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October 2013

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CRT of no benefit in HF with narrow QRS complex

Multimodal screening for breast cancer

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Excessive gestational weight gain can be prevented

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Improving early recognition of sepsis in pregnancy

Electronic cigarettes help smokers to quit safely in landmark trial

2 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.

3 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.”

Prolonged DAPT necessary in all PCI patients?

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

The overall impact of antiplatelet therapy cessation post-PCI, especially in stable patients, was negligible.

4 October 2013

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 risk 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. “However, when patients don’t comply or have to stop DAPT due to bleeding, their risk for adverse events is significantly increased. For these pa-tients, the risk of MACE was highest during

the first 7 days of disruption, representing 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.

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 Philippine FocusOctober 2013

PCP warns against improper use of stem cell therapy

Dr. Yves Saint James Aquino

The Philippine College of Physicians (PCP) held a health forum last August 13, 2013 in Quezon City to discuss why

stem cell therapy should not be a standard of care in medicine at present.

The medical organization explained in its position statement the growing concern on unsafe and unproven use of stem cell therapy in the Philippines, which poses serious safety issues to unsuspecting clients.

“We, the undersigned presidents of medi-cal professional organizations, push the Food and Drug Administration (FDA) to is-sue stricter regulations on stem cell therapy,” read the PCP’s position statement.

Members of the medical organization also

urged the FDA to declare which diseases have been proven to benefit from stem cell therapy, such as cancers of the blood and bone marrow, and some primary immuno-deficiencies treated by stem cell transplants. PCP recommends for the FDA explicitly state that the therapy has not been proven in conditions such as cardiovascular, neuro-logic, dermatologic, and infectious diseases, among others.

More controversial aspects of the stem cell issue were discussed during the open forum, which was moderated by Dr. Ma. Encarnita Limpin, chair of the Advocacy Committee of PCP.

Dr. Ramon Abarquez, cardiologist and past president of PCP, explained that we should not automatically fault ‘stem cell therapy,’ and instead, we must pay attention to those

Heads of specialty societies sign the position statement on stem cell therapy.


who are giving the therapy. “Is he a legitimate doctor? Does he have license? Does he have business permit? These are some of the ques-tions we have to address,” he said.

Despite the difficulty of performing clinical studies, PCP encourages performing proper-ly designed studies that have been screened and approved by technical review and ethics boards to document the potential benefits of stem cell therapy. The organization clarified that costs of such research should be shoul-dered by the sponsor of the study and that it would be unethical to ask for patients to pay for the treatment.

Dr. Honorata Baylon, a hematologist with the Philippine Society of Hematology and Blood Transfusion, explained the difference between ‘experimental stem cell therapy’ and the stem cell therapy that has been used in treating hematologic diseases.

“To differentiate it, we use the terms blood and marrow transplant, bone mar-row transplant, peripheral blood trans-

plant, umbilical cord blood transplant or hematopoietic stem cell transplantation,” said Baylon. These procedures are legiti-mate and proven to be effective treatments in specific hematologic conditions. She ex-plained that the media and patients should be aware of this difference and not cat-egorize all stem cell therapies as experimental.

In order to maximize the benefits of stem cell therapy while avoiding misuse and profi-teering, PCP supports the FDA in performing its administrative role “to conduct appropri-ate tests on all applicable health products prior to the issuance of appropriate authori-zations to ensure safety, efficacy, purity and quality.”

PCP urged the Department of Health to enforce legal mandates and issue guidelines for the use of stem cell therapy. Everyone is encouraged to report unaccredited institu-tions and misuse of stem cell therapy with the FDA.

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CONFERENCE COVERAGE

2013 Joint Annual Convention of the Society of Gynecologic Oncologists of the Philippines, Philippine Society for Cervical Pathology and Colposcopy and the Philippine Society for the Study of Trophoblastic Diseases, 25-26 July 2013, Manila Diamond Hotel, Roxas Boulevard, Manila

Multimodality screening for breast cancer

Dr. Nicolo L. Cabrera

Lesions in the breast discovered by self-examination, clinical examination or imaging may or may not turn out to be

benign. Some lesions such as atypical ductal hyper-

plasia, though benign, are associated with an increased risk of breast cancer later in life. In-filtrating ductal carcinoma still makes up 50 to 75 percent of invasive breast cancer.

