of the Basque village of Guernica by German and Italian war-planes on the orders of Spanish nationalist forces on 26 April 1937 during the Spanish Civil War.

It depicts the tragedies of war and the suf-fering, particularly of innocent civilians. You can witness the pain and the fear, maybe even feel it. I heard (in my head) John Lennon’s song ‘Imagine’ and the words ‘Nothing to kill or die for, and no religion too, imagine all the people living life in peace’ ringing true or taking in-spiration from the Biblical verse, “… and they shall beat their swords into plowshares, and their spears into pruning hooks: nation shall not lift up sword against nation, neither shall they learn war anymore.” It invoked the paci-fist in me, and I hope it will continue to inspire and teach humanity a lesson – grow up and stop fighting!

63 October 2013 Humor

“You were lucky that you were wearing safety boots!”

“When I said ‘cough” I meant you, not him!”

“Mr. Lovborg, you’re about to make history!”

“Don’t you worry about side effects. There are all kinds of

medications for that!”

“Funny, my mother used to say the same thing!”

“We decided it was too dangerous to perform a

cesarean and opted instead for the Heimlich maneuver!”

“I haven’t the foggiest idea what that thing is. I would say

put it back. I’m sure it was there for a reason!”

MT(REG-SG)Aug13_FINAL.indd 11 7/31/13 5:25 PM

Professor Nimish Vakil talks about management of patients with refractory GERD.“Successful treatment of refractory GERD requires thorough investigation of the patient situation.”

Professor David Liebermanshares his perspective on the present and future of colorectal cancer screening.“There is a lot of potential to prevent many cancers if we can improve the rate of CRC screening.”

Dr Markus Cornbergdiscusses the management of chronic hepatitis B.“The aim of therapy should be the cure or control of HBV infection without the need for life-long treatment.”

In this Series, find out what these medical experts have to say about latest updates in the management of refractory GERD, the management of chronic hepatitis B and the present & future of colorectal cancer screening.

Current Opinion in Gastroenterology

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