Hostility Events Dog Small Minority of SSRI Users

BANGOR, Wales, Sept. 12 — Selective serotonin reuptake inhibitors (SSRI) can have a rare paradoxical effect, sparking aggressive or violent behaviors in otherwise placid patients.

So reported three researchers here who concluded from an odd mix of studies and reports on the antidepressants, including e-mail responses to a TV documentary, that Paxil (paroxetine) and other SSRIs can trigger what they called “hostility events.”

The three study authors have all served as expert witnesses in legal cases revolving around antidepressants and violence or suicide. Their findings have legal implications, they reported in the September issue of the online journal PLoS Medicine, because “many jurisdictions appear not to have considered the possibility that a prescription drug may induce violence.”

“Our main finding is that unselected sets of placebo-controlled trials of antidepressants show evidence for an increased relative risk of aggressive behaviors on treatment, although such outcomes apply to only a small subset of patients,” wrote psychologist David Healy, Ph.D., of Cardiff University here, and colleagues.

The investigators reviewed data on the SSRIs Paxil, Prozac (fluoxetine), and Zoloft (sertraline), looking at controlled trials and other sources. They found in a pooled analysis of studies of children and adults treated with Paxil, 0.65% had a “hostility event,” versus 0.31% of patients on placebo (odds ratio [OR]: 2.10; 95% confidence interval [CI]: 1.37-3.48).

They cautioned that in criminal or civil cases involving a suspected influence of antidepressants on behavior, the relative rarity of the documented events should be taken in consideration.

“When violence is a suspected outcome, every case has to be considered carefully, on the principle that individuals are responsible for their conduct, unless there is clear evidence of compromised function that cannot be otherwise explained,” they wrote.

They focused their attention on Paxil because of the availability of data from legal cases in which the drug was implicated, as well as data sets provided to British regulators by GlaxoSmithKline, makers of Paxil.

In their study, Dr. Healy and David B. Menkes, Ph.D., also at Cardiff University, and Andrew Herxheimer, Ph.D., a clinical pharmacologist at the United Kingdom Cochrane Center in Oxford, reviewed data presented to the United Kingdom’s Committee on Safety of Medicines Expert Working group on placebo controlled trials of Paxil in adults and children, as well as placebo-controlled studies of Zoloft in children.

They also reviewed data from United Kingdom Drug Safety Research Unit prescription-event monitoring studies on Paxil and Prozac.

In addition, the authors considered e-mails from 1,374 patients who responded to a BBC program on Paxil broadcast in 2002.

They found that in clinical trials of Paxil, regulatory agencies lumped aggression and violence together under the heading “hostility,” using clinical codes that include homicide, homicidal acts, and homicidal ideation as well as aggressive events and conduct disorders.

In a pooled analysis of hostile events occurring in both children and adults, both on therapy and during a 30-day drug-free phase after patients were tapered off the drug, 60 of 9,219 patients (0.65%) overall had hostile events. In contrast, there were 20 hostile events among 6,455 patients (0.31%) on placebo.

“In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal,” the authors wrote. However, although the difference in the pooled analysis in adult and pediatric placebo-controlled trials was significant, the odds ratios for individual conditions (depression, obsessive compulsive disorder, anxiety and premenstrual dysphoria disorder) were not in the combined analysis.

The highest rates occurred in children with obsessive-compulsive disorder, who had a nearly 17-fold greater risk for a hostile event (CI: 2.22-130.0) compared with those on placebo.

Additionally, the authors found that in studies of Paxil in healthy volunteers, hostile events occurred in 1.1% of those on the active drug, compared with none on placebo.

“Although not statistically significant, this finding is striking because hostile events are unusual in healthy volunteer trials,” they wrote.

In prescription-event monitoring studies of Paxil and Prozac, there were 18 reports of aggression among 13,741 patients (0.13%) during the first six month of treatment with Paxil, compared with 20 of 12,692 patients (0.16%) among patients on Prozac. There was one reported murder, committed by a patient on Paxil.

