Study heralds dawn of the cardiovascular polypill

Medical Tribune May 2009 P1&6

David Brill

A five-drug combination tablet could cut the risk of coronary heart disease by more than 60 percent and nearly halve the risk of stroke, results of the first major ‘polypill’ trial suggest.

The Indian Polycap Study (TIPS) found that combining the medications did not hinder their potency – offering effective blood pressure (BP) and lipid control with a simple once-daily capsule.

The study paves the way for further trials to see whether the pill improves clinical outcomes on a wide scale, say the researchers.

The Polycap formulation used in TIPS contains low doses of aspirin (100 mg), simvastatin (20 mg), thiazide (12.5 mg), atenolol (50 mg) and ramipril (5 mg).

It was tested in a double-blind randomized controlled trial of 2,053 people aged 45 to 80 who had one existing risk factor but no history of cardiovascular disease (CVD).

Lead researcher Dr. Salim Yusuf stressed the need for further trials but called the potential to lower CVD risk with a single pill “a huge step in the management of patients.” He said that the Polycap has “definite” applicability for secondary prevention, and would lower costs and improve compliance in CVD patients who are already taking the individual drugs.

“The big question … is whether you take the whole world at large, over a certain age group, don’t measure anything, and then give them all a polypill. I will withhold judgment on whether that’s the right thing to do or not right now,” he said at a press conference.

TIPS was presented at the 58th Annual Scientific Session of the American College of Cardiology and published online in The Lancet. [2009 Mar 30; Epub ahead of print]

The study, carried out at 50 centers in India, comprised nine groups: 412 patients took the Polycap, while around 200 each were assigned to one of eight different permutations of the drugs alone and in combination.

After 12 weeks of Polycap therapy, mean systolic and diastolic BPs decreased by 7.4 mmHg and 5.6 mmHg, respectively, as compared to people taking no BP-lowering drugs. This magnitude was similar to that achieved with three BP-lowering drugs, either with or without aspirin.

LDL cholesterol was reduced by 0.70 mmol/L in Polycap users – a slightly lesser reduction than with simvastatin alone (0.83 mmol/L; P=0.04) but still highly significant compared to people who did not take a statin (P less than 0.0001).

The Polycap, manufactured by Cadila Pharmaceuticals, India, was well tolerated: discontinuation rates were similar to other treatment groups and largely attributable to social reasons.

The projected risk reductions for taking the Polycap were 62 percent for coronary heart disease events and 48 percent for stroke. These were calculated using the methods of Drs. Wald and Law, who first proposed the polypill concept in a seminal British Medical Journal paper. [2003 Jun 28;326(7404):1419]

Yusuf, director of the Population Health Research Institute at McMaster University, Canada, said that clinical event-driven trials of polypills could be published within 6 months to a year.

He acknowledged concerns that polypills could promote the wrong message if marketed incorrectly, stressing that lifestyle modification is the “the crux and the fundamental basis of CVD prevention.” He rejected, however, the suggestion that widespread medication could be a difficult idea to promote.

“There’s something inherently repulsive to most of us to say we’re medicalizing the whole population. Just think of the millions of people in the world taking multivitamins with no evidence.

“The concept of taking a pill to improve your health is really not new – it is embedded in most cultures, whether it is Asian, Western or wherever else,” he said.

Guidelines grow but offer opinions, not evidence

Medical Tribune May 2009 P4
David Brill

The complexity of cardiology guidelines is growing but new recommendations are often unsupported by scientific evidence, a recent study has found.

The analysis of American College of Cardiology (ACC) / American Heart Association (AHA) clinical practice guidelines shows that the number of recommendations has risen considerably in the past 24 years.

The balance of recommendations, however, has shifted towards ‘class II’ – those that reflect a conflict of evidence or a divergence of opinion. The proportion of class I recommendations has remained largely unchanged.

Just 11 percent of all recommendations in the most recent guidelines are based on evidence level A. Almost half are based on level C – the lowest level – comprising expert opinion, case studies or standards of care.

The study, published in the Journal of the American Medical Association, was accompanied by an editorial calling for guidelines to be abolished unless the present system can be overhauled. [2009;301(8):831-41; 2009;301(8):868-9]

“Unfortunately, too many current guidelines have become marketing and opinion-based pieces, delivering directive rather than assistive statements,” wrote Drs. Terrence Shaneyfelt and Robert Centor from the University of Alabama, US.

“If all that can be produced are biased, minimally applicable consensus statements, perhaps guidelines should be avoided completely. Unless there is evidence of appropriate changes in the guideline process, clinicians and policy makers must reject calls for adherence to guidelines.”

Dr. Pierluigi Tricoci, lead author of the study, was more cautious in his response – acknowledging room for improvement with the format of guidelines but saying that they remain “important and useful” documents.

“The main message of our paper is that in cardiology, which we believe is one of the most advanced and evidence-based fields in medicine, we have a huge gap in knowledge,” said Tricoci, a cardiologist at Duke University, US. “In most situations that we find in clinical practice we don’t have enough supporting evidence that helps us make clinical decisions on what’s best for the patient.

“We hope that [this study] gives out the right message because we are not in a very good situation right now. Institutions and the government have to understand that there is a lot of research that is not well funded … we want to improve our current situation to close those gaps.”
Tricoci and colleagues reviewed 53 separate guidelines covering 22 topics. Excluding those which were never revised or updated, the number of recommendations has risen by 48 percent from the first to the latest editions of each document. The total number of recommendations rose from 1,330 in 1984 to 1,973 in 2008.

The levels of evidence vary widely between diseases. More than 20 percent of recommendations in heart failure and ST-segment elevation myocardial infarction guidelines, for example, have evidence level A. For valvular heart disease guidelines, however, just one of 320 recommendations is based on level A.

The ACC and the AHA welcomed the study’s findings in a joint statement, calling it a “valuable and important message” about the need to invest more in research.

“There are gaps in the evidence base for patient care, gaps that could be eliminated if more clinical research were funded, especially comparative effectiveness research that specifically compares one kind of diagnostic procedure or treatment with another,” said ACC president Dr. Douglas Weaver.

“Improving our evidence base can lead to even greater improvements in treatment and in saving lives.”

Statin ‘reloading’ improves PCI outcomes

Medical Tribune May 2009 P8

David Brill

Topping up a patient’s statin levels before percutaneous coronary intervention (PCI) could improve outcomes in long-term statin users, a new study suggests.

The ARMYDA*-RECAPTURE trial found that “reloading” with high-dose atorvastatin before PCI reduced the relative risk of major adverse cardiac events by 48 percent at 30-day follow-up.

Treating seventeen patients with this strategy would prevent one such adverse event, the investigators reported.

The study, which involved 352 chronic statin users, extends the findings of the earlier ARMYDA trial which demonstrated the benefits of a statin loading dose in statin-naïve patients undergoing PCI.

