Famotidine protects against aspirin GI damage

Medical Tribune September 2009 P6
David Brill

Histamine H2-receptor antagonists can limit the gastrointestinal side effects of low-dose aspirin and could offer a viable alternative to proton-pump inhibitors (PPIs), a recent study suggests.

The randomized, phase III FAMOUS* trial found that 12 weeks of treatment with famotidine significantly reduced the incidence of gastric ulcers, duodenal ulcers and erosive esophagitis compared to placebo.

The study, published in The Lancet, included 404 adults who were taking low-dose aspirin and had no ulcers or esophagitis at baseline. [2009;374:119-25]

Aspirin use continues to soar worldwide, yet there are few options for prevention of associated gastrointestinal complications. PPIs are known to be effective but have faced safety concerns – particularly over the risk of adverse interactions with clopidogrel.

“There is little doubt that aspirin and other anti-clotting drugs are very useful in the prevention of heart, brain, and other vascular diseases, hence their increasing use worldwide. Patients on such drugs should continue using them as advised by their family doctors or hospital specialists,” said the study’s lead author Dr. Ali Taha, of the University of Glasgow, UK.

“However, everybody should be aware that aspirin use can also be associated with a variety of gastrointestinal or digestive system problems, which sometimes can be serious. The results of this research widen the options for the prevention of such problems, particularly when more than one clotting drug is required,” he said.

Twelve weeks after randomization, 7 of 204 patients on famotidine had developed gastric ulcers, compared to 30 of 200 taking placebo (3.4 percent versus 15 percent; odds ratio 0.2; P=0.0002).

Just one patient developed a duodenal ulcer on famotidine, compared to 17 on placebo (0.5 percent versus 8.5 percent; OR 0.05; P=0.0045). Nine and 38 patients developed erosive esophagitis in the famotidine and placebo groups, respectively (4.4 percent versus 19 percent; OR 0.2; P<0.0001).>

Diabetic children often oblivious to hypoglycemia

Medical Tribune September 2009 P7

David Brill

Almost one in three children with type 1 diabetes cannot tell when their blood sugar dips low, and could face serious consequences from slipping into hypoglycemia, a study suggests.

A survey of 656 Australian children found that 29 percent had impaired awareness of hypoglycemia – a deficit in the adrenergic symptoms that ordinarily serve as a warning sign.

Children with impaired awareness were over twice as likely to have experienced a severe hypoglycemic episode in the previous year, involving loss of consciousness or seizure.

The effect was even more pronounced in the very young: children under 6 with impaired awareness were almost six times as likely to have had a serious episode.

Senior author Dr. Tim Jones said that hypoglycemia unawareness has traditionally been considered to be an adult problem, but urged physicians to step up screening among younger patients in light of the new findings.

“Ask the child: ‘do you get your usual symptoms? Do you still feel shaky when you go low? Or is the first thing you notice about being low that you find a low reading when you test yourself?’ It only takes a minute if you know what to ask,” he said.

Hypoglycemia unawareness appears to be caused by hypoglycemia itself, with repeated episodes successively dampening the adrenergic response, added Jones, head of the department of endocrinology and diabetes at Princess Margaret Hospital for Children, Perth, Australia.

The good news, however, is that the problem seems to some extent to be reversible, he said. Once impaired awareness is identified, the patient should meticulously ensure that they avoid hypoglycemia for around a month, and the warning symptoms may begin to return.

Further testing can also be carried out – particularly using continuous glucose monitoring systems to track a child’s blood sugar over time. This can help to identify and avoid episodes of hypoglycemia, regardless of whether the child is aware of it.

The study involved type 1 diabetic children aged from 6 months to 19 years. All were taking insulin – ranging from twice-daily injections to four times a day with insulin analogs and subcutaneous infusion therapy. [Diabetes Care 2009 Jul 8; Epub ahead of print]

A total of 161 hypoglycemic episodes had occurred in the year leading up to the study. The rate of episodes among children with impaired awareness was 37.1 episodes per 100 patient-years, compared to 19.3 per 100 patient-years in children with normal awareness.

Patients with impaired hypoglycemia awareness tended to be younger, had an earlier onset of diabetes, and had lower mean HbA1C levels since diabetes onset.

MIMS.com hailed for excellence in technology

Medical Tribune September 2009 P7
David Brill

Asia’s leading online drug database has been lauded for its innovative approach to digital technology at the recent Asian Multimedia Publishing Awards (AMPA).