Additionally, data submitted by Pfizer on two clinical trials of Zoloft in children with depression showed that aggression was most common cause of discontinuation.

“When discontinuations for any manifestation of treatment-induced activation (suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression) were considered, there were 15 discontinuations on sertraline compared with two on placebo, a relative risk of 7.3 (95% CI, 1.70-31.5, P=0.0015),” the authors noted.

In a review of nearly 1,400 responses to a BBC program on Paxil, Dr. Healy found that people who had taken the drug frequently reported severe mood changes associated with dosing changes in the first week of treatment, later dosage increases, dosage decreases, and drug withdrawal.

The legal implications of their findings, the authors wrote, are that “if antidepressants can in principle trigger violence, a need will always remain to establish whether such a general possibility might have been realized in an individual case. The principles involved in making such assessments will involve a consideration of the timing of the events in relation to treatment, the merits of competing explanations, and the existence of evidence in a particular case for a mechanism through which treatment may have led to violence.”

Primary source: PLoS Medicine

Source reference:
Healy D et al. “Antidepressants and Violence: Problems at the Interface of Medicine and Law.” PLoS Med 3(9): e372. DOI: 10.1371/journal.pmed.0030372

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Tanning Beds May Be Even Riskier Than Thought

Indoor tanning beds may be even more likely to cause skin cancer than previously believed.

New research published online Oct. 6 in the Journal of Investigative Dermatology suggests that the main type of ultraviolet rays used in tanning beds — UVA1 — may penetrate to a deep layer of skin that is most vulnerable to the cancer-causing changes caused by UV rays.

The new study comes as the U.S. Food and Drug Administration considers banning the use of tanning beds among children under 18. The American Academy of Pediatrics is on record that it supports such a ban.

In the study, 12 volunteers were exposed to UVA1 and UVB rays on their buttocks. (One difference in the waves is length: UVB waves are shorter.)

The UVA1 was more damaging to the skin’s basal layer then the UVB light. The UVA1 induced a type of lesion called thymine dimers on the deeper basal layers of the skin. UVB radiation caused more of these lesions, but they did not go as deep, and thus may be less likely to cause the changes linked to skin cancers.

“The doses we used were comparable for erythema — sunburn — for UVA and UVB. That would be roughly equivalent to the doses needed for tanning in each spectrum,” said study co-author Antony R. Young, a professor at the St. John’s Institute of Dermatology at King’s College School of Medicine in London.

“Indoor tanning is like smoking for your skin,” said Dr. Doris Day, a dermatologist at Lenox Hill Hospital in New York City. “It’s the single worst thing you can do in terms of skin cancer and premature aging.”

Many indoor tanning salons advertise that tanning beds can help boost the body’s production of vitamin D, known as the sunshine vitamin because skin makes it when exposed to the sun’s rays. “This is nonsense and an excuse,” Day said. “We know people burn in tanning beds and that UVA and UVB are toxic.”

Teens are particularly vulnerable, she said. “They are immortal in their mind, and skin cancer and aging seem a long ways away.” Melanoma, a potentially fatal form of skin cancer, “is not an old person’s disease,” she said. The new study provides “a little bit more muscle in helping to warn people about the dangers of tanning, but an FDA ban is what we need,” she added.

“I do think there should be legislation on sunbed use under 18 years of age,” said Young, who added that such use is already prohibited in England.

John Overstreet, executive director of the Indoor Tanning Association, a Washington, D.C.-based trade group representing the industry, said that if there was science to back up many of these claims, the FDA would have acted by now. The agency has been mulling these claims since March 2010, he noted.

What’s more, the new study is about ultraviolet radiation, not tanning beds, he said. “Tanning beds have the same ratio of UV waves as the sun. UVA-1 is the primary wave length emitted by the sun, too,” he said. “The sun and indoor tanning pose the same risks and benefits if you don’t burn. There is no science that shows non-burning exposure to sun or a sun lamp causes cancer.”