“These findings may support a strategy of routine reload with high-dose atorvastatin early before intervention, even in the background of chronic therapy,” said lead investigator Dr. Germanio Di Sciascio, of the University of Rome, Italy.

“If confirmed by future studies, the results of ARMYDA-RECAPTURE may influence practice patterns, particularly for the acute care of non-ST elevation acute coronary syndromes [ACS].”

The researchers randomized 175 patients to placebo and 177 to atorvastatin reloading, which comprised an 80mg dose 12 hours before angiography, followed by a further 40mg dose 2 hours before.

Just 3.4 percent of statin-treated patients reached the primary endpoint – a composite of cardiovascular death, myocardial infarction and target vessel revascularization – as compared to 9.1 percent of those in the placebo group (P=0.045).

This effect was driven largely by patients who presented with ACS, rather than those presenting with stable angina. In a separate analysis of ACS patients alone, the relative risk reduction with atorvastatin was 87 percent and the number needed to treat was 9.

Atorvastatin reloading also significantly reduced the proportion of patients with elevation of creatine kinase-MB and troponin-I following PCI, and non-significantly reduced the proportion with elevated C-reactive protein. These findings suggest that a rapid LDL-independent effect may underlie the cardioprotective phenomenon, said Di Sciascio.

Dr. Robert Harrington, director of the Duke Clinical Research Institute, US, said that ARMYDA-RECAPTURE adds to the literature supporting early, intensive statin therapy both before and after ACS.

“The trial was very carefully done and it adds to the totality of the data. It is, however, small, and it does have borderline P values with very broad confidence intervals, suggesting a high degree of uncertainty as to the true estimate of effect.

“The limitations of the trial, I believe, warrant replication or validation before recommending widespread adoption of statin reloading,” he said. “Efforts to reduce periprocedural MI should absolutely explore options other than anti-thrombotic therapy, and inflammation certainly is a reasonable target.”

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*Atorvastatin for Reduction of Myocardial Damage during Angioplasty

Japanese CPR success could light the way for Asia

Medical Tribune May 2009 P10
David Brill

Japan’s “impressive” success at tackling out-of-hospital cardiac arrests could inspire other Asian countries to improve their own survival rates, according to the chairman of the Singapore Heart Foundation (SHF).

One-month survival after a witnessed ventricular fibrillation episode has risen from 15 to 31 percent since a program was implemented in Osaka in 1998, researchers reported recently in Circulation. [2009;119:728-734] Neurologically-intact 1-month survival has risen from 6 to 16 percent.

The initiative has also reduced delays in calling for medical services, initiating cardiopulmonary resuscitation (CPR), and delivering a first shock, the study shows.

In Singapore, just 2.7 percent of people currently survive following an out-of-hospital cardiac arrest (OHCA), according to the SHF, which launched its own CPR initiative last year.

“This is a very encouraging study because it inspires us to put more effort into CPR training and providing defibrillators,” said SHF chairman Associate Professor Terrance Chua.

“What is most impressive is that they were able to improve survival rates. Having this clear documentation is good for morale because otherwise you can commit a lot of resources without knowing how much benefit you are getting from it,” he said. “We really take our hats off to them for having done this in a prospective registry so that they can monitor the improvements.”

The Utstein Osaka Project focuses on a four-step “chain of survival,” comprising activation of emergency medical services, CPR, defibrillation and advanced life support measures given by healthcare providers. The survival benefits were driven largely by improvements in the first three links of the chain, suggesting that the program’s public education component has had a significant impact.

Some 120,000 citizens per year have been trained in conventional CPR since the introduction of the program in Osaka, covering an area with a population of 8.8 million.

“This study proves that improvement in the chain of survival results in increased survival from out-of-hospital cardiac arrest in the real world,” said Dr. Taku Iwami, an assistant professor at Kyoto University Health Service, who led the research.

“We need to increase the number of automated external defibrillators [AEDs] in public places as well as train people in not only CPR but in the use of AEDs,” he said. “In many areas of the world, there are serious delays in the use of CPR and AEDs. We hope this study encourages other emergency medical service systems to start or continue their efforts to improve based on objective data.”

The study included 42,873 OHCAs in which resuscitation was attempted, occurring from May 1998 to December 2006. The median time from collapse to call for medical attention dropped from 4 to 2 minutes, and the time from collapse to first CPR dropped from 9 to 7 minutes. Median time from collapse to first shock decreased from 19 to 9 minutes.

In Singapore the public response to learning CPR has so far been “pretty positive,” according to Chua, who noted that despite the improvements in Osaka’s survival rates the study still highlights that there is further room for improvement.

The SHF launched its 3A (Anyone, Anytime, Anywhere) program in November 2008. The project includes the provision of CPR kits which include a mannequin, DVD and other reference materials, all of which can be used at home with the intention of creating a ”multiplier effect” whereby CPR skills are passed on to friends and family.

Thailand and Indonesia have also expressed an interest in adopting similar programs, Chua said.

The SHF has already trained some 2,000 students from seven schools using the CPR kits, which are on sale at a subsidized price of S$20 for students and S$50 for corporations and communities.

Several commercial facilities, including Suntec City and VivoCity shopping centers, have already installed their own AEDs since the launch of the 3A program, according to Chua. Changi Airport has also backed the project, and is currently in the process of developing and implementing its own AED installation program.

A 2002 study from three airports in Chicago, US, reported that 11 out of 18 patients who arrested with ventricular fibrillation over a 2-year period were successfully resuscitated using AEDs. Ten were alive and neurologically intact a year later. Six of the 11 rescuers had never used an AED before, although three were medically trained. [N Engl J Med 2002 Oct 17;347(16):1242-7]

Vaccinate the young against HPV, says Nobel Laureate

Medical Tribune May 2009 SFIII

David Brill

Countries should “seriously consider” offering widespread human papillomavirus (HPV) vaccinations, according to the Nobel Prize-winning scientist who first linked the virus to cervical cancer.

Professor Harald zur Hausen, addressing the media on a recent visit to Singapore, said that boys and girls alike would benefit from the vaccine, but stressed that it should be given prior to the onset of sexual activity.

For older women who are already sexually active, it should be a personal decision whether or not to be vaccinated, he said.

zur Hausen also rejected the argument that effective screening programs can be superior to widespread vaccination.

“I think that’s a mistake because screening and vaccination do something different,” he said. “In screening you discover lesions which need to be removed. In vaccination you prevent the lesions, and therefore you don’t [need] surgical intervention.”

Vaccination has been shown to be safe and highly effective for preventing HPV infections but opinions remain divided about who, when and how to vaccinate. Australia, for example, has approved vaccination of women aged 10 to 45, whereas the US FDA limits approval to 9 to 26 year-olds.

“It would really be something which one should seriously consider – to vaccinate everyone,” said zur Hausen, winner of the 2008 Nobel Prize in Physiology or Medicine.

