Fucoidan Bermanfaat pada Ulkus Lambung Imbas - Aspirin

Aktivitas anti-peptik fucoidan saat ini telah cukup dikenal dan bahkan telah dipasarkan untuk indikasi tersebut. Mekanismenya yang telah diketahui hingga saat ini meliputi:

•Menstabilkan basic fibroblast growth factor yang diperlukan untuk proses penyembuhan ulkus lambung.

•Menstimulasi sel epitel untuk memproduksi epithelial growth factor.

•Tidak memiliki sifat pro-inflamasi seperti polisakarida lain.

Suatu studi terkini pada hewan coba mencit menilai manfaat pemberian fucoidan pada kondisi ulkus lambung yang diinduksi aspirin. Pemeriksaan yang dilakukan meliputi pemeriksaan biokimia dan imunologi.

Hasilnya menunjukkan bahwa pemberian fucoidan menghasilkan proteksi bermakna (p<0,05) terhadap ulserasi dengan menghambat alterasi akut AST (aspartate transaminase), ALT (alanine transaminase), sitokin, dan kadar glikogen dalam lambung. Namun, terdapat peningkatan kadar interferon gamma pada populasi yang diberikan fucoidan.

Hasil studi tersebut mengindikasikan adanya sifat anti-ulkus dari fucoidan yang berkontribusi dalam melindungi kerusakan oksidatif inflamasi yang dimediasi sitokin terhadap mukosa lambung. (HSD)

Reference:

1.    Effect of fucoidan on aspirin-induced stomach ulceration in rats.Chem Biol Interact. 2010;183(1):249-54.

2.   Properties of fucoidan from Cladosiphon okamuranus tokida in gastric mucosal protection.Biofactors. 2000;11(4):235-45.

3.      The efficacy of fucoidan on gastric ulcer.Indonesian Journal of Biotechnology. 2006;11(2).

Sumber: http://adf.ly/5K15Q

Read More

CCB dan Losartan Menurunkan Risiko Gout pada Pasien Hipertensi

Obat antihipertensi golongan CCB (calcium channel blockers) dan losartan menurunkan risiko gout pada pasien hipertensi. Temuan ini terungkap lewat penelitian yang dilakukan oleh Prof. Hyon Choi dan kolega dari Section of Rheumatology and the Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Amerika Serikat. Hasil penelitian ini telah dipublikasikan online dalam British Medical Journal.

Menurut sebuah penelitian, obat antihipertensi golongan diuretik terungkap meningkatkan risiko gout dan hiperurisemia, sedangkan penelitian lainnya juga memperlihatkan bahwa obat golongan beta-blockers juga meningkatkan kadar asam urat. Temuan ini berlawanan dengan hasil penelitian yang menggunakan obat antihipertensi golongan CCB dan losartan. Obat-obat golongan CCB dan losartan diketahui dapat menurunkan asam urat dalam darah, sehingga pemberiannya diperkirakan dapat menurunkan kejadian gout. Untuk memastikan hal tersebut, sebuah penelitian dilakukan untuk mengetahui hubungan tidak langsung antara penggunaan obat-obat antihipertensi dengan risiko gout diantara pasien-pasien penderita hipertensi.

Penelitian tersebut berupa analisis terhadap penelitian-penelitian kontrol kasus, yang datanya diambil dari praktik umum di Inggris tahun 2000-2007. Data yang terkumpul adalah 24.768 kasus gout di antara pasien berusia 20-79 tahun, dengan sampel acak sejumlah 50000 sebagai kontrol. Outcomeutama yang dinilai adalah kejadian gout yang berhubungan dengan penggunaan obat antihipertensi. Para peneliti telah melakukan penyesuaian terhadap umur, usia, indeks massa tubuh, jumlah kunjungan ke dokter, asupan alkohol, hubungan dengan obat-obatan lain, dan faktor-faktor komorbiditas.

Hasil penelitian memperlihatkan bahwa multivariate relative risks untuk kejadian gout yang berhubungan dengan penggunaan antihipertensi antara pasien-pasien hipertensi lebih rendah pada kelompok terapi CCB dan kelompok terapi losartan dibandingkan dengan kelompok terapi antihipertensi lainnya. Hasil yang sama juga diperoleh untuk pasien-pasien yang tidak menderita hipertensi. Multivariate relative risks untuk lamanya penggunaan CCB di antara pasien yang menderita hipertensi adalah 1,03 untuk penggunaan < 1 tahun dan 0,88 untuk penggunaan 1-1,9 tahun dan 0,75 untuk >= 2 tahun (p<0,05 untuk trend), sedangkan untuk losartan adalah 0,98 untuk penggunaan < 1 tahun dan 0,87 untuk penggunaan 1-1,9 tahun dan 0,71 untuk >= 2 tahun (p <0,05 untuk trend).