Current recommendations include a breast self-examination starting at age 20, clinical breast examination every 3 years from age 20 to 30 and possibly annually from 40 and above. The mammogram is still the gold stan-dard, but there is growing support for a mul-timodality approach to imaging. High-risk women should have yearly mammograms and magnetic resonance imaging (MRI).

Several technologies have been developed to improve the utility of diagnostic imaging for breast cancer screening, but not all are rec-ommended for routine use. “With the avail-ability of PET scans locally, some [patients] are requesting our hospital to just blindly do a PET scan for the purpose of screening which, of course, is not recommended,” said Dr. Ale-jandro C. Dizon, assistant professor at the De-partment of Surgery at the University of the

East Ramon Magsaysay Memorial Medical Center.

Mammographic screening is associated with a 15 to 20 percent relative reduction in mortality from breast cancer. It identifies le-sions that warrant further imaging or biopsy, but is less reliable in young women and in women with dense breasts.

Breast ultrasound detects lesions as small as 2 mm. It is unable to detect microcalcifi-cations, but reliably differentiates cystic and solid lesions. It is considered an important part of a multimodality strategy, particular-ly in younger women or women with dense breast tissue, and increases yield when used


Minimally invasive surgery in gynecologic oncology

Dr. James A. Salisi

“There is an increase in the use of minimally invasive surgery (MIS) in gynecologic oncology as it con-

fers many benefits for patients such as shorter hospital stay and better quality of life, says a gynecologic oncologist.

However, the cost of laparascopy and the need for experienced personnel remain sig-nificant limiting factors to its widespread use, said Dr. Renee Vina Sicam, of the Makati Medical Center.

In the US, the use of MIS has shifted from diagnosis of adnexal masses (69 percent of cases in 2004 to 39 percent in 2007) to lapar-ascopically-assisted vaginal hysterectomy in uterine cancer (10 percent in 2004 to 43 per-cent of cases in 2007). The perceived benefits of MIS, such as decreased hospital stay, im-proved quality of life, patient preference, im-proved cosmesis and improved visualization, may have brought about this shift.

The benefits have been demonstrated by a study conducted by experts at the Philippine General Hospital. They gathered data from

to guide biopsy.Automated breast volume scanner (ABVS) is

a new technology which allows the operator to push a single detector against the breast, there-by minimizing operator dependence. However, it can be more uncomfortable for some patients compared to conventional ultrasound.

MRI is a useful modality in select high-risk patients or newly diagnosed breast cancer pa-tients to evaluate the extent of ipsilateral and contralateral breast involvement. It is the only modality available for patients with silicone-injected breasts. As it detects lesions that are not detected by mammography or ultrasound, it may be included in the multimodality screen-ing strategy for selected high-risk patients.

Fine needle aspiration (FNA) biopsy is un-able to distinguish between in situ and inva-sive disease. Since this finding would affect operative options, a core needle biopsy is con-

sidered superior to FNA. Additionally, a core needle biopsy specimen may be subjected to breast panel testing for possible adjuvant therapies. Should there be any suspicion of malignancy, an excisional biopsy should not be performed as this limits operative manage-ment options.

For lesions detected solely by mammogra-phy, stereotactic biopsy may be used to guide the core needle to the area and is less invasive. But it requires that the patient can be placed in a prone position and that the lesion is deep and distinctly visible on imaging.

“One thing that I have to emphasize, at least in our center, [is that] we really work as a team. Though I have training in ultrasound and mammography, I still believe that work-ing with the radiologist improves the out-come of our diagnostic procedures,” said Dr. Dizon.


New drugs for resistant trophoblastic diseaseDr. Carol Tan

New chemotherapeutic agents are be-ing studied for treatment of resistant gestational trophoblastic neoplasia

(GTN), according to Dr. Agnes Soriano-Es-trella, associate professor at the Department of Obstetrics and Gynecology, University of the Philippines.

“Chemotherapy in GTN has evolved to a point where patients are generally cured even in the presence of widespread metastasis,” added Estrella.

The first line of treatment for non-metastat-

ic low risk GTN is single agent chemotherapy using methotrexate. Patients with metastatic high-risk GTN are given the EMACO regimen which consists of etoposide, methotrexate, ac-tinomycin, cyclophosphamide and vincristine.

However, studies have shown that ap-proximately 25 percent of patients with GTN will be resistant to the EMACO regimen. Drug resistance is defined as three consecutive hu-man chorionic gonadotropin (hCG) values that have declined less than ten percent over two weeks, two consecutive increases in hCG values, or presence of new metastasis.