“[But] let me be quite clear about it – the vaccine is really only protective in preventing the infection. If there has [already] been an infection the vaccine has no effect whatsoever.

“Up to the onset of sexual activity, yes, you can clearly say it’s worthwhile. But subsequently it’s more difficult to make a statement along those lines.”

Neither of the HPV vaccines is presently approved for use in males, but zur Hausen outlined several supporting arguments. Firstly, it would protect women from cervical cancer by reducing HPV transmission. Secondly, men themselves would gain protection from genital warts and other HPV-positive cancers, including anal and oropharyngeal cancers. Upcoming data from the first clinical studies in boys “look very promising,” he said.

zur Hausen also called for reductions in the price of HPV vaccines, which are presently “unaffordable” for parts of the developing world. This would pave the way for global vaccination programs, offering “the theoretical chance to eradicate some of these infections which lead to cervical cancer.”

Professor zur Hausen delivered the 6th Humphrey Oei Distinguished Lecture at the National Cancer Center, Singapore, and the second opening lecture at the Asian Oncology Summit 2009.

Singapore to wait and see on HPV vaccination

Medical Tribune May 2009 SFIII
David Brill

Singapore will not rush to make human papillomavirus (HPV) vaccination part of its national immunization program.

Insteady, the city-state will await the outcomes of vaccination programs in other countries before making its own decision, said Dr. Balaji Sadasivan, senior minister of state, Ministry of Foreign Affairs.

In the meantime, the nation will continue strengthening its Pap smear screening coverage. The HPV vaccine will remain available on an optional basis, giving individual parents the right to choose whether to vaccinate their daughters.

“As a country with a lower incidence of cervical cancer, the risk-benefit ratio will be lower in Singapore. We should therefore be cautious in making any national recommendation with regard to vaccination,” said Balaji at the recent Asian Oncology Summit 2009.

“If we put it in our national immunization program almost every young girl will get vaccinated. That’s a very, very major step, and sometimes … it’s not necessarily the wisest thing to be the first to try something out because you’re basically the guinea pig. It may just be safer to wait and see how other countries proceed with this.”

Balaji singled out the UK in particular as one “for us to watch,” following the September 2008 introduction of a national HPV immunization program for girls aged 12 to 13. “If it turns out to be safe to do it on a national scale then I think it would make sense for us to consider doing the same thing,” he said, adding that it would be “a few years” before any conclusions could be made.

Balaji also expressed clinical concerns about the vaccine, notably that it remains unclear whether immunity is long-lasting. It is also unknown whether other strains of HPV could become dominant if current strains are contained.

“From an ethical standpoint, there is also the issue of consent, which has to be viewed in the local context, where the community’s moral viewpoint is that offering such a vaccination program sends out the wrong message – that teenage sex is condoned by the community,” he said.

“Pap smear screening is one of the most effective ways of reducing the risk of cervical cancer, and we have pretty good coverage of about 60 to 70 percent. We should continue to build on that program and not neglect [it] because of the possibility of vaccination. That is a reasonable alternative while waiting to have better data,” he concluded.

Dr. Balaji delivered the opening address at the Asian Oncology Summit 2009, and spoke directly with the media.

Folic acid-vitamin combo cuts AMD risk in women

Medical Tribune May 2009 P11
David Brill

Taking folic acid with vitamins B6 and B12 could help to prevent age-related macular degeneration (AMD) in women at high risk of cardiovascular disease (CVD).

Women who took daily supplements for 7 years reduced their relative risk of AMD by around a third, a recent trial reported.

The analysis included 5,205 women aged over 40 who had a history of CVD and a minimum of three CVD risk factors but no AMD at baseline. There were 55 cases of AMD in the treatment group and 82 in the placebo group at trial’s end. [Arch Intern Med 2009 Feb 23;169:335-41]

Lead author Dr. William Christen, an associate professor at Brigham and Women’s Hospital and Harvard Medical School, US, said that the intervention is safe and inexpensive and could, theoretically, be applied on a wide scale. However, he stressed the need for more research before making any specific recommendations.

“This is the first trial to suggest a possible benefit so I think it’s important at this point to corroborate the findings in other populations,” he said.

“Other than avoiding cigarette smoking we have no means to prevent the early stages of AMD so these findings, if they’re corroborated … will be particularly important from a public health perspective.”

AMD is the leading cause of blindness in European and US over-60s and is thought to be on the rise in Asia.

The Singapore Malay Eye Study found that in its early stages the condition affects 3.5 percent of Malays aged 40 to 80 – a comparable figure to that reported in the Australia. The prevalence of late-stage AMD among Malays was 0.34 percent. [Ophthalmology 2008;115(10):1735-41]

For elderly Singaporeans in general the prevalence of AMD could be as high as 27 percent, according to a study of 574 over-60s. Awareness of the condition however seems to be low – for every AMD patient with a confirmed diagnosis there were 154 who did not know they had the condition. [Singapore Med J 1997;38(4):149-55]

Vitamins are not currently recommended for primary AMD prevention but have been shown to delay progression in those who already have intermediate-stage disease. A combination of high-dose antioxidants (vitamins C, E and beta carotene) and zinc reduced the odds of developing advanced AMD by 28 percent, as compared to placebo, in a trial of 3,640 patients with an average of 6.3 years of follow up. [Arch Ophthalmol 2001 Oct;119(10):1417-36]

Christen et al. randomized participants to placebo or a regimen of 2.5 mg/day folic acid, 50 mg/day vitamin B6 and 1 mg/day vitamin B12 – higher dosages than typically given over the counter. The relative risk in the treatment group was 0.66 for AMD (95 percent CI 0.47-0.93; P=0.02) and 0.59 for visually significant AMD (95 percent CI 0.36-0.95; P=0.03). Mean follow-up was 7.3 years.

The study could also provide important new insights into the much-debated role of homocysteine in vascular disease. The marker has been strongly linked to atherosclerosis, CVD and AMD, but trials have yet to show that homocysteine-lowering therapies, notably folic acid and B vitamins, significantly improve outcomes.

“If these findings are real for AMD then one possible explanation would be … that there may be a difference between small vessel and large vessel disease in the response to homocysteine lowering. At this point we can only speculate,” said Christen.

New jab shows promise for CMV prevention

Medical Tribune May 2009 P12

David Brill

American researchers have scored “a home run” in the quest to prevent congenital cytomegalovirus (CMV) infections – a leading cause of birth defects in newborns.

In a recent phase II trial they found that a new vaccine was 50 percent effective at preventing CMV infection among women, after a minimum of 1 year follow-up.

Just 18 of 234 women who were vaccinated went on to develop CMV infection, compared to 31 of 230 women in the placebo group. [N Engl J Med 2009 Mar 19;360(12):1191-9]

Further trials are now needed to confirm whether immunizing mothers will actually translate to a reduction in congenital infections, said lead researcher Dr. Robert Pass.