Para ahli dalam penelitian ini menyimpulkan bahwa pemberian CCB dan losartan disertai dengan risiko gout yang lebih rendah dibandingkan dengan obat-obat antihipertensi lainnya pada pasien-pasien hipertensi. Sebaliknya, diuretik, beta-blockers, angiotensin converting enzyme inhibitors, dan obat golongan ARB non-losartan disertai dengan peningkatan risiko gout. (YYA)

Reference:

1. Pathogenesis of gout. Ann Intern Med. 2005;143:499-516.
2. Antihypertensive Drugs and Risk of Incident Gout Among Patients With Hypertension. Available from:http://www.medscape.com/viewarticle/757006
3. Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med. 1980;93:817-21.
4. Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther. 2003;17:397-414.

Sumber: http://adf.ly/5K1ss

Read More

HPV Vaccine Policy: At Odds With Evidence-Based Medicine?

January 31, 2012 — Is the policy for the human papillomavirus (HPV) vaccine at odds with evidence-based medicine?

Yes, according to an essay published online December 22, 2011, in the Annals of Medicine.

Canadian researchers Lucija Tomljenovic, PhD, and Christopher Shaw, PhD, from the Neural Dynamics Research Group, University of British Columbia, in Vancouver, point out that there is a major discrepancy in claims regarding the safety and efficacy of Gardasil (Merck & Co) and Cervarix (GlaxoSmithKline) — the 2 HPV vaccines that are currently on the market.

The vaccines have been heavily promoted in the United States by their respective manufacturers, the essayists report. In addition, the vaccines are backed by government agencies in the United States, including the Center for Disease Control and Prevention and the US Food and Drug Administration, and by medical authorities in a number of other countries.

HPV vaccination has been mired in controversy since the first vaccine was approved in the United States in 2006. There have been clashes among politicians, parents, professional and advocacy organizations, and public health officials, with heated exchanges over issues ranging from safety, the premise that vaccination will promote sexual activity in teens, cost, and concerns about aggressive lobbying by Merck to make the vaccine mandatory for girls.

Drs. Tomljenovic and Shaw note that skepticism about the vaccine has been increasing for a number of reasons, despite reassurances from the public-health sector. In their essay, they examine the current evidence to answer a key question: "Is it possible that HPV vaccines have been promoted to women based on inaccurate information?"

Does it Prevent Cancer?

One major issue is the claim made by medical authorities that HPV vaccines are an important tool in preventing cervical cancer. The efficacy of the vaccines in preventing cervical cancer has not been demonstrated because the study periods have been too short, say the essayists.

The longest follow-up from phase 2 trials for Gardasil is 5 years and for Cervarix is 8.4 years, but invasive cervical cancer can take 20 to 40 years to develop from the time of HPV infection.

"We don't know the duration of the immune response of the vaccines," Dr. Tomljenovic told Medscape Medical News, "so we don't know if they are actually preventing cervical cancer or simply postponing it."

Both vaccines very effectively prevent persistent infections with high-risk HPV types 16 and 18 and the associated cervical intraepithelial neoplasia (CIN) 2/3 lesions in HPV-naïve young women. However, note the essayists, even persistent HPV infections caused by high-risk strains generally do not lead to precursor lesions in the short term or to cervical cancer in the long term.

The reason for this is that up to 90% of HPV infections resolve spontaneously within 2 years; even among those that remain, only a small proportion progress to a malignancy. Research shows that high-grade CIN can resolve or stabilize over time, the essayists explain, adding that neither vaccine is able to clear existing HPV16/18 infections or to prevent the progression of existing infections to high-grade lesions.

True Value of Vaccines

The essayists "have clearly and succinctly shown that the true value of HPV vaccines is not necessarily in the number or oncogenicity of HPV types included in the vaccine, but in how long the immunogenicity and efficacy of the vaccine is to this epithelial immune-system-avoidant HPV virus," said Diane Harper, MD, professor of medicine at the University of Missouri in Kansas City, who was approached by Medscape Medical News for independent comment.

HPV vaccines must maintain a near 100% efficacy for a full 15 years, at a minimum, for cervical cancer to be prevented, she explained. "If we vaccinate 11- and 12-year olds and Gardasil only lasts 10 years, then 21- and 22-year-old women are no longer protected," explained Dr. Harper, who was involved in clinical trials for both vaccines.

So far, Merck has not conducted any studies, nor are any planned, to evaluate the long-term immunogenicity and efficacy of needed booster shots, she continued. "Merck stopped their immune memory challenge study 1 month after the booster shot was provided, so that long-term immunokinetics and efficacy could not be evaluated. The cost-effectiveness models, which include a sensitivity analysis of finite duration, show that Gardasil is no longer cost effective if it requires a booster shot."

Can it Reduce the Cancer Rate?

An important question is whether the HPV vaccines can lower the rate of cervical cancer to below what has been achieved with Pap test screening. In industrialized nations, where screening is common, there has been a 70% reduction in the incidence of cervical cancer during the past 50 years, write the essayists. So even though cervical cancer is cited as the second most common cancer in women worldwide, existing data show that this only applies to developing countries.

Rachel Winer, PhD, assistant professor in the Department of Epidemiology at the University of Washington, Seattle, agrees that the vaccine can have the greatest impact in developing countries that lack adequate screening programs.

Although "it's true that Pap screening has been instrumental in reducing rates of cervical cancer in developed countries, over half of cervical cancers in the United States occur in women who are underscreened," said Dr. Winer. "Therefore, interventions such as vaccines are still important to further reduce rates of cervical cancer in developed countries."

In addition, she explained, vaccination can reduce rates of precancerous lesions, which place a tremendous burden on women and the healthcare system.

Charlotte Haug, MD, PhD, editor-in-chief of the Journal of the Norwegian Medical Association, pointed out that one of the problems in discussions of the HPV vaccine is that the risks, benefits, and cost effectiveness are very different, depending on whether you are in industrialized or developing countries. "The risk of cervical cancer is high in many developing countries, and women in these countries hardly have access to healthcare at all," said Dr. Haug, who was approached for independent comment.

Precursor lesions will not be easily detected without access to regular care, she noted. "Reducing the prevalence of cervical cancers in these countries can be done easily, and most cost effectively, by offering women a minimum of standard gynecological follow-up."

Even though cervical cancer does not have the same impact in industrialized nations as it does in the developing world, it still does occur. "This is where the HPV vaccine comes in," said Dr. Haug. "The studies show that, hypothetically, there might be a chance that we could lower the prevalence of cervical cancer even more."

However, she noted that the potential benefit is currently unclear and the cost is high. "So if you look only at industrialized countries, there may be no rational justification for introducing the vaccine," she said.

With the cervical cancer screening that is already in place in the United States, 8.0 in 100,000 women develop the disease every year, according to a study coauthored by Dr. Harper (Discov Med. 2010;10:7-17). Estimates of the impact of HPV vaccination in the absence of screening, based on modeling and the assumptions that efficacy will last a lifetime and that all women will be vaccinated, predict that 9.5 in 100,000 women will develop cervical cancer annually with Cervarix, as will 14 in 100,000 women with Gardasil.

The combination of screening and vaccination would not be expected to significantly reduce these numbers.

"The incidence of cervical cancer in the United States in 1999 was 9.7 in 100,000 women; in 2000, it was 9.6 in 100,000 and in 2001 it was 9.1 in 100,000," said Dr. Harper, noting that the year-by-year numbers vary quite a bit, so a 5-year weighted average is used to get an idea of trends.

There is a lot of variability in the number of women who get cervical cancer, Dr. Harper explained. "The American Cancer Society has varied its estimates of cervical cancer anywhere from 10,000 a couple of years ago to 12,200 most recently, so there is inherent variation in the success rate of Pap screening," she said. 

"Under the modeling assumptions of lifetime immunity (without the need for boosters), 100% efficacy against the HPV types, and 100% population uptake of the vaccine, the number of women who would not get cervical cancer, outside of those whose cervical cancer is detected by Pap screening, is very, very small," she added.

However, the vaccine might be beneficial in other ways. "Using the vaccines will decrease the number of abnormal Pap screens, the number of colposcopies, and the number of excisional procedures," Dr. Harper pointed out. "This is the true benefit of HPV vaccines in the United States."

Risk vs Benefit

Health agencies and regulatory bodies worldwide have stated that the HPV vaccines are safe and effective, and that the benefits outweigh the risks, note the essayists. "However, the rationale behind these statements is unclear, given that the primary claim that HPV vaccination prevents cervical cancer remains unproven," they write.

According to data from the World Health Organization, the current age-standardized death rate from cervical cancer is 1.7 in 100,000, they note.

This is 2.5 times lower than the rate of serious adverse reactions from Gardasil that have been reported to the Vaccine Adverse Event Reporting System (VAERS) (4.3 in 100,000 doses distributed). In the Netherlands, the reported rate of serious events from Cervarix is 5.7 in 100,000 doses administered, which is nearly 4 times higher than the age-standardized death rate from cervical cancer (1.5 in 100,000).

"It may not be fair to compare serious adverse events with death from cervical cancer, but we really have to look at the whole picture," explained Dr. Tomljenovic. "Cervical cancer is not a disease that affects teenagers and it can be prevented with regular Pap screening, which carries no risk."

Reported serious adverse reactions associated with HPV vaccination from Australia, France, Ireland, the Netherlands, the United Kingdom, and the United States include death, convulsions, paraesthesia, paralysis, Guillain–Barreì syndrome, transverse myelitis, facial palsy, chronic fatigue syndrome, anaphylaxis, autoimmune disorders, deep vein thrombosis, pancreatitis, and pulmonary embolism.

"We have to ask if it's worth receiving a vaccine that has been associated with a permanent debilitating disease, or death, in young girls, said Dr. Tomljenovic, emphasizing that these vaccines only have "a theoretical potential to prevent a disease that may or may not develop until decades later, and which can be easily prevented in another, safer way."

But Dr. Winer pointed out that some of the information regarding adverse events is misleading. "For example, comparing the serious adverse event rate from VAERS to the cervical cancer rate is misleading; there is currently no indication that any of the serious adverse events reported to VAERS were caused by the HPV vaccine," she said, noting that as the essayists themselves indicate, "a report to any passive vaccine surveillance system does not by itself prove that the vaccine caused an adverse drug reaction.'"

More Rigorous Assessment Needed

Since 2006, when Gardasil was approved in the United States, there have been 18,727 adverse reactions reported to VAERS — 1498 (8%) of which were serious (68 of which were deaths). Passive vaccine surveillance systems are inadequate in proving cause and effect, the essayists note.

They add that active surveillance needs to replace passive surveillance, and that systematic prospective controlled trials are needed to accurately establish or reject causal relations for drug-related adverse reactions of any type. Currently, many medical authorities have dismissed potential links between HPV vaccination and serious adverse events too quickly, they note.

The unusually high frequency of reported adverse events related to the HPV vaccines, along with their consistent patterns, indicates that "the risks of HPV vaccination may not have been fully evaluated in clinical trials," they write.

In addition, independent scientific reports have linked HPV vaccination to a number of serious adverse events.

They also note that the aggressive marketing strategies by the manufacturers have been questionable in some cases. More disturbingly, the "aggressive marketing strategies employed by the vaccine manufacturers is the practice by which the medical profession has presented partial information to the public."

Better surveillance is needed for adverse-event reporting, more independent research is needed, and long-term data are needed to evaluate the true duration of the vaccines. "Independent evaluation of HPV vaccine safety is urgently needed and should be a priority for government-sponsored research programs," Drs. Tomljenovic and Shaw conclude. "Physicians should adopt a more rigorous evidence-based medicine approach in order to provide a balanced and objective evaluation of vaccine risks and benefits to their patients."

Drs. Tomljenovic and Shaw "have succinctly and accurately portrayed the significant unknowns of Gardasil and the complicit interaction of the public-health system to politely not ask the embarrassing questions about true long-term efficacy and true cost effectiveness," said Dr. Harper.

This study was supported by the Dwoskin, Lotus, and Katlyn Fox Family Foundations. Dr. Tomljenovic and Dr. Shaw have disclosed no relevant financial relationships.

Ann Med. Published online December 22, 2011. Abstract

Source: http://adf.ly/5K1z0

 

Read More

Statins Reduce Cardiovascular Events and All-Cause Mortality in Women

January 30, 2012 (Boston, Massachusetts)— A large meta-analysis has shown that statins are as effective in women as in men for the reduction of cardiovascular outcomes and all-cause mortality, leaving investigators to conclude that statins should be used in all appropriate patients regardless of sex [1].

"There have been a large number of clinical trials looking at the benefits of statin use, but the ability for us to prove that the benefits extend to both men and women has been limited, in part because of numbers," lead investigator Dr William Kostis (Massachusetts General Hospital, Boston) told heartwire . 

"There have been studies that have shown benefits in men, and where they have shown a trend toward benefit in women they were unable to show a statistically significant difference. Because of this, we undertook the meta-analysis, and what we found was what we had hoped to find, and that was that the benefits of reducing cardiovascular outcomes and all-cause mortality extend to both men and women."

The meta-analysis, published in the February 7, 2012 issue of the Journal of the American College of Cardiology, included 18 clinical trials of statin therapy with clinical outcomes for men and women. The analysis included 141 235 subjects, including 40 275 women, from studies such as JUPITER, ALLHAT-LLT, ASCOT-LLA, Heart Protection Study, MEGA, PROVE-IT, and TNT, among others. Ten of the studies were secondary-prevention studies, and eight studies were designed as primary-prevention trials, although five of the primary-prevention studies did include a proportion of patients with cardiovascular disease.

In an editorial accompanying the study [2], Dr Lori Mosca (Columbia University Medical Center, New York) states that the finding of "no interaction by sex in this contemporary meta-analysis is concordant with prior meta-analyses that were limited by smaller numbers of women and suggests statin therapy has similar proportional benefits for men and women, regardless of the type of end point studied or the level of population risk."

Primary- and Secondary-Prevention Studies

In the meta-analysis, statin therapy significantly reduced the risk of cardiovascular events 19% in women and 23% in men. The treatment effect in women was more pronounced in the secondary-prevention studies, where a 22% reduction in the risk of cardiovascular events was observed, compared with the 15% reduction in outcomes found in the primary-prevention studies. The reduction in events was similar in studies that used placebo/usual care and low-dose statin therapy as the control arm.

Regarding all-cause mortality, the researchers report that treatment with statin therapy significantly reduced the risk of death in women by 10% in the primary- and secondary-prevention studies and by 13% when the primary-prevention studies were analyzed separately. The effect of statin therapy on all-cause mortality in women enrolled in the secondary-prevention studies was not statistically significant, and there was only a trend toward a reduction in all-cause mortality in men enrolled in the primary-prevention studies.

When investigators stratified patients by expected mortality, they found that statin therapy resulted in a significant reduction in cardiovascular outcomes in patients at low, medium, and high risk.

"This is a very large meta-analysis and it gives us good evidence to show that the benefit of statin use extends to both men and women," said Kostis. "It even extends to people considered low risk. I think going forward, as there will continue to be other statin trials and new agents, we want to make sure that women and people from all demographics are represented in the population studies, because it will allow us to show that benefits extend to all subpopulations, and if there are differences to see what they are with regard to safety and efficacy."

The Institute of Medicine has recently called for more sex-specific reporting of data for safety and efficacy outcomes. In the meta-analysis by Kostis and colleagues, there were not enough data to evaluate the adverse side effects of statin therapy in women, as just two studies reported sex-specific adverse-outcomes data. Future sex-specific results in cardiovascular medicine trials are needed to assess absolute and relative benefits, adverse outcomes, and cost-effectiveness.

Good for the Goose . . . 

In her editorial, Mosca points out that "only a handful" of primary-prevention studies were available for analysis, and four of these trials enrolled patients at low risk for cardiovascular events, making it difficult to provide much clarity surrounding the controversy of statin use in women. In addition, the meta-analysis focused on the relative reduction in risk and does not provide data on the absolute benefit of treatment.

If treatment decisions regarding statins are driven by the annual mortality risk of the patient in primary prevention, the absolute risk of cardiovascular disease and corresponding proportional reduction in risk from statin therapy are needed to make "informed clinical choices."

"Only then we will know with less uncertainty whether what is good for the gander is also good for the goose," writes Mosca.

References

Source: http://adf.ly/5K228

Read More

Working Long Hours May Double Depression Risk

January 30, 2012 — Working overtime appears to be a risk factor for depression, new research shows.

In a prospective cohort study led by Marianna Virtanen, PhD, from the Finnish Institute of Occupational Health, Helsinki, Finland, British civil servants who worked 11 or more hours a day had an almost 2.5-fold greater risk of having a major depressive episode than their counterparts who worked 7 to 8 hours a day.

The study is published online January 25 in PLoS ONE.

The cohort consisted of 1626 men and 497 women who were participants of the Whitehall II study, which aimed to assess the health of London-based civil servants aged 35 to 55 years.

The mean age of the cohort was 47 years at study entry. All the participants were healthy, reporting no symptoms of depression when initially surveyed.

Participants were asked about their work hours. They were followed for a mean of 5.8 years (range, 3.8 - 7.2 years).

At the end of the follow-up period, the workers were screened again. The presence of a major depressive episode during the previous 12 months was assessed using the University of Michigan version of the Composite International Diagnostic Interview (UM-CIDI), which was adapted for a self-administered computerized interview.

"We defined a major depressive episode as a medical diagnosis with 3 core symptoms — depressed mood, anhedonia, reduced energy — and 7 additional symptoms — loss of self-confidence, unnecessary feelings of guilt, changes in appetite or weight, sleep disturbances, difficulties in concentration or indecisiveness, suicidal thoughts or thinking of death, and slowing or agitation of movement," Dr. Virtanen told Medscape Medical News.

Mechanism Unclear

At least 2 core symptoms and at least 4 additional symptoms lasting at least 2 weeks were required for a major depressive episode.

The researchers found that "healthy" employees who worked 11 hours or longer per day at the beginning of the study were 2.43 times more likely to have a diagnosis of clinical depression 4 to 5 years later (95% confidence interval [CI], 1.11 - 5.30), after adjusting for sociodemographic factors at baseline.

After adjusting further for chronic physical disease, smoking, alcohol use, job strain, and work-related social support, the odds ratio was 2.52 (95% CI, 1.12 - 5.65), Dr. Virtanen reported.

The study also showed that a high socioecomic status, which came with an increased likelihood of working long hours, seemed to protect against depression.

"Our findings are in accordance with observations from other studies that showed a positive association between long working hours and depression," Dr. Virtanen said. "But we cannot draw conclusions as to why long working hours are associated with depression from our study."

People should be aware, however, that among many other contributing factors, excessive working hours may predispose to depression, Dr. Virtanen said.

It might also be a good idea for doctors to ask their patients whether they work long hours, and if the answer is yes, to ask whether this is a habit that has lasted a long time, she suggested.

"We do not know whether short periods of long hours at work are harmful. It is also known that many stress factors, when present together, increase the risk of depression. Thus, reducing those factors could be beneficial. At any rate, if people are able to make some changes to the hours they work, it is likely to be better than no change," Dr. Virtanen said.

Downtime Important

Commenting on the study for Medscape Medical News, Dr. Alan J. Gelenberg, MD, Shively/Tan professor and chair of psychiatry at Penn State University, Hershey, Pennsylvania, said that the study marks another step toward increasing understanding of the factors that contribute to depression.

"One of the more interesting aspects is that in this group, which was biased towards British males in white collar jobs, the upper echelon of high-level civil servants seemed immune from this effect, even though they worked long hours," Dr. Gelenberg said.

Stressing that he was speculating, Dr Gelenberg said: "One reasonable possibility is that additional work coupled with the fact that you may not have any control over it could predispose you to depression. That’s why the upper echelons may have been immune; they probably had more control over their work projects."

Dr. Gelenberg added that people who have less control but who are given extra work have additional stress and perhaps less time for the "de-stressing, fun, relaxing things that are part of a healthy lifestyle."

Dr. Gelenberg said that people need time to exercise, to kick back, and to restore their batteries. In addition, he said people need time with their family and that they should get enough sleep. "All of these things contribute to their overall sense of well-being and functioning," he said.

Dr. Virtanen and Dr. Gelenberg have disclosed no relevant financial relationships.

PLoS One. January 25, 2011. Full article

Source: http://adf.ly/5K25Q

Read More

Clazosentan Reduces Vasospasm After Subarachnoid Hemorrhage

February 1, 2012 (New Orleans, Louisiana) — In a randomized trial, treatment with clazosentan, a still-investigational endothelin receptor antagonist, reduced the risk of vasospasm after aneurysmal subarachnoid hemorrhage (SAH) but did not improve functional outcomes.

The authors report that clazosentan, especially at 15 mg/h, significantly reduced morbidity related to post-SAH vasospasm at 6 weeks, but no effect was seen with the 5 mg/h dose.

In addition, "neither dose improved functional outcomes," noted lead investigator R. Loch Macdonald, MD, head of neurosurgery at St. Michael's Hospital at the University of Toronto in Canada, at a press conference here. He suggested that the 3-fold greater use of rescue therapy in the placebo arm of the study may have influenced this outcome.

The new results, from the Effect of Clazosentan on Clinical Outcome after Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling trial (CONSCIOUS-3), were reported at the American Stroke Association's International Stroke Conference (ISC) 2012. The study was funded by Actelion Pharmaceuticals.

Few Alternatives

"We don't have very effective treatments for this complication," Dr. Macdonald said of vasospasm after SAH. "The treatment in use now [nimodipine] is very expensive and risky and doesn't work very well, and about half of the patients suffer permanent problems from it."

In a previous study, CONSCIOUS-1, clazosentan was shown to reduce angiographic vasospasm after ruptured aneurysm in a dose-dependent fashion. The current study aimed to assess whether clazosentan improved vasospasm-related morbidity and all-cause mortality after aneurysmal SAH.

The CONSCIOUS-3 study was a randomized, double-blind, placebo-controlled trial that included 571 patients aged 18 to 75 years with SAH caused by ruptured saccular aneurysm, which was secured by endovascular coiling. Patients were randomly assigned to receive intravenous clazosentan 5 mg/h (n = 194), clazosentan 15 mg/h (n = 188), or placebo (n = 189) for ≤2 weeks.

The primary endpoint was a composite of all-cause mortality, vasospasm-related new cerebral infarct, delayed ischemic neurological deficit caused by vasospasm, and rescue therapy in the presence of confirmed angiographic vasospasm. Patients were evaluated for the endpoint 6 weeks post-SAH and were further assessed centrally by a blinded critical events committee. The main secondary endpoint was the extended Glasgow Outcome Scale (GOSE) at week 12.

CONSCIOUS-3 was halted prematurely after the parallel CONSCIOUS-2 study, in which patients were treated with surgical clipping, showed only a trend for improvement in the primary endpoint of mortality or vasospasm-related morbidity at 6 weeks and no improvement in functional outcomes with clazosentan. The investigators planned a target 1500 patients in CONSCIOUS-3, but ultimately only 577 were enrolled and 571 treated.

Higher Dose Associated With Benefits

In this trial, a primary composite endpoint event occurred in 27% of the placebo group compared with 24% of the low-dose clazosentan group and 15% of the high-dose clazosentan group.