Estrella explained that the EP/EMA regi-

members of the Society of Gynecologic On-cologists of the Philippines, who performed MIS on patients with gynecologic malignan-cies. Ten patients were included in the study with a mean age of 46 years.

Seven patients underwent laparascopic hysterectomy with bilateral salphingoopho-rectomy (BSO) with lymph node dissection, two underwent laparascopic hysterectomy with BSO, and one underwent laparoscop-ic radical hysterectomy, BSO with bilateral lymph node dissection.

The operative time in many cases was long. Only one case had an operative time of less than 200 minutes, four were done under 300 minutes, two under 400 minutes, and three under 500 minutes. “The steep learning curve for laparascopic techniques may prolong operative time, and one way to

decrease this is by having a more experi-enced buddy while doing the surgery,” Si-cam said.

Despite this, blood loss in all the patients was minimal at less than 500 ml. Most pa-tients were discharged early.

Furthermore, there was no conversion to laparatomy and there were no intraoperative and postoperative complications recorded. In a study called LAP 2, the conversion rate reached up to 25.8 percent because of poor exposure, cancer requiring resection, bleed-ing and equipment failure. Old age, high BMI and metastatic disease also increased conver-sion rates.

The higher costs of laparascopy are com-pensated by lower costs for hospital stay, and may be reduced by reusable instruments, innovation and training, said Sicam.


men, which consists of etoposide and cispla-tin, with etoposide, methotrexate and dacti-nomycin, is the most widely used salvage regimen for resistant GTN. There is a high response rate to EP/EMA at 75 percent; how-ever, adverse effects such as myelosuppres-sion, hepatotoxicity and bleeding are com-mon, leading to dose reduction and treatment delay.

Several alternative regimens have been studied to replace the EP/EMA regimen, the most promising of which are the BEP regimen (bleomycin, etoposide, cisplatin) which has a response rate of 74 percent, and the TP/TE regimen (cisplatin, paclitaxel/cisplatin, etopo-side) which has a response rate of 67 percent. Adverse effects with these regimens are less common compared to the EP/EMA regimen.

The FA regimen (floxuridine, actinomycin), which is widely used in China and Japan, also has good remission rates. Patients resistant to the FA regimen are given FAEV (floxuridine, actinomycin, etoposide, vincristine) which

has a 60 percent response rate with low inci-dence of adverse effects.

Other regimens that were discussed in-clude the PVB (cisplatin, vincristine, bleo-mycin) and the ICE (ifosfamide, cisplatin, etoposide) regimens. These are no longer recommended due to bad response rates and serious adverse effects such as hematologic and renal toxicity.

New agents that are still to undergo studies include antimetabolites such as capecitabine and gemzitabine, methylating agents such as temzolamide, anti-angiogenesis compounds such as thalidomide, topoisomerase inhibi-tors such as irinotican, and anti-folate drugs such as pemetrexed.

“Of all the regimens we have now, TP/TE is the one that shows to be promising, aside from BEP which is the one being used by the trophoblastic disease center in Chicago,” con-cluded Estrella. More studies need to be con-ducted to provide stronger evidence for these salvage therapies.

What it should have been

A Symposium Highlights sponsored by Hi-Esai entitled “Clinical impact of cccDNA in the management of chronic hepatitis B” was published on page 17 of the August issue of Medical Tribune. The introduction should have stated that the forum was attended by family physicians instead of gastroenterologists, as written. We regret any confusion caused. –Ed.


Dr. Carol Tan

The identification of oncogenes and tu-mor suppressor genes involved in the pathogenesis of gestational tropho-

blastic diseases (GTD) can help physicians in prognosticating and treating patients, accord-ing to Dr. Laureen Mondragon, a fellow of the Philippine Society for the Study of Tropho-blastic Diseases.

“Although we are yet in the stage of iden-tifying the clinically relevant oncogenes and tumor suppressor genes, the discovery of these aberrantly expressed genes represents a critical milestone in the development of novel prognostic and therapeutic strategies,” said Mondragon.

Normal proliferation of trophoblastic cells is maintained by the balance between cellu-lar synthesis and cellular apoptosis. Proteins responsible for cell growth are encoded in protooncogenes while proteins responsible for apoptosis are encoded in tumor suppres-sor genes. When mutations occur, protoon-cogenes become activated into oncogenes, leading to overexpression of proteins for cell growth. Mutations in tumor suppressor genes result in insufficient production of proteins responsible for apoptosis. These mutations result in abnormal proliferation of malignant

cells, explained the speaker. Immunohistochemistry studies have been

used to detect dysregulated genes. Gene over-expression would lead to accumulation of protein products, causing stronger immunos-taining. The predicitive role of these genes in the malignant transformation of hydatidiform mole has been the focus of almost all studies.