With phase III trials also required it is likely to be at least 5 years before the vaccine is licensed, he said. It also remains unclear whether CMV immunity persists or would need boosters.

Successful CMV vaccines have so far proved elusive: none are currently licensed despite more than 30 years of research and a ‘top priority’ listing by the US Institute of Medicine in 2001.

“CMV is a very complex virus which has a long-standing relationship with its host,” said Pass, who is professor of pediatrics at the University of Alabama at Birmingham, US.

“When this trial was initiated most people did not think we would find any efficacy for prevention of maternal infection. So to find that the vaccine was actually able to prevent infection in women was essentially a home run.”

Around 0.7 percent of babies are born with a congenital CMV infection – 11 percent of whom are symptomatic at birth. Fetal damage typically occurs in cases where the infection is acquired during pregnancy: around 0.5 percent of such babies die and up to 20 percent have permanent disabilities. [N Engl J Med 2009 Mar 19;360(12):1250-2]

CMV is endemic in Singapore – the virus was present in 87 percent of antental women screened at KK Women’s and Children’s Hospital (KKH) from 1997 to 1998. [Singapore Med J 2000 Apr;41(4):151-5]

Dr. Lai Fon Min, a consultant and head of the antenatal risk assessment unit at KKH, said that there is an important need for CMV vaccines since there are limitations to both maternal and fetal screening, and no accepted therapy for congenital infections.

“If a highly effective vaccine for CMV is developed there may be justification in introducing it in Singapore as we have a high prevalence rate,” he said, but added that it “remains to be seen” whether routine vaccination would be cost effective.

The vaccine tested by Pass and colleagues comprises 0.02 mg of CMV envelope glycoprotein B, along with 13.25 mg of a squalene-in-water emulsion known as MF59. The rights are owned by Sanofi Pasteur.

The study was not designed to assess outcomes among newborns but the findings appear promising: just one of 81 babies born to vaccinated mothers had CMV, whereas three of 97 babies born to placebo-group mothers were infected.

The trial enrolled CMV-seronegative women who had given birth within the previous year. They were vaccinated at 0, 1 and 6 months, and tested quarterly for CMV infections over 42 months.

Injection-site reactions were more common in the vaccinated women but overall adverse event rates were not significantly different to placebo.

Pass added that vaccination could either be performed in pre-teen girls – potentially in combination with the human papillomavirus vaccine – or in very young children, since they are the main source of CMV infections for pregnant women.

Picking and choosing: No way to lose weight

Medical Tribune May 2009 P13
David Brill

Weight loss diets which promote one particular food group may not be the best way to shed the kilos, a recent study suggests.

In one of the longest trials of its kind, US researchers found that there was ultimately little difference in weight loss whether diets emphasized carbohydrates, protein or fat.

Nor did waist circumferences differ significantly after 2 years of following the diets, the study of 811 overweight adults showed.

"This is important information for physicians, dieticians and adults, who should focus weight loss approaches on reducing calorie intake," said lead author Professor Frank Sacks, Harvard School of Public Health, US.

Participants were randomized to one of four diets. The compositions varied, but all targeted a 750 kcal decrease in daily intake. [N Engl J Med 2009;360(9):859-73]

Weight loss peaked at 6 months – when participants had lost an average of 6 kg, or 7 percent of their initial weight. Weight regain began after 12 months: those who completed the study had lost an average of 4 kg at its conclusion.

The researchers also found that people who attended the most group counseling sessions lost the most weight – an average of 0.2 kg per weekly session.

"These findings suggest that continued contact with participants to help them achieve their goals may be more important than the macronutrient composition of their diets," said Sacks.

Singapore’s Health Promotion Board (HPB) welcomed the study as an informative, but not definitive, addition to the literature.

“The study was limited in that the differences in the macronutrient content of the different diets was not as substantial as originally planned, hence the resultant diets did not fully replicate the macronutrient distribution of popular ‘low-carb’ or low-fat diets,” said Mr. Benjamin Lee, manager and nutritionist, adult health division, HPB.

The HPB advocates a holistic approach to weight loss including exercise and stress management, added Lee. Specific dietary recommendations are to focus on calorie reduction while maintaining a diet which covers four food groups: rice and alternatives, fruit, vegetables, and meat and alternatives (including dairy foods).

Ms. Jamie Liow, a nutritionist and member of the Singapore Nutrition and Dietetics Association, said that carbohydrate intake is typically a concern among Asians who diet.

“Most would either have a low-carbohydrate, high-protein diet, or no carbohydrates at all. Crash dieting seems to be popular among younger girls as well,” she said.

Liow also emphasized the importance of getting nutrients from “a whole spectrum of foods,” adding that doctors should refer their patients to dieticians for specific advice on the best way to lose weight.

The four diets tested by Sacks et al. comprised: 20 percent fat, 15 percent protein and 65 percent carbohydrate; 20 percent fat, 25 percent protein and 55 percent carbohydrate; 40 percent fat, 15 percent protein and 45 percent carbohydrate; or 40 percent fat, 25 percent protein and 35 percent carbohydrate.

The lowest-fat and the highest-carbohydrate diets brought about the greatest reduction in LDL cholesterol levels, whereas the lowest-carbohydrate diet yielded the biggest increase in HDL cholesterol. Triglyceride levels dropped similarly for all diets.

Dieters were also encouraged to exercise for 90 minutes per week, and received weekly group counseling sessions and 8-weekly individual sessions.

Despite this intensive encouragement, dieters did not meet their nutrient intake targets when questioned at 6 months and 2 years. This appears to be a common problem in weight-loss trials, say the authors, noting that many previous studies have also found that adherence declines after a few months.

Simple online tool predicts type 2 diabetes risk

Medical Tribune May 2009 P14
David Brill

A simple new tool could allow GPs to identify patients at high risk of developing type 2 diabetes without the need for laboratory tests.

The QDScore, developed with electronic medical record data from some 2.5 million patients, is quick and easy to use and is freely available online.

It is the first prediction algorithm to include ethnicity and social deprivation alongside conventional diabetes risk factors, and is intended for routine use in primary care.

The QDScore performed well in a recent study – accurately predicting 10-year diabetes risk in a diverse patient population drawn from 176 UK general practices. [BMJ 2009 Mar 17;338:b880]

“There is good evidence that lifestyle changes and medical intervention at an early stage can prevent type 2 diabetes in up to two-thirds of high-risk cases and that early diagnosis is likely to improve outcomes,” said lead researcher Professor Julia Hippisley-Cox, professor of clinical epidemiology and general practice at the University of Nottingham, UK.

“As the number of people diagnosed with diabetes in the UK continues to rise, this new algorithm will be an invaluable tool to help doctors identify those at greatest risk who are most likely to benefit from interventions.”