Dr. Heidi A. Waldorf, director of Laser and Cosmetic Dermatology at Mount Sinai Hospital in New York City, said that the new study adds to the body of evidence about the damaging effects of the sun’s rays. “This finding fits with our understanding of UVA as the deeper penetrating ‘aging’ rays,” she said. “The data is important as we discuss regulatory changes in the labeling of broad-spectrum sun protection products and as we educate patients, particularly young women, about the dangers of indoor UVA tanning beds.”

The FDA now requires sunscreens to have a minimum sun protection factor (SPF) of 15 and be labeled as broad spectrum to show that that protect against both UVA and UVB waves.

More information

Find out more about the dangers of tanning at the Skin Cancer Foundation.

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MRI May Prove Useful in Breast Cancer Assessment

Researchers at Boca Raton Community Hospital in Florida assessed the potential of contrast-enhanced magnetic resonance imaging (MRI) to augment mammography and/or sonography in the diagnosis of early-stage breast cancer.

In the past, MRI was not routinely used for breast cancer imaging due to a high rate of false positives. The authors of the current study, appearing in the American Journal of Radiology, used an enhanced MRI method, based on computer-assisted diagnosis, which determined the tumor’s morphology and the kinetics of its uptake and release of contrast image agent. Tumors that rapidly lit up and faded were usually cancerous.

The investigators designed a trial in which they performed contrast-enhanced bilateral breast MRIs on 65 patients with highly suspicious results from mammography, sonography, or both (BI-RADS category 4 or 5). At the time of the MRI, all patients were considered candidates for breast conservation. In addition to characterizing the primary lesion, investigators also evaluated additional ipsilateral and contraleteral lesions. After MRI and biopsy, subjects were re-evaluated for appropriateness of breast-conservation therapy.

Primary breast lesions in 46 patients (71%) were determined to be malignant (39 invasive cancers, 5 intraductal, 2 lymphomas). MRI sensitivity was 100% for breast malignancy while specificity was 73.7% (14/19) for benign lesions.

MRI detected 37 additional lesions, 23 cancerous, in addition to those detected by mammography or sonography. Biopsies of the 19 patients whose lesions were deemed benign by MRI were all negative.

MRI was associated with a higher recommendation for mastectomy in 18% of confirmed breast cancer patients and additional biopsy of 14 benign lesions, 6 of which were atypical ductal hyperplasia.

Researchers concluded that MRI enhances standard clinical evaluation afforded by sonography and mammography in early-stage breast cancer, and could assist in patient management.

Study investigator Dr. Jonathan Wiener in an interview released by the American Roentgen Ray Society suggested that the 15% recurrence rate for breast cancer might be due to tumors that are initially missed by conventional imaging methods. “The addition of MRI will improve the accuracy of breast cancer diagnosis,” he said.

It is important to note, as the authors pointed out, that this study population consisted of patients thought to potentially have breast cancer. As a result, a large percentage of the lesions were malignant with many invasive cancers. They stated that “The accuracy of these MRI methods can therefore not be assumed for detection of early-stage cancer (e.g., ductal carcinoma in situ) or in a low-risk screening population. MRI will likely prove efficacious as a screening tool in difficult-to-image or high-risk populations such as gene carriers; patients with atypia, atypical ductal hyperplasia, or lobular carcinoma in situ on biopsy; patients with dense breasts; and those with a strong family history or a personal history of breast cancer.”

Primary source: American Journal of Radiology

Source reference:
Wiener JI et al. Assessment of Suspected Breast Cancer by MRI: A Prospective Clinical Trial Using a Combined Kinetic and Morphologic Analysis AJR 2005; 184:878-886.