Mondragon discussed many oncogenes which have been found to be related to the development of GTD. The most studied onco-gene is the c-erbB2, also known as her2-neu. Significantly stronger staining of c-erbB2 has been found in complete mole and choriocar-cinoma. Other oncogenes found in increased levels in complete mole and choriocarcinoma are the epidermal growth factor receptor, PAK1, PAK4, c-myc, Akt, c-erbB3, MdM2 and Ki67 genes. The expression of these genes in hydatidiform moles can serve as an index for prediction of malignant transformation.

Some tumor suppressor genes which may be of predictive value in the malignant trans-formation of hydatidiform moles include RasGAP, P21, Rb, P53, maspin, NP23, ASPP1, ASPP2, and c-ras genes.

Mondragon stated that identification of these genes in hydatidiform moles can guide the post-surgical management. Preventive measures such as chemoprophylaxis or pro-phylactic hysterectomy may be offered, to

CONFERENCE COVERAGE


Oncogenes help in GTD prognostication and treatment


reduce incidence of GTD. Appropriate ad-justment of chemotherapy protocol and fre-quency of monitoring may also be done.

The discovery of these genes also has im-plications on the chemotherapeutic drugs for GTD. The theory of oncogene addiction postulates that tumor proliferation depends upon the continued activity of a single domi-nant oncogene, such that inhibiting this gene would stop the neoplastic process. Drugs that specifically target the involved gene would potentially cause the death of malig-nant cells. However, this strategy requires novel methods to identify the specific onco-gene. Currently, no drugs have been discov-

ered that would specifically target genes in-volved in GTD.

The theory of tumor suppressor gene hy-persensitivity postulates that the reintroduc-tion of a tumor suppressor gene into a tumor lacking that gene can result in tumor regres-sion. However, due to technical difficulties, pharmacological research supporting this theory is still scanty.

“Contradictory results necessitates further research, including meta-analysis studies, to validate findings before these novel prog-nostic markers be incorporated in the man-agement strategy of GTD,” concluded Mon-dragon.

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Updates on cervical cancer screening

Dr. Nicolo L. Cabrera

Two years ago, 25 organizations met to establish guidelines for screening as-ymptomatic women for cervical cancer.

Among those involved were the American Society of Colposcopy and Cervical Pathol-ogy (ASCCP), the American Cancer Society (ACS) and the American Society of Clinical Pathology (ASCP) together with 22 other or-ganizations. The following year, cervical can-cer screening guidelines were released.

“So when our country got this report, we felt a little disconcerted because we’d like to know if these guidelines is [sic] applicable to our setting,” said obstetrician-gynecol-ogist and gynecologic oncologist Dr. Mary Christine F. Palma, an associate professor at the St. Luke’s College of Medicine.

Based on a meta-analysis in 1999, findings of atypical squamous cells of undetermined significance and low-grade squamous in-traepithelial lesion (LGSIL) as positive, Pap smear was found to have a sensitivity of 51 percent and a specificity of 98 percent.

However, according to a local study pub-lished in the Philippine Journal of Obstet-rics and Gynecology in 2001, the sensitivity of visual inspection with acetic acid (VIA) was 37.1 percent, exceeding that of cytol-ogy with spatula and swab (14.6 percent) or cervical brush (24.2 percent). Specificity for

VIA was lower at 90.7 percent compared to Pap smear using a spatula and swab (97.2 percent) and cervical brush (97 percent). Given the differences in reported sensitivi-ties and specificities of screening methods performed abroad and in the local setting, these guidelines may not be appropriate for the care of Filipino women.

The Philippine Society for Cervical Pa-thology and Colposcopy (PSCPC), an affili-ate of the Philippine Obstetrical and Gyne-cological Society, published clinical practice guidelines on cervical cancer screening in September 2012. The Grading of Recom-mendations, Assessment, Development and Evaluation system was used wherein evi-dence for each recommendation is rated as high quality, moderate, low or very low.

Pap smear collection tools and methodsCombined use of spatula and cyto-

brush was deemed superior to the use of a Cervex-Brush in adequacy of smears. In detecting abnormalities, the Cervex-Brush

CONFERENCE COVERAGE



was superior to spatula and the extended-tip spatula was superior to the spatula. The PSCPC thus strongly recommends based on low to moderate quality of evidence that combined use of spatula and cyto-brush as the most effective in obtaining sat-isfactory smears and collecting endocervi-cal cells. In low-resource settings, the Ayre’s spatula and saline-dipped cotton swab may be used

Instead of directly smearing the collected sample on a slide as in conventional cytolo-gy techniques, liquid-based cytology (LBC) involves dipping the collection tool with sample in a fluid that is then centrifuged to remove mucus and blood. This leaves a thin layer of cells. Data has shown no statistical difference in sensitivity favoring LBC over conventional cytology. If unsatisfactory smears are included in the pooled analysis, however, LBC was favored. The PSPC has thus strongly recommended based on low to moderate quality of evidence that it is not enough evidence to recommend or dis-courage LBC as an alternative provided that conventional cytology is satisfactory.

HPV DNA testingDr. Palma emphasized that while there

are many human papilloma virus (HPV) DNA tests available in the market, all rec-ommendations apply only to the United States Food and Drug Administration-ap-proved HPV DNA tests. Of the five FDA-approved tests in the market, only Digene Hybrid Capture 2 high-risk HPV DNA test is available in the Philippines.

HPV DNA testing does not suffer from interobserver variability and is thus more reproducible, equipping it with at least a theoretical advantage over Pap smear. Based

on three randomized controlled trials, it has better sensitivity but poorer specificity com-pared to conventional cytology. Accord-ing to an observational study in Colombia, the most cost-effective screening strategy appears to be HPV DNA testing every 3 or 5 years.

The PSPC says there is limited evidence to recommend for or against use of primary HPV DNA testing in asymptomatic women 30 years old and above as an alternative screening method for cervical cancer at this time.

However, cotesting or the combined use of HPV DNA testing and cytology as an alter-native tool to screen for cervical intraepithe-lial lesion 2 (CIN 2) was supported by high quality evidence. A meta-analysis pooled data from 63,046 patients ages 29 to 60 years who all underwent colposcopy. A statistically significant difference favoring cotesting for detection of CIN 2 was found. This strategy may increase length of interval of screening. The PSCPC therefore recommends the use of cotesting to detect CIN 2 among women age 30 years and older.

Visual inspection methodsInspection of the cervix with the naked

eye after application of 3 to 5 percent ace-tic acid by cotton swab or spray has been performed as an alternative screening test. Abnormal cells have increased nuclear pro-tein that coagulate and manifest as a well-defined, opaque acetowhite lesion or cause the transformation zone, external orifice or entire cervix to turn acetowhite.

A trial with 453,217 participants com-pared VIA with colposcopy and biopsy plus cryotherapy when indicated with no screen-ing. VIA resulted in a 25 percent reduction


in incidence and a 35 percent reduction in mortality. Thus the PSCPC recommends that in areas where conventional cytology is not available, VIA is an acceptable alter-native screening method for cervical CA in asymptomatic women.

Visual inspection with Lugol’s iodine (VILI) is a method that will allow mature superficial cells with glycogen to take up iodine and stain mahogany brown or black. Columnar, dysplas-tic and cancerous cells contain little glycogen and turn mustard. A meta-analysis showed that although cytology has a sensitivity of 59 percent compared to 91 percent of VILI, it has better specificity at 95 percent compared to 85 percent for VILI. Due to limited and poor qual-ity of evidence, the PSCPC opted not to recom-mend the use of VILI.

Screening schedulesAccording to the Philippine Demographic

and Health Survey in 2003 the mean age of sexual debut among women was 21.9 years old. A study on HPV infection in 608 students with a mean age 20 years, only 9 percent con-tinued to be infected at 24 months. Regression of LGSIL in patients aged 13 to 22 years old was 61 percent by 12 months and 91 percent by 36 months. To avoid the adverse events as-sociated with overtreatement, the PSCPC rec-

ommends screening 3 years after onset of vag-inal intercourse but not earlier than 21 years.

Highest HPV prevalence is found be-tween ages 20 to 24 years old and thus the PSPC finds that for women 21 to 29 years, cytology every 3 years is acceptable. How-ever, due to disease burden and low sen-sitivity of cytology in the local setting, ei-ther annual screening with conventional cytology or biennial screening with LBC is recommended.

ASCCP, ACS and ASCP recommend co-testing with HPV DNA and cytology every 5 years for women who are 30 to 65 year old and finds testing by cytology every 3 years acceptable. While the PSCPC says this is ac-ceptable as well, due to disease burden either annual conventional cytology or biennial LBC may also be performed.

ACS, ASCCP and ASCP recommend ces-sation of screening beyond the age of 65 years old. However due to high rate of cer-vical cancer in women older than 65 in our setting, the PSCPC still recommends annual conventional cytology, biennial LBC or co-testing every 5 years.

Screening for vaginal cancer in women after total hysterectomy for benign condi-tions except premalignant cervical lesions is not recommended.


FIGO guidelines emphasize holistic approach to palliative care

Dr. James Salisi

The holistic and multidisciplinary ap-proach to the care of terminally ill patients is at the heart of the new In-

ternational Federation of Gynecology and Obstetrics (FIGO) guidelines for palliative care in developing countries according to Dr. Fidelis Manalo, head of The Medical City, Section of Hospice and Palliative Care of the Cancer Center.

“Our tagline is optimizing the quality of life. In a sense, the existence of the subspe-cialty palliative care has somehow solved the

problem of our terminally ill patients suffer-ing so much pain from contemplating the possibility of requesting euthanasia,” Manalo said.

Dealing with terminally ill patients may re-quire referral to specialist palliative care and the indications for which are: when there is no longer a prospect of cure, when death is an-ticipated in foreseeable time, when the focus of care is the alleviation of difficult and dis-tressing symptoms, and when maintenance of comfort and quality of life is the primary intent of management.

Most patients who should be referred to a palliative care specialist are those with ad-

TREATMENT FOCUS: PALLIATIVE CARE


vanced cancer and with an expected prog-nosis of 12 months or less. They may already have metastasis to the bone, lung or liver and with kidney or liver failure, obstructive urop-athy, or with cardiac complications.

“When you refer your patients to a pallia-tive care specialist, it would be good to spec-ify exactly what kind of assistance you need from us. Are you just asking us for pain man-agement or control of distressing symptoms? Or you want end of life care or the family is having a difficult time coping so you need assistance with grief therapy and bereave-ment support? Or you would like us to visit the patient home? And as far as psychosocial support is concerned, we have been trained to conduct individual and family counseling and grief therapy. For spiritual care we are prepared for that as well but we ask assistance from the chaplain or the pastors depending on the preference of our patient,” Manalo ex-plained.

Terminally ill patients such as those suffer-ing from cancer and AIDS experience a multi-tude of symptoms but the most common and distressing of them is pain such that it has be-come one of the main focus of palliative care specialists. Understanding the concept of to-tal pain is a prerequisite for pain control ac-cording to Manalo.

One has to look at the complex and inter-related dimensions of pain for total pain care, a concept advanced by UK specialist Dane Cicely Saunders. The physical, psychological, social and spiritual dimensions of pain inter-act and must be adequately addressed to help control the symptoms of pain.

Palliative care specialists differ from pain specialists in the fundamental approach to pain treatment, the former is concerned with the dimensions of pain whereas the latter is

specialized in addressing physical pain ac-cording to Manalo.

Identifying the cause of pain is very impor-tant. Assessment starts by asking about the provocative and palliative factors, quality, radi-ation, severity, and timing of pain. Understand-ing the difference between nociceptive pain and neuropathic pain must be emphasized because the pharmacology differs for each.

The World Health Organization (WHO) classifies pain into mild, moderate and se-vere pain according to a visual analog scale (VAS). The WHO pain ladder provides guidelines on the pharmacologic treatment for each rung of the ladder. For example, paracetamol and NSAIDs are recommended for mild pain or VAS score of 1 to 4, trama-dol for moderate pain or VAS score of 5 to 7, and morphine for severe pain or VAS score of 8 to 10.

Pharmacologic treatment is preferably ad-ministered by mouth, by the clock and by the ladder. Oral route is the simplest and safest route possible especially for patients who are brought home. Giving the analgesics regu-larly without waiting for pain to recur helps adequate pain control. And when pain is not controlled, the WHO recommends moving up the ladder by providing stronger analge-sics such as morphine.

Morphine is the only strong opioid anal-gesic that can be administered per os or per rectum. It has the same bioavailability in ei-ther route making it a good choice of analge-sic for terminally ill patients who are sent to and are cared for at home, and are unable to take any drug by mouth. In spite of this and the effectiveness of morphine in controlling pain, myths and misconceptions limit its use in many terminally ill patients.