The QDScore calculates risk using age, sex, ethnicity, family diabetes history, personal cardiovascular disease history, hypertension medications, steroid usage, smoking status and body mass index. It was derived from a cohort of more than 2.5 million 25 to 79 year-olds – over 78,000 of whom developed type 2 diabetes over 10 years of follow up.

There were considerable differences in diabetes risk between ethnic groups. Bangladeshi men were the most likely to develop diabetes, with an adjusted hazard ratio (HR) of 4.53 as compared to Caucasian men. The subsequent male risk hierarchy was: Pakistani, Indian, Other Asian, Black African, Chinese and Black Caribbean (adjusted HRs 2.54, 1.93, 1.89, 1.67, 1.41 and 0.80 respectively).

The risk patterns were similar for women, although Chinese ethnicity conferred a greater risk than in men. Bangladeshi women were the most likely to develop diabetes, followed by those of Pakistani, Chinese, Indian, Other Asian, Black African and Black Caribbean origin (adjusted HRs 4.07, 2.15, 1.96, 1.71, 1.26, 0.81 and 0.80, respectively).

The QDScore was tested on records from more than 1.2 million patients – over 37,500 of whom developed diabetes. It scored highly on validation statistics, out-performing the Cambridge risk score in all domains for both men and women. It is available at: http://www.qdscore.org/.

Sputum testing offers key to improving asthma therapy

Medical Tribune May 2009 P15

David Brill

Individualizing therapy on the basis of sputum cell counts could help to improve the treatment of severe asthma, new research suggests.

A recent small-scale randomized study found that patients treated in this way had significantly fewer exacerbations and were able to safely reduce their prednisone doses.

The trial involved a rare subset of patients with high levels of eosinophils in the sputum, but the same principles could be extended to other types of asthma, the researchers say.

“Our philosophy ... has been to measure bronchitis by a simple processing of sputum. Identify the type of bronchitis and treat it accordingly based on the type of cell. It’s a very simple message,” said lead author Dr. Parameswaran Nair, an associate professor of medicine at McMaster University, Ontario, Canada.

“Most patients with eosinophilia are easy to treat and can be controlled with small or moderate doses of inhaled corticosteroids. But in the severe patients people [should] take a step back if the patient is not getting better with prednisone and think ‘what is the type of bronchitis? Should we not understand what’s going on here before we increase or add new treatments?’”

The study, which lasted 26 weeks in total, included only patients whose sputum eosinophilia had persisted despite prior prednisone treatment. Nine received five monthly infusions of mepolizumab (750 mg) – a monoclonal antibody which disrupts the activation of eosinophils by targeting interleukin-5 – and 11 received placebo. [N Engl J Med 2009 Mar 5;360(10):985-93]

There was only one asthma exacerbation in the mepolizumab group and this was associated with sputum neutrophilia rather than eosinophilia. Placebo patients, in contrast, experienced a total of 12 exacerbations – nine associated with eosinophilia and three with neutrophilia (P=0.002).

Patients taking mepolizumab reduced their prednisone dosage by a mean of 83.4 percent of the maximum possible reduction, compared to 47.7 percent for patients on placebo (P=0.04).

The accumulation of eosinophils in the airway is thought to be an important event in the pathogenesis of asthma but the exact role of the cells remains unclear. Previous studies have failed to show any benefit of anti-interleukin-5 antibodies as a therapy for asthma, but these trials did not tailor the therapy to specific patients.

“We argued that if we give it to every patient with asthma it’s not going to work – it’s only going to work if you’ve got eosinophilia to begin with,” said Nair.

The McMaster respiratory group, led by Professor Freddy Hargreave, has already demonstrated the benefits of individualizing therapy in an earlier randomized trial of 117 asthma patients. The number and severity of eosinophilic exacerbations were both reduced using the sputum-based approach, as compared to standard treatment according to Canadian guidelines. [Eur Respir J 2006 Mar;27(3):483-94]

Nair hopes that latest new study will raise awareness of the benefits of sputum testing for asthma, admitting that he is “very frustrated” that such a simple procedure has not caught on more widely.

“A rheumatologist would aspirate fluid from a joint to look at inflammation before giving anti-inflammatories, and a gastrointestinal surgeon would take a rectal biopsy for colitis before giving corticosteroids.

“But we in respiratory medicine are giving bucketloads of corticosteroids and anti-inflammatory drugs without measuring inflammation. Most physicians all over the world only measure forced expiratory volume in 1 second (FEV1), which is just a measure of airway caliber and not of bronchitis,” he said.

The results of another study, published in the same edition of the journal, lend further support to the theories of Nair et al. In a randomized double-blind trial of 61 patients, UK researchers showed that mepolizumab, compared to placebo, reduced severe exacerbations and improved quality of life in patients with refractory eosinophilic asthma. [N Engl J Med 2009 Mar 5;360(10):973-84]

A separate study, meanwhile, is already underway at McMaster to assess the effects of blocking neutrophils, which are typically found in asthma patients who have bronchitis caused by an infection.

Conquering Kinabalu

Medical Tribune April 2009 P18
David Brill

Mount Kinabalu is widely promoted as a straightforward climb for the everyday tourist. David Brill wonders whether Superman has been writing travel books in his spare time.

Pulling myself up a sheer cliff face in the pitch black at 4 a.m. I realized I’d been misled. With my hands slipping on the wet rope, the cramp aching in my legs and the insidious cold penetrating four layers of clothing, it began to dawn on me that climbing Mount Kinabalu was not going to be as simple as I’d been led to believe. When I saw a grown adult burst into tears, my worst suspicions were confirmed.

Rising to 4,095 meters above sea level, Mount Kinabalu is the highest mountain in Borneo although not, as often claimed, the highest in Southeast Asia (Myanmar and Indonesia boast loftier peaks). With 47,848 climbers in 2008 alone –26,595 of them non-Malaysians –it is considered to be one of the world’s most accessible mountains, and no specialist climbing skills are required.

Armed with a personal assurance that conquering the peak would be “easy,” we had arrived in the town of Kota Kinabalu on Friday night and travelled straight to the Kinabalu National Park, the UNESCO World Heritage site where the mountain is located. The drive usually takes around 2 hours but with heavy rain, thick fog and herds of cows mysteriously crossing the road, our progress was a little slower than might be expected. We arrived in the small hours of Saturday and, 5 hours sleep in a freezing dormitory later, were ready to begin the climb.

Only the bravest attempt to ascend and descend Mount Kinabalu in a single day, and the majority of tourists spend a night at Laban Rata –an accommodation compound situated around 3,000 meters up. With the mountain entirely shrouded in mist, it was left to our imaginations as to how high this might actually be, and we set off with the blissful optimism that accompanies blind ignorance.