MIMS.com – used by over 250,000 doctors and pharmacists in Asia – was named a runner-up in the ‘Use of Digital Technology’ category at the AMPA ceremony in Manila.

The award marks the 40th year of the directory, which is now used in 15 countries across the Asia-Pacific region and receives over 300,000 unique visitors each month. It was chosen out of 74 entries from 9 different countries.

Mr. Ben Yeo, Chief Executive Officer at CMPMedica Asia, publishers of MIMS and Medical Tribune, said: “This award commemorates the achievement that MIMS has attained in Asia at its 40th anniversary, further underscoring CMPMedica’s leading position in delivering drug information and scientific publishing in Asia. Our teams are keeping up their momentum in achieving the highest standards in the industry.”

The award makes CMPMedica the most highly decorated healthcare publisher at the Asian Publishing Convention, having previously picked up an award in 2007.

MIMS.com is used by doctors, pharmacists and healthcare professionals to access comprehensive drug information such as dosage, indications, safety and interactions. It is accessible online, and integrated within some hospital formularies.

Aspirin trial seeks to tackle colorectal cancer in Asia

Medical Tribune September 2009 P8
David Brill

A major new trial is set to launch in Asia to establish whether aspirin can prevent recurrence of colorectal cancer.

The ASCOLT study will involve over 2,000 patients from centers across Southeast Asia, China and India, and will be led jointly by the National Cancer Centre Singapore (NCCS) and the University of Oxford, UK.

Patients will be randomized to aspirin (200mg/day) or placebo for 3 years, following surgery and adjuvant chemotherapy for high-risk stage II and III colorectal cancer. The primary endpoint will be disease-free survival over 5 years of follow-up.

A growing body of evidence suggests that aspirin is effective for primary prevention of colorectal cancer, but ASCOLT is thought to be the first prospective clinical study to investigate the drug in the adjuvant setting after chemotherapy.

If positive, the results could have a huge impact on the treatment of colorectal cancer in Asia and worldwide, according to Dr. Toh Han Chong, head of the department of medical oncology at NCCS and one of the ASCOLT lead investigators.

“It’s incredible how many people you could save from relapse with the addition of aspirin if this study is positive. If you go to a village in India you can’t really give costly [monoclonal antibodies], so there is compelling power of social responsibility here,” he told Medical Tribune.

“We have undervalued the power of simple drugs. It’s time to redress the balance – change the paradigm and go cheap.”

Recruitment for ASCOLT is already underway, with centers confirmed in Singapore, Hong Kong, Jakarta and several cities in India.

More study centers are still needed in order to reach the target of 2,000 patients however said Toh, who extended the invite to all Asian delegates at the recent ‘Best of ASCO’ conference in Singapore.

“It’s a drug trial that cannot be done in the West. Many people over the age of 50 in the US are popping aspirin over the counter for heart conditions or stroke prevention,” he said. “Fewer people are on aspirin in Asia. That’s why it’s a perfect study to do here.”

Colorectal cancer is the second leading cause of cancer death in North America, Europe and Australasia according to a 2007 global report from the American Cancer Society. In Southeast Asia, it is the third biggest killer (behind liver and lung cancer) – responsible for 7.9 percent of cancer deaths.

In Singapore, colorectal cancer is the leading cancer among men and the second most common among women, data from the national cancer registry show.

A recent study found that regular use of aspirin after a diagnosis of colorectal cancer was associated with lower overall mortality (hazard ratio [HR] 0.79; 95% CI 0.53 – 0.95) and cancer-specific mortality (HR 0.71; 0.53 – 0.95), after a median of 11.8 years of follow-up. [JAMA 2009;302(6):649-58]

A 2007 paper, meanwhile, reported that taking 300 mg/day or more of aspirin for 5 years was effective for primary prevention of colorectal cancer, according to pooled data from two large randomized trials (HR 0.74; 95% CI 0.56 – 0.97; P=0.02). [Lancet 2007;369(9573):1603-13] Earlier trials have also shown that aspirin can prevent colorectal adenomas – the precursors to cancer – both in patients with, and without, a prior history of cancer. [N Engl J Med 2003;348(10):883-90; N Engl J Med 2003;348(10):891-9]

“Why should oncologists do an aspirin trial? Because the epidemiological data is strong, the data on polyp reduction is very convincing, the retrospective observational studies are very compelling and remarkable in terms of hazard ratios, and the data preclinically is scientifically robust,” added Toh.

ASCO award set to boost Asian cancer research

Medical Tribune September 2009 P8
David Brill

A Singapore oncologist has become the first Singaporean, and one of the first Asia-based recipients, to pick up a prestigious research award from the American Society of Clinical Oncology (ASCO).

Dr. Daniel Tan of the National Cancer Centre Singapore (NCCS) will receive a US$50,000 grant as part of the Young Investigator Award, bestowed by the ASCO cancer foundation.

The money will help fund his research on the molecular mechanisms of tyrosine kinase inhibitors (TKIs) in nasopharyngeal cancer. The work aims to understand why some patients respond better to targeted therapies than others – so as to improve patient selection and avoid unnecessary exposure to ineffective treatment and side effects.

“One of the challenges with any of these new-generation drugs is to find out how we can use them better – to get the right drug to the right patient. Understanding the reasons for response and resistance can also allow us to develop much more effective treatment strategies that hopefully translate to improved survival,” said Tan, who will work alongside his mentor Professor Teh Bin Tean, director of the NCCS-VARI laboratory – a joint project with the Michigan-based Van Andel Research Institute.

Tan’s ASCO proposal was borne out of clinical observations from a phase II trial of pazopanib, which saw a subset of nasopharyngeal cancer patients respond better to therapy than others. This trial is currently ongoing under principal investigator Dr. Darren Lim, a senior consultant at NCCS specializing in thoracic and head and neck cancers.

The goal now is to understand which proteins are targeted by the drug, and how this differs between patients and tumor types. Tan’s work will be done largely in a series of co-culture experiments and mouse xenograft models – allowing detailed analysis of how the drug affects each cellular compartment within a tumor.

Tan is also aiming to secure more local funding for his research, and hopes in the long term to help establish a comprehensive drug development program, which would also provide patients with access to novel therapeutic agents.

He added that he was pleased to receive the award, and is especially encouraged that the proposal was deemed to have sufficient scientific merit for further study.

“It is heartening to know that one’s ideas are being taken seriously by a highly regarded scientific body. Furthermore, the award is rarely given out to institutions outside of America, so it’s a nice endorsement of the research infrastructure at NCCS,” he said.

Cetuximab offers hope for Asian lung cancer patients

Medical Tribune September 2009 P8
David Brill

A novel lung cancer therapy could be of particular benefit to Asian patients, results of a recent trial suggest.

The international FLEX* study reported that adding the monoclonal antibody cetuximab to chemotherapy prolonged survival of advanced lung cancer patients from 10.1 months to 11.3 months.

Further analysis revealed, however, that Asians treated with the drug survived for a median of 19.5 months, whereas non-Asians survived only 9.6 months.

The randomized trial involved 1,125 patients – 121 of whom were from Asian centers (predominantly in Hong Kong, Taiwan, Singapore and South Korea). [Lancet 2009;373(9674):1525-31]

There are several possible explanations for the ethnic discrepancy but also questions that remain unanswered, according to Professor Kenneth O’Byrne, one of the FLEX investigators, who spoke to Medical Tribune during the recent ‘Best of ASCO’ conference in Singapore.

Asian lung cancer patients are more likely to be women, non-smokers and have adenocarcinomas than non-Asian patients – all groups which tend to survive longer, he said. Moreover, epidermal growth factor receptor (EGFR) mutations are more common among Asians – a characteristic which not only improves prognosis in itself, but also makes patients eligible for first-line EGFR tyrosine kinase inhibitors which can further improve outcomes.

“So there is a combination of reasons as to why but it’s not just that – there may be some intrinsic sensitivity to treatment here that’s not present in the West,” said O’Byrne, adding that further study is needed to better understand these biological similarities and differences.

Cetuximab is presently licensed for use only in colorectal and head and neck cancers. An application for lung cancer licensing was recently rejected by the European Medicines Agency (EMEA), but is currently under appeal from the manufacturer, Merck Serono.

The verdict has also come as a surprise to many experts in the field and will face “a strong challenge,” said O’Byrne, a consultant medical oncologist at St. James’s Hospital and a clinical professor at Trinity College, Dublin, Ireland. The FLEX trial was published before the EMEA decision, with investigators concluding that cetuximab can be considered as standard first-line therapy for all patients with advanced non-small cell lung cancer (NSCLC).

“Cetuximab is the first drug to show a survival benefit in all histological types: adenocarcinoma, squamous carcinoma – across the board. Secondly, the toxicities are all very predictable – we know how to manage them and they’re straightforward. Thirdly, not only was the FLEX trial positive but when you take in all the other trials together … as a collective they show a positive result,” said O’Byrne. He added that US National Comprehensive Cancer Network guidelines already recommend that the drug be considered for lung cancer patients, and that many oncologists in Europe have begun off-label usage.