Addiction to morphine is one such myth


and has been found to be extremely rare. Fur-thermore, physical dependence and the de-velopment of a “withdrawal syndrome” on abrupt dosage reduction is an intrinsic prop-erty of opioid drugs but is not important clin-ically as long as patients are instructed not to discontinue medications abruptly.

According to Manalo, tolerance to mor-phine’s analgesic effects is not a problem since there is no ceiling amount of morphine that can be used safely and there is no reason to wait until the pain is intolerable. Fear of re-spiratory depression is unfounded because clinically significant respiratory depression does not occur in cancer patients when mor-phine dosage is titrated to the patient’s pain. Tailoring the dosage to the pain of the patient is the key to dispelling the other myth that morphine turns patients into unresponsive zombies.

Although analgesics may provide ad-equate pain control for prolonged periods, breakthrough pain or intermittent exacerba-tions of pain or related to activity still occurs. This phenomenon is addressed by providing for rescue doses which is given as needed ev-ery one or two hours.

Morphine prescription must always be ac-companied with a prescription for laxative because constipation is one of the most com-mon side effects of morphine that persists. In contrast, other side effects of morphine im-prove with time. These are nausea and vom-iting which can be relieved by medicines, drowsiness, confusion, dizziness, dry mouth, pruritus, myoclonus, miosis, acute urinary re-

tention and sweating.Respiratory depression is usually not clini-

cally important and tolerance to this develops rapidly. It is only in severe respiratory depres-sion (respiratory rate < 8-10/min) accompa-nied by depressed consciousness that nalox-one 0.4 mg diluted in 10 ml saline is given via slow intravenous infusion.

To take care of the dying means dealing with concerns that include communication, site of care, resuscitation, nutrition and flu-ids, cessation of oral medications, adequacy of analgesia, management of distress and un-relieved symptoms, noisy breathing, care is-sues, and duties after patient death.

According to Manalo there is always some-thing that can be done even during these last hours such that the words “There is noth-ing more that can be done” does not exist in the lexicon of palliative medicine. In the last 24 to 72 hours of life, a dying patient may experience pain, breathlessness, delirium and terminal secretions. These symptoms can be managed by giving opioids for pain and breathlessness, antipsychotic medications for delirium, and anticholinergics for terminal secretions.

Manalo also emphasized the importance of psychosocial support and spiritual care for the dying because they can counter the feel-ings of depression and anxiety brought about by the imminence of death. At the moment of the patient’s death, grief therapy and bereave-ment support help the patient’s family to accept the death and move on with their lives.


PHA celebrates World Heart Day

The Philippine Heart Association (PHA) and its local chapters led the Philippine celebration of the annual World Heart Day (WHD) 2013 with

the theme “Take the Road to a Healthy Heart.” The event aims to promote healthy lifestyle, longevity and quality of life among the general public.

According to PHA secretary Dr. Alex Junia, part of the WHD celebration, the PHA Heart Fair conducted at the Met-ro Manila Development Authority (MMDA) headquarters. The event subjected the MMDA field employees to cardiol-ogy consultation and risk factor screening including blood pressure, cholesterol and sugar determination, ECG and ankle-brachial index. The data collected from the event was included in the PHA Heart Fair risk factor screening registry. The patients with risk factors are advised to follow-up during the Heart Month Fair in February.

MARKET WATCH

DHA improves reading ability and memory performance

In the recent “Impact of Nutrition on Children’s Health and Performance” press conference, Dr. Hua Jing, nutrition science & advocacy manager for DSM Nu-

tritional Products Asia Pacific, stressed the importance of vitamins A, C, D, E and DHA as nutrients for optimal im-mune health of children.

The event also cited the findings of a new observational study funded by a grant from DSM Nutritional Products and conducted at the University of Oxford in the United Kingdom which found that increased dietary intake of omega-3s is associated with better reading, working mem-ory and behavior in children.

The study is part of the DHA Oxford Learning Behavior randomized, placebo-controlled trial which found that children with low reading levels have significantly enhanced reading performance and behaviour after an increase in dietary intake of algal DHA.

L-R: Dr. Helen Ong-Garcia, PHA director; Dr. Eugene Reyes, PHA president; Dr. Alex Junia, PHA secretary

Dr. Hua Jing, nutrition science & advocacy manager for DSM Nutritional Products Asia Pacific


Abbott launches bioresorbable vascular scaffold

Global healthcare company Abbott introduces a revolu-tionary treatment for coronary artery disease (CAD) in the Philippines through the world’s first drug elut-

ing fully bioresorbable vascular scaffold called Absorb.Absorb is a unique “disappearing” device for the treatment

of CAD. It is a small mesh tube designed to open a blocked heart vessel in the same way as a traditional metallic stent, and then dissolves naturally over time. This allows the blood vessel to resume its natural function and movement thereby providing long-term benefit for patients.

“Today, Abbott is introducing Absorb, an innovation that highlights Abbott’s focus on improving the lives of Filipinos through the development of groundbreaking medi-cal technologies,” said Anil Suri, Abbott Vascular general manager for South East Asia.

PDS advocates public skin safety

The Philippine College of Physicians (PCP) and the Philip-pine Dermatological Society (PDS) recently held a health forum called “Procedures Gone Wrong“ which is part of

the society’s skin safety campaign which discussed the growing number of complications resulting from blotched procedures.

Procedures such as skin peels and laser treatments should be done by a dermatologist who has undergone proper specialty training in order to ensure that the patient will receive an effec-tive and safe medical, surgical and cosmetic treatments for skin, hair and nails.

The PDS is the only medical society for dermatology that is recognized by the Philippine Medical Association, the PCP and the Philippine Health Insurance Corporation. It is also a member of the League of ASEAN Dermatological Societies and the International League of Dermatological Societies..

L-R: Dr. Rosalina Nadela PDS president; Dr. Daisy Ismael, PDS vice president; Dr. Teresita Gabriel, PDS immediate past president

MARKET WATCH


SC Johnson initiates campaign against dengue

In keeping with its commitment to protect Filipino families against dengue mosquitoes, SC Johnson Phil-ippines launched the “Mission: Zero Dengue Mosqui-

toes” at the Mind Museum in Bonifacio Global City, Taguig. The advocacy encourages families to take vigilant steps when it comes to dengue mosquito prevention.

“We need to help raise awareness to the fact dengue mos-quitoes are a real threat – it just takes one bite from dengue carrying mosquitoes to become an unfortunate victim,” said SC Johnson Philippines general manger Floyd Pedernal.

Guest of honor during the event was Department of Health Assistant Secretary Dr. Enrique Tayag. He talked about the importance of searching for mosquitoes and destroying breeding places, observing self-protection measures, seeking early consultation and saying no to indiscriminate fogging.

MARKET WATCH

The Medical City acquires new retinal camera

Newborn eye imaging is now available at The Medical City using the newly acquired Ret-cam 3, a fully-integrated wide-field digital

retinal camera used for the early detection of retinopa-thy of prematurity (ROP) and other potentially harmful eye disorders.

“ROP is a potentially blinding condition in preterm infants but preventable as long as the problem is detected and treated early,” says Dr. Pauline Santiago, pediatric ophthalmologist at The Medical City.

The Retcam3 can also be used for normal newborns to document baseline evaluations during universal vision screening. Other patients who may benefit from the Retcam3 include those with congenital anomalies, ocular tumors and congenital glaucoma. Adults with diabetic retinopathies and other retinal diseases can be imaged using this technology.

L-R: Lyn Ching-Pascua, event’s host; Dr. Enrique Tayag, Department of Health assistant secretary; Floyd Pedernal, SC Johnson Philippines general manager; Abbie Ng-Reyes, SC Johnson Philippines marketing manager

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25 October 2013 Conference Coverage

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

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

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

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-tomatic VTE patients from 39 countries to re-ceive double-blind treatment with either edox-aban 60 mg once daily or 30 mg once daily (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 symptom-atic VTE, which occurred in 130 patients in the edoxaban group (3.2 percent) and 146 patients in the warfarin group (3.5 percent) [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 edox-aban group and 423 patients (10.3 percent) 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 edox-

aban) and hoped for an improvement in safety, and that’s what we got. But what is more im-portant with this new anticoagulant is a dif-ferent pattern of bleeding,” said the researcher Dr. Harry Buller of the Academic Medical Cen-ter in Amsterdam, The Netherlands.

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 bleed-ing in the two groups, respectively. A total of 938 patients with PE had right ventricular dys-function, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels; the rate of recurrent VTE in this subgroup was 3.3 percent in the edoxaban group and 6.2 per-cent 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 Kon-stantinides.


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



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.

29 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.

30 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.

35 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

36 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, doc-tors often fail to order the right laboratory tests. There is a reluctance to treat infection until 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.

37 October 2013 Humor

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

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

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

“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)Sep13_FINAL.indd 25 8/29/13 4:18 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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