Stage one of the climb is straightforward but cannot be described as easy. Five hours on a steep, meandering path, clambering over boulders and slipping in the mud, was achievable but not an experience I’d wish to repeat. When cramp set in it became genuinely challenging, and the need for effective hydration was a lesson learned the hard way. Cramp does not seem to be a problem for the porters, however, who regularly ferry supplies and equipment back and forth up the slopes, hardly breaking a sweat as they do so. There can be few experiences in life more demoralizing than struggling your way up a mountain, only to be overtaken by a man running full pelt with a dishwasher strapped to his back.

The relief upon arriving at Laban Rata was palpable. Accommodation here must be reserved before beginning the climb and is often booked up as far as 6 months in advance. There are a few different options within the compound, which can hold a total of 146 climbers on any single night, but the Laban Rata Rest House is promised as offering the greatest level of luxury. However with ice-cold showers and an electric radiator that struggled to generate heat but succeeded in unleashing a torrent of sparks during the night, I can only imagine what comforts await in the other buildings. The wisdom of reserving early was firmly reinforced.

Any last lingering hopes of a relaxing weekend break were finally shattered by the 2:30 a.m. wake up on the Sunday morning. Half an hour later we were on our way to Low’s Peak –an ironic title dedicated to British Explorer Sir Hugh Low who in 1851 became the first documented person to reach the summit. The warmth that was enjoyed at 3,000 meters quickly plummets along this stretch, and it is here that the rewards of a sensible packing list are reaped. A good pair of waterproof gloves and a head torch are extremely useful for sections where a rope is required, and a warm, windproof jacket will come in handy throughout. As the temperature drops so too does the vegetation –the lush greenery of the lower slopes giving way to sweeping expanses of bare rock that offer little shelter from the wind.

With altitude sickness, fatigue and depression setting in, we finally reached the peak around 2 hours after leaving Laban Rata. We did not have to wait long for the mood to lift, however. As the sun crept up over the horizon sometime after 5 a.m. the misery of all that had gone before was forgotten, replaced with a delirium-heightened wave of elation which swiftly swept through
the group. Aches and pains were put on hold as we reveled in the collective sense of achievement – 13 members of our motley crew had set off from Singapore and 13 were now sitting at the peak of Mount Kinabalu.

The view, as expected, is breathtaking. And as the sun began to provide some warmth, so the urgency to descend diminished. For the first time on the trip we were able to take in our surroundings without the sense of impending dread at what was to follow, leaving us free to return to Laban Rata in a more relaxed fashion than that in which we left. The rocks are significantly easier to traverse with the benefit of daylight, and we were breakfasting at the hostel around an hour after leaving the peak.

The rest of the descent is no simple task, and is considered by some to be the hardest part of the journey. Stiffness sets into the muscles and the height of the steps places considerable strain on the knees and calves. Buoyed by the knowledge that the worst was over, however, the pain became bearable and personally I came dangerously close to enjoying myself. Descending at a leisurely pace brought us back to base camp within 4 hours, while quicker members of the group made it inside 3. The porters, needless to say, sprinted past like Olympic mountain goats.

Climbing Mount Kinabalu is a physical and emotional rollercoaster. It took me a week to regain the full use of my legs, but it’s a small price to pay to know that I made it. Easy? No. Worth every second? Undoubtedly.

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For details of accommodation and climbing fees for Mount Kinabalu, see: www.suterasanctuarylodges.com.my/climbing_mt_kinabalu.php

Urine test shows promise for prostate cancer detection

Medical Tribune April 2009 P4

David Brill

A prototype urine test has been shown to be highly specific for detecting prostate cancer and could even help to reduce the number of unnecessary biopsies, US researchers suggest.

Moreover the results showed some correlation to disease severity markers, suggesting that the test could be used to distinguish between mild and aggressive forms of cancer.

The urine test detects the presence of a fusion between the TMPRSS2 (T2) and ERG genes, which is found in around 50 percent of prostate cancers.

“Many cancers detected at biopsy are low volume, low grade. There is a real need for tests that can help determine which of those men should receive aggressive treatment such as prostatectomy, and which could potentially be monitored more conservatively,” said lead researcher Dr. Jack Groskopf, who presented the results at the recent Genitourinary Cancers Symposium in Orlando, US.

“The key next steps here are to follow up and confirm the results that we have generated to date and, perhaps more importantly, to start looking at the correlation between the urine test and pathologic features in prostatectomy tissues, such as tumor volume stage and grade,” he said.

Commenting on the results, Dr. Howard Sandler, chair of radiation oncology at Cedars-Sinai Medical Center, Los Angeles, said: “The fact that this gene fusion is related to the progression and development of prostate cancer in half of all men who develop prostate cancer has major implications for diagnosis but hopefully for therapy as well. This unique fusion protein might become a therapeutic target at some point in the future.”

In a preliminary study of 556 men due to undergo prostate biopsy the urine test was 84 percent specific, reported Groskopf, a senior research scientist at Gen-Probe Incorporated, the San Diego-based company which is developing the test. For serum prostate-specific antigen (PSA) testing this figure is just 27 percent, he said, adding that the other current screening method – digital rectal exam – is also hampered by its low specificity.

“As a result the majority of prostate biopsies are negative, and you could argue that we are doing too many biopsies,” he said.

The sensitivity of the urine test was 42 percent – a favorable result considering that with only half of cancers containing the T2:ERG gene fusion, the theoretical maximum would be 50 percent, Groskopf added.

The urine test showed significant correlations to aggressiveness indicators such as the Gleason Score, the percentage positive prostate cores and the Epstein criteria.

Researchers from the University of Michigan, who are collaborating with Gen-Probe on the test, recently published another research paper linking sarcosine, a glycine derivative, to more aggressive forms of prostate cancer. This metabolite and its pathways could not only serve as a disease severity marker but also as a target for therapeutic intervention in future, they suggest. [Nature 2009 Feb 12;457:910-4]

CRT holds promise for atrial fibrillation in heart failure

Medical Tribune April 2009 P9
David Brill

The benefits of cardiac resynchronization therapy (CRT) for heart failure could extend to those sicker patients who have atrial fibrillation (AF), according to a leading Hong Kong cardiologist.

Although more randomized controlled studies are needed, observational data so far appear to support the use of CRT for these patients said Dr. Jeffrey WH Fung, director of cardiac electrophysiology and pacing services at the Prince of Wales Hospital, Chinese University of Hong Kong.

Fung estimated that up to 30 percent of heart failure patients have AF, but noted that guidelines currently exclude this group from the class I indications for CRT. This top-level recommendation is presently reserved for those who are in sinus rhythm, while AF patients are grouped under class IIa indications – reflecting a lower level of evidence in support of the treatment.