O’Byrne acknowledged that cetuximab therapy would be costly, but noted that around half of patients display a strong predictive marker in the form of a skin rash, which develops after one round of chemotherapy. These patients tend to survive for around an extra 5 months, which may justify the cost, he said. More work is needed to confirm whether cetuximab offers any benefit for those who do not develop a rash, but it appears likely that therapy could be discontinued after one cycle in these patients, he said.

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*FLEX: First-Line Erbitux in Lung Cancer

Low-salt diet offers key to treating stubborn high blood pressure

Medical Tribune September 2009 P9

David Brill

Cutting down on salt can dramatically lower blood pressure (BP) in patients with resistant hypertension and could offer a genuine alternative to ramping up medications, a study suggests.

American researchers found that BP dropped by 22.7/9.1 mmHg after a week of a low-salt diet compared to a high-salt diet – a magnitude roughly equivalent to adding two more drugs.

This drop came on a background of heavy medication: patients in the study were already taking an average of 3.4 antihypertensive drugs per day.

Although small – just 12 patients took part – the study has been greeted enthusiastically by experts, who are calling for a renewed focus on salt reduction for patients whose BP remains uncontrolled.

Leading hypertension expert Dr. Lawrence Appel described the results as “striking,” particularly given that all study patients were taking hydrochlorothiazide. This volume-reducing therapy might have been expected to attenuate the effects of a low-salt diet, he wrote in an accompanying editorial. [Hypertension 2009 Jul 20; Epub ahead of print]

“The data presented … strongly suggest that persons with resistant hypertension are extremely sensitive to the BP-lowering effects of sodium reduction. The observed reductions in BP were huge – roughly equivalent to adding 2 antihypertensive medications,” wrote Appel, a Professor of Medicine at Johns Hopkins University, Baltimore, US.

“Although clinicians commonly focus on the next drug (e.g. aldosterone blocking therapy) and sometimes a device (e.g. Rheos systems that stimulate carotid baroreceptors), a renewed and aggressive emphasis on lifestyle modification, specifically sodium reduction, is warranted in patients with resistant hypertension and uncontrolled BP.”

Dr. Low Lip Ping, chairman emeritus of the Singapore Heart Foundation and founding president of the Singapore Hypertension Society, said: “This small but interesting study showed that among patients with medication-resistant hypertension, salt restriction has a substantial impact on lowering blood pressure by reducing intravascular fluid retention and improving vascular function.”

“Dietary salt restriction, ideally to less than 100 mEq of sodium/24 hours, should be recommended for all patients with resistant hypertension. With a low-salt diet these patients could have their blood pressure controlled with fewer medications,” said Low, also a private practitioner at the Low Cardiology Clinic, Mount Elizabeth Medical Center.

The study is the first to demonstrate that the benefits of salt reduction extend beyond patients with just mild or moderate hypertension, according to lead author Dr. Eduardo Pimenta.

“A low-salt diet is beneficial for all patients with hypertension but in patients with resistant hypertension the effect is stronger. Before prescribing another antihypertensive medication, doctors should spend more time with their patients explaining about low-salt diets and, if possible, refer the patient to a nutritionist,” said Pimenta, now a clinical research fellow at the Endocrine Hypertension Research Center, University of Queensland School of Medicine, Brisbane, Australia. The study itself was undertaken at the University of Alabama at Birmingham, US.

Study subjects had a mean office BP of 145.8/83.9 mmHg at baseline. All were randomized to either a high- or low-salt diet for 1 week, then a 2-week washout period, followed by a final week of the opposite diet. The low- and high-salt diets provided 50 and 250 mmol of sodium per day, respectively. [Hypertension 2009 Jul 20; Epub ahead of print]

All measures of BP were reduced by the low-salt diet as compared to the high-salt diet: systolic and diastolic; office and ambulatory; and daytime, nighttime and 24-hour.

The Singapore Heart Foundation and Hypertension Society have already been promoting the message about salt reduction – especially in light of National Nutrition Survey data suggesting that nine out of 10 Singaporeans exceed the recommended sodium intake of 2,000 mg/day.

In a joint statement to mark World Hypertension Day in May this year, the societies urged “all residents in Singapore to reduce their salt intake to reduce their risk of hypertension and hypertension-related diseases.” They also called on chefs and restaurants to lower the salt content of foods, and to avoid routinely providing soy sauce unless requested by the customer.