"Despite having less than half of the intended patients in the study, we were encouraged to see that at a high dose, there was a significant reduction in vasospasm in patients initially treated with endovascular coiling," Dr. Macdonald said.

The improvement was significant in the comparison of the 15 mg/h experimental group vs placebo, with an odds ratio of 0.474 (P = .007). The odds ratio for the 5 mg/h group was 0.786 and was not statistically significant (P = .340).

"When we broke out the 4 components of the primary endpoint, we saw no significant difference in the death rate, but all the other components were strikingly reduced in the 15 mg/h group," he observed.

At week 12, mortality rates were similar between groups, but delayed ischemic neurological deficits diminished in a dose-dependent manner.

Table. Mortality and Delayed Neurologic Deficit by Treatment

Endpoint	Placebo	Clazosentan 5 mg/h	Clazosentan 15 mg/h
Mortality Rate (%)	6	4	6
Delayed Neurologic Deficits (%)	21	18	10

Vasospasm-related new cerebral infarct occurred in 13% of the placebo group, 16% of the 5 mg/h group, and 7% of the 15 mg/h group. A 3-fold greater use of rescue therapy was seen in patients receiving placebo (21%) compared with the 15 mg/h clazosentan dose (7%).

Functional outcomes, however, were not improved with treatment. Poor functional outcome (GOSE ≤ 4) occurred in 24% of the placebo recipients, 25% of the 5 mg/h group (P = 0.748), and 28% of the 15 mg/h group (P = 0.266).

Treatment-emergent adverse events of specific interest for the placebo group, the 5 mg/h group, and the 15 mg/h group, respectively, were lung complications (21%, 36%, 37%), anemia (10%, 13%, 13%), and hypotension (7%, 11%, 16%).

According to Dr. Macdonald, greater benefits, especially improvements in neurological outcomes, might be observed with different doses and administration regimens, and in the absence of vasodilators. A study is ongoing in Japan.

Going forward, he said the manufacturer will have several options: to seek regulatory approval based on the small subset of patients in the coiling group receiving the higher dose (the 15 mg/h dose was not tested in the clipped patients); conduct another study using the higher dose in clipped and coiled patients; and use an endpoint other than GOSE at 90 days.

"GOSE is the traditional endpoint, which is accepted by the FDA, but it was not developed for patients with SAH and it is not sensitive to the kinds of deficits they have," he noted. "A better clinical outcome measure assessing patients' cognition and other functions likely to be affected by SAH may allow us to demonstrate a clinical benefit."

Hindsight 20-20

Steven Greenberg, MD, professor of neurology at Harvard Medical School, Boston, Massachusetts, commented on the problem of vasospasm and clazosentan as a potential solution. "This is an active area of research," Dr. Greenberg told Medscape Medical News. "We are understanding the biology of vasospasm at a higher level, and we hope that from the biology will come new drug approaches," he said in an interview.

"But a clinical trial is like steering the QE2," he cautioned. "It's such an expensive and difficult proposition, and in retrospect there are things that we might have done differently. If we had to do it again, the previous CONSCIOUS-2 study might have included the dose that looks fairly promising, but it did not, because in CONSCIOUS-3, there did seem to be a dose response," he suggested.

"It would be great, in an ideal world, to have a study of the 15-mg/h dose, to convince us this effect is real," Dr. Greenberg said. "And it would be an important advance to have a second drug for preventing vasospasm. Nimodipine has a significant effect but it's a small effect, and it does not prevent the majority of vasospasms."

The study was funded by Actelion Pharmaceuticals. Dr. Macdonald reported receiving research grants from Modest and Actelion Pharmaceuticals; having an ownership interest in Edge Therapeutic; and serving as a consultant or advisor for Actelion Pharmaceuticals. Dr. Greenberg has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2012. Presented February 1, 2012. Abstract #2421

CONSCIOUS-1, CONSCIOUS-2

Read More

'Cardiovascular Health' New Focus of the AHA, Linked With Reduced Mortality

Michael O'Riordan

February 1, 2012 (Chapel Hill, North Carolina) — Individuals meeting five of seven cardiovascular health metrics outlined by the American Heart Association (AHA) had a significantly lower risk of all-cause mortality and deaths from diseases of the circulatory system compared with unhealthy individuals who met none of the metrics [1]. The findings support the new AHA course on focusing on cardiovascular health, say investigators, noting that attaining the cardiovascular metrics outlined by the AHA could result in substantial reductions in mortality.

"I think the AHA goals really emphasize to clinicians the importance of getting after their patients and working with them," lead investigator Dr Earl Ford (Centers for Disease Control and Prevention, Atlanta, GA) told heartwire . "If they smoke, we want to get them to stop smoking. We want to control hypercholesterolemia, to bring blood pressure down, or if they have elevated blood glucose levels, to get that down as well. In terms of physical activity and diet, these are also important as well, as important as the other risk factors in one way or another."

The results of the study are published online January 30, 2012 in Circulation.

The 2020 Impact Goal

The AHA 2020 Impact Goal is to improve the cardiovascular health of Americans by 20% while also reducing cardiovascular deaths by 20%. In order to achieve these goals, the AHA adopted a new concept of cardiovascular health, one that is made up of seven components. These components include four ideal health behaviors--not smoking, body-mass index (BMI) <25 kg/m², physical activity at goal levels, and diet that includes three or more servings of fruits and vegetables daily--and three ideal health factors, including total cholesterol <200 mg/dL, systolic blood pressure <120 mm Hg and diastolic blood pressure <80 mm Hg, and fasting plasma glucose levels <100 mg/dL.

Each of these individual behavior and risk factors are well supported by data, but there have been few studies that have addressed the relationship between clusters of the risk factors/behaviors and health outcomes. "Even though a lot of the health metrics are rooted in sound science, it's still a relatively new index," said Ford. "To me, we needed to learn about how well it predicts and how well it behaves, because this particular index hadn't really been explicitly tested."

In their study, Ford and colleagues collected data on 7622 adults 20 years of age and older participating in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2002. In the absence of AHA-specific metrics, such as dietary and glycemic measures, they used alternative measurements, such as the use of HbA_1c concentrations as a stand-in for fasting plasma glucose and the Healthy Eating Index (HEI) for dietary assessments.

Overall, just 1.0% of subjects met all seven metrics of sound cardiovascular health, a disappointing number that is in line with previous studies. In total, 13.8% of subjects met five of the seven metrics of cardiovascular health and 5.4% met six metrics, while 1.5% of the study population met none of the ideal cardiovascular health criteria.

After a median of 5.8 years of follow-up, there were 532 deaths, including 186 deaths caused by diseases of the circulatory system. The data showed a significant and inverse relationship with all-cause mortality and death from circulatory diseases with an increasing number of ideal cardiovascular metrics. Compared with individuals with no ideal health measures, those with five or more had a 78% lower risk of all-cause mortality and an 88% lower risk of death from diseases of the circulatory system. The results were the same when researchers excluded patients who died in the first year of follow-up and when patients with cardiovascular disease were excluded from the analysis.

"No," said Ford when asked if he was surprised by the findings. "The preceding body of literature that used different metrics or different combinations of metrics often shows results within the same ballpark as ours, often up to a 90% reduction in subjects meeting ideal criteria. So, no, the results didn't really come as a surprise. It would have been a surprise if it hadn't."

With the exception of diet and exercise, which are behavioral components, Ford said that the criteria for ideal cardiovascular health are already being measured and assessed during routine office visits. He noted that he can't even visit his own doctor "without getting a blood pressure [cuff] slapped on my arm, regardless of why I'm there."

Cardiovascular Health Equals Population Health

In an editorial [2], Dr Lawrence Appel (Johns Hopkins University, Baltimore, MD), who was a member of the AHA task force that refocused on cardiovascular health, said the shift toward ideal cardiovascular health is extremely relevant to the long-term goal of eliminating health disparities and improving population health. Appel notes that disparities in four cardiovascular risk factors--smoking, blood pressure, blood glucose, and adiposity--help explain more than 50% of the racial differences in cardiovascular mortality in the US.

Regarding population health, Appel said that risk factors and behaviors that improve cardiovascular health are related to noncardiovascular outcomes and the improvement of overall population health, as shown by the significant reduction in all-cause mortality. "Efforts must now focus on interventions that assist individuals and populations in achieving and sustaining cardiovascular health, which hopefully will become the default, rather than the exception," writes Appel.

Better Middle-Age Heart Health if Prevention Starts Early

Another study published the same day in Circulation by Dr Kiang Liu (Northwestern University, Chicago, IL) used a sample of patients from the CARDIA study, including 3154 black and white subjects aged 18 to 30 years old, and reported that the maintenance of a healthy lifestyle in young adulthood is strongly associated with a lower risk of cardiovascular disease in middle age.

Similar to the study by Ford and colleagues, the researchers assessed healthy lifestyle factors such as obesity, alcohol intake, diet, physical activity, and smoking status. For these subjects, an increased number of healthy lifestyle factors in young adulthood led to a greater prevalence of a low cardiovascular disease risk profile when assessed 20 years later.

The findings have significant public-health implications, according to Liu et al, suggesting that a better heart health in midlife can be achieved if individuals adopt and maintain healthy lifestyle patterns early in adulthood.

References http://adf.ly/5K2IF

Source: http://adf.ly/5K2CI

Read More