Fung, however, pointed to a recent paper from the Multicentre Longitudinal Observational Study (MILOS) group – the largest study so far to address the use of CRT in AF patients. After a median of 34 months following CRT, all-cause and cardiac mortality were similar between the 243 AF patients and the 1,042 sinus rhythm patients. [Eur Heart J 2008 Jul;29(13):1644-52]

Further support for these findings comes from a meta-analysis of 5 observational studies involving 1,164 patients, which showed that AF and sinus rhythm patients had similar mortality 1 year after CRT initiation. Improvements in New York Heart Association functional class were also comparable for the two groups. [J Am Coll Cardiol 2008 Oct 7;52(15):1239-46]

“It seems that sinus rhythm and AF patients behave similarly after receiving CRT,” Fung summarized. He noted that sinus rhythm patients appear to fare better on quality of life measurements, but said that this finding is “consistent with other heart failure studies which show that AF patients are much sicker than those who remain in sinus rhythm, no matter what therapies they receive.”

Besides the clinical benefits, CRT also seems to offer comparable improvements between the two patient groups when it comes to echocardiographic parameters, he added.

The jury is still out, however, on whether AF patients should undergo atrio-ventricular junction (AVJ) ablation alongside CRT, said Fung. The MILOS study found that ablation improved survival compared to CRT alone but other studies have produced inconsistent results, he said, cautioning that AVJ ablation renders patients device-dependent for the rest of their lives and should not be done unless necessary.

“I think we need a properly randomized study to try to ascertain the merits of ablation or pharmacological rate control and understand which one is really preferred in patients with heart failure and permanent AF,” he said.

“We should try to maximize drugs and sometimes maybe if there is a very low percentage of pacing you may ask the patient to undergo AVJ ablation. But looking in our database it seems that most of the patients are doing fine with more than 90 percent pacing just with drugs,” he concluded.

Healthcare technology saves lives, boosts care

Medical Tribune April 2009 SFI

David Brill

Adopting the latest healthcare information technologies can save lives, reduce complications and cut costs, a new report from 41 US hospitals shows.

It is one of the first studies to provide generalizable, empirical evidence that technology actually improves outcomes, the researchers say.

Inpatient mortality dropped by 15 percent in hospitals with the most highly automated notes and record systems. Complication rates were reduced by 16 percent in those with the highest levels of electronic decision support. [Arch Intern Med 2009;169:108-14]

Lead author Dr. Ruben Amarasingham, assistant professor of medicine at the University of Texas Southwestern Medical Center, said that the study “provides good news and caution” as governments worldwide debate healthcare stimulus packages.

The findings were welcomed in Singapore, where the upgrading of electronic systems across the healthcare clusters continues apace (inset).

Dr. Chong Yoke Sin, group chief information officer at SingHealth, said: “This study is reassuring for the people who invest in information technology for hospitals. There is now evidence to prove that it is indeed useful.”

Although happy with progress so far Chong stressed the importance of performing “meticulous” checks to ensure the integrity of new systems.

“When you use any kind of technology you have got to do it right, otherwise you are propagating the wrong faster and more pervasively. If a human being writes a wrong prescription you have only got that one wrong prescription, whereas if technology is not performing correctly it’s systemic,” she said. “At SingHealth we are always improving with constant feedback from clinical staff on the ground, which enables us to review workflow for better efficiency.”

Amarasingham agrees. “Our results suggest that investment in information technology is a necessary part to improving healthcare. But it’s clearly not sufficient – there needs to be a lot of other action taken.

“It has to be done carefully and thoughtfully over a prolonged period of time with careful outcome measures. If [investment] is not accompanied by a deliberative, strategic approach within hospitals and clinics then you may end up with worse systems, or at least a waste of money,” he said.

Over at the National Healthcare Group Mr. Ho Khai Leng, information technology director, said that new technology “improves care” by giving clinicians quicker and more accurate access to medical information. New systems also “facilitate the seamless transfer of patient information between care providers,” he said.

The digitization of x-rays has been particularly successful – cutting turnaround time from 2 or 3 days down to an hour or less, and saving “significant costs” for NHG and patients alike, he said. Tan Tock Seng Hospital alone saved $16,000 on films and chemicals between January and March 2006, following implementation of the project.

Amarasingham and colleagues reviewed data from 167,233 over-50s who were admitted to urban Texas hospitals between December 1 2005 and May 30 2006. They graded hospitals using the Clinical Information Technology Assessment Tool (CITAT), which measures the level of computerization in four clinical areas.

Average patient costs were reduced by US$538 ($816), US$132 ($200) and US$110 ($167) in hospitals with high scores on decision support, CPOE and test results, respectively. Costs were not significantly different within the notes and records domain.

Amarasingham acknowledged a “generational gap” with technology use, but said that all opinions must be considered when implementing new systems.

“If there are physicians who are reluctant or scared of using it then we need to reach out to them and involve them in the process. They are sometimes our best physicians with enormous experience that they can bring to the table,” he said.

Singapore center set to tackle childhood cancer in Asia

Medical Tribune April 2009 SFIV

David Brill

A new Singapore center could help raise childhood cancer survival rates across Asia, thanks to a recent $24 million funding boost.

The money will expand treatment facilities and strengthen research at the Viva-University Children’s Cancer Centre, which has already treated some 40 overseas children and begun training visiting specialists.

Around four out of five children with leukemia are cured in Singapore but in nearby countries this figure can be as low as one in 20.

“There is an urgent need for us to respond to the cries of children with cancer in Singapore and the whole region,” said Mrs. Jennifer Yeo, director and secretary of Singapore-based Viva Foundation for Children with Cancer.

“We are confident that with the support of all our donors, volunteers and strategic partners we can save many young lives,” she said.

The center, known as VUC3, has been operational for a year but was officially opened last month. Two specialists from the Philippines have already trained there, and one each from Myanmar and Brunei are currently in training.

The new funding comprises a $12 million gift from the Goh Foundation – a nonprofit private group – matched like-for-like by the Singapore government.

Four main research programs will be established, comprising bone marrow transplantation, childhood leukemia, bone cancer and ‘after completion of therapy,’ which focuses on the long-term impact of cancer treatment. This research will have a strong translational clinical focus with a view to raising cure rates, lowering treatment costs and minimizing side effects, said Associate Professor Allen Yeoh, medical director of VUC3.

“This will provide us with a quantum leap in the care of childhood cancer in Singapore, and help ensure that no child dies in the dawn of life. In the current severe recessionary climate, we are truly grateful to the Goh Foundation for their generosity,” said Yeoh, also a consultant at the University Children’s Medical Institute, National University Hospital, which houses VUC3.

Pediatric cancer survival is “dismal” in low-income countries, according to a study published last year. Five-year survival in the Philippines was estimated at 10 percent and in Vietnam just 5 percent. [Lancet Oncol 2008 Aug;9:721-9]

Between 120 and 140 new pediatric cancer cases are diagnosed in Singapore each year – some 40 percent of which are leukemia. Around 40 local children have been treated at VUC3 so far.

The center has already installed five new bone marrow transplant rooms and raised the number of inpatient beds from 12 to 17. The funding has also helped establish the Viva-Goh Foundation Professorship in Pediatric Oncology.