Additional source: American Roentgen Ray Society press release

Source reference:
MRI Proves Useful in Assessment of Suspected Breast Cancer Patients

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One-Time Colon Exam Yields Big Benefits

A single sigmoidoscopy study in middle age reduced colorectal cancer mortality by more than 40% and incidence by one-third, data from a large, randomized clinical trial in the U.K. showed.
Patients assigned to this limited examination of the colon had a 50% reduction in cancer of the distal colon, compared with a control group that did not have sigmoidoscopy.
Flexible sigmoidoscopy also was associated with a trend toward lower overall mortality, and the results suggested the one-time procedure would save money by reducing the incidence of colon cancer and associated treatment costs, investigators reported online in The Lancet.
“There’s never been trial evidence that removing polyps prevents cancer,” Wendy S. Atkin, PhD, of Imperial College London, said at a news conference to announce the results. “There has been lots of indirect evidence, but there has never been a trial.”

“A once-only examination gives a very big effect over the whole of the bowel, including that it isn’t even examined,” she added.

U.S. specialists, who generally prefer more extensive, and expensive, colonoscopy — gave the study mixed reviews. But they agreed that it provides ammunition for the overall benefits of colorectal cancer screening.

“This is an extremely significant study which clearly shows, within the context of a randomized clinical trial, that endoscopic screening leading to the removal of polyps . . . will reduce colon-cancer specific mortality,” Robert Mayer, MD, of Dana-Farber Cancer Institute in Boston, said in response to a query from MedPage Today and ABC News.

“Such a positive effect had been assumed for several years and is incorporated into present screening guidelines in the U.S. . . . but — until the publication of this report — had not been validated prospectively.”

In contrast, Roshini Rajapaksa, MD, of New York University, said the results were “not that significant.” Like most other American specialists contacted, she defended full colonoscopy.

“Previous studies have shown that flexible sigmoidoscopy reduced mortality from colorectal cancer. And if the study had compared sigmoidoscopy with colonoscopy, the colonoscopy patients most likely would have had a greater reduction in mortality. So colonoscopy still remains the best test for colorectal cancer screening. However, sigmoidoscopy is cheaper, and certainly better than no test at all,” Rajapaksa said.

All of the specialists who responded to the query noted the most glaring limitation of sigmoidoscopy.

“The significance of this study is that it provides further evidence that colorectal cancer screening saves lives,” said Fritz Francois, MD, also of New York University. “However, we know that colon polyps and cancer can occur on the side not examined by the sigmoidoscope [right colon], and therefore colonoscopy remains the much more complete gold standard able to detect and remove precancerous lesions.

“In the U.S. we have seen a shift in the distribution of colonic lesions towards the right side, and this is particularly evident in certain racial/ethnic groups. Therefore, sigmoidoscopy would not be the best option,” he added.

The results came from a study involving 170,000 people ages 55 to 64, living in England, Wales, and Scotland. All of the participants responded to a questionnaire indicating their willingness to be screened for colon cancer. Subsequently, the participants were randomized 2:1 to no screening or to a one-time, flexible sigmoidoscopy procedure.

The rationale for the study came from the recognition that screening can prevent colorectal cancer by detection and removal of adenomas.

Two-thirds of colorectal cancers and adenomas arise in the rectum and sigmoid colon, where they can be identified and examined by flexible sigmoidoscopy, Atkin and co-authors wrote in The Lancet.

Most people who develop distal (left-sided) colon cancer have adenomas by age 60, the authors continued. Use of sigmoidoscopy to detect and remove adenomas affords long-term protection against distal colon cancer.

The clinical trial tested the hypothesis that a single sigmoidoscopy performed in people 55 to 64 would be a cost-effective and acceptable method to reduce colorectal cancer incidence and mortality.

Atkin and co-authors reported results from 11 years of follow-up.

During that time, 1,818 members of the control group developed colorectal cancer as did 706 in the sigmoidoscopy group. Additionally, 538 patients in the control group died of colorectal cancer compared with 189 in intervention group.

The differences translated into a 23% reduction in the incidence of colorectal cancer (HR 0.