VUC3, built at a cost of $5 million from the Singapore Tote Board and Viva Foundation, is working closely with the St. Jude Children’s Research Hospital in Memphis, US – one of the world’s leading childhood cancer centers.

Statin-associated adverse events under-appreciated, experts say

Medical Tribune April 2009 P11

David Brill

The potential hazards of taking statins may be under-appreciated by the medical community, with adverse reactions often overlooked and sometimes even dismissed, according to US researchers.

Attention has largely focused on the most commonly-reported issue of muscle problems but the full side effect profile is wider than typically thought, they warn.

Cognitive problems are the second most common reaction to statins, followed by peripheral neuropathy-type symptoms, such as numbness and burning, said Dr. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego (UCSD).

Rarer reports have also linked statins to a range of other conditions including sexual dysfunction, glucose elevation and vision problems.

Golomb is head of the Statin Study Group at UCSD, which is currently conducting an observational study looking at the adverse effects of the drugs. She also recently co-authored a literature review which, with almost 900 references, she believes to be the most comprehensive look at the subject to date. [Am J Cardiovasc Drugs 2008;8(6):373-418]

“In clinical trials, adverse events look rare. But for those of us who see real-world patients they’re a really big problem,” she told Medical Tribune.

Golomb highlighted a French observational study reporting that 10.5 percent of patients experienced muscle symptoms, and a Danish population-based study which showed that current statin users had a roughly 16-fold increased risk of polyneuropathy compared to non-users. [Cardiovasc Drugs Ther 2005 Dec;19(6):403-14; Neurology 2002 May 14;58(9):1333-7] She noted, however, that adverse event rates vary between different studies and populations, making it difficult to provide definitive overall figures.

Meta-analyses, meanwhile, have yielded significant odds ratios of 1.4 and 1.44 for any adverse event on statins (the latter with intensive therapy), although both also recorded substantial clinical benefits. [Clin Ther 2006 Jan;28(1):26-35; Clin Ther 2007 Feb;29(2):253-60]

“I think there is a lack of awareness of these problems from physicians,” added Golomb, pointing to an earlier survey of 650 patients which found that doctors were “more likely to deny than affirm a connection” in cases of adverse statin reactions. [Drug Saf 2007;30(8):669-75]

“Even for patients who met literature criteria for probable or definite causality of their problems, the physicians denied the possibility of a connection about 50 percent of the time for each of the top three best known and most reported symptoms. And when we asked who initiated the conversation it was overwhelmingly the patients, even though it should be the physician who is aware of the connection of those specific symptoms to statins,” said Golomb.

Golomb believes that the most of the problems are class effects, and largely relate to the dose and potency of the statin rather than to any particular brand. Her literature review also notes that mitochondrial mechanisms are implicated in several adverse effects and proposes that this may be a common underlying factor behind a wide range of the problems.

She added that muscle problems occurring with statins are not always associated with a rise in creatine kinase levels, and that this can sometimes cause them to be overlooked.

Other academic authors have reached different conclusions about the risk profile of statins. The most recent such review paper in The Lancet, for example, concluded that statins are “a well-tolerated and extensively studied group of drugs.” [2007; 370:1781-90]

“With a few caveats, and while awaiting good-quality randomized data for the newer drugs, statins seem to be a remarkably safe group of drugs when used at their usual doses,” wrote Dr. Jane Armitage, of the University of Oxford, UK.

Golomb added, however, that the side effects reported so far could be just “the tip of the iceberg,” cautioning that even more problems could ultimately be shown to be related to statins.

“We’ve had reports from patients who have developed accelerated hearing loss or tinnitus with onset of statins. We don’t have data to demonstrate an association but that’s one of the domains in which I predict an association will likely be found in future,” she said.

Orbit of JUPITER extends to stroke prevention

Medical Tribune April 2009 P12
David Brill

The benefits of rosuvastatin for patients with elevated high sensitivity C-reactive protein (hsCRP) could include a reduction in the risk of stroke, according to new data from the JUPITER* trial.

The relative risk of any stroke was reduced by 48 percent among patients taking the drug, the study’s investigators reported recently at the International Stroke Conference in San Diego, US.

This finding appears to have been driven largely by a reduction in ischemic stroke rates – just 23 of the 8,901 patients in the treatment group experienced this outcome compared to 47 in the equally-sized placebo group (hazard ratio 0.49; P=0.004). Rates of hemorrhagic stroke, conversely, were not significantly different – six events occurred in the intervention group and nine in the placebo group (hazard ratio 0.67; P=0.44).

The new stroke data bring fresh fuel to the debate about the role of hsCRP in risk stratification and the use of statins for primary prevention – questions that have risen to prominence since the presentation of the original JUPITER study at the American Heart Association’s annual Scientific Sessions in November last year. [N Engl J Med 2008 Nov 20;359(21):2195-207]

“The bottom line is that we now have conclusive evidence for the efficacy of statins specifically for primary prevention of stroke,” said Dr. Robert Glynn of Brigham and Women’s Hospital in Boston, US, one of the JUPITER investigators who presented the latest findings.

LDL cholesterol is not typically considered as a risk factor for stroke in patients without established vascular disease, said Glynn, noting that CRP, however, has been shown to be a valid predictor of stroke risk. Statin therapy, which lowers levels of both biomarkers, could therefore be particularly beneficial for stroke prevention in patients with elevated CRP, he added.

The ARIC** study implicated hsCRP as a risk marker for stroke. The study, which involved 12,762 middle-aged men and women followed up for around 6 years, showed that those with an hsCRP level above 3 mg/L had an adjusted hazard ratio for ischemic stroke of 2.7 when compared to those with an hsCRP level below 1 mg/L. [Arch Intern Med 2005 Nov 28;165(21):2479-84]

The SPARCL*** study, meanwhile, demonstrated the benefits of atorvastatin (80 mg daily) for secondary stroke prevention in a population of 4,731 patients with a recent history of stroke or transient ischemic attack. After a median follow up of 4.9 years, overall stroke risk was reduced by 16 percent in the statin group compared to placebo (adjusted hazard ratio 0.84; P=0.03) with comparable mortality between the two groups. There was, however, an increase in the number of hemorrhagic strokes: 55 events occurred in the atorvastatin group and 33 in the placebo group. [N Engl J Med 2006 Aug 10;355(6):549-59]

The original JUPITER trial found that after a median of 1.9 years of follow up rosuvastatin (20 mg daily), as compared to placebo, reduced the relative risk of major cardiovascular events by 44 percent in a cohort of 17,802 overtly healthy subjects with baseline hsCRP levels above 2 mg/L and LDL cholesterol levels below 130 mg/dL (hazard ratio 0.56; P<0.00001). Over the course of the study hsCRP levels were reduced by 37 percent and LDL cholesterol levels by 50 percent. *JUPITER: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin **ARIC: Atherosclerosis Risk in Communities *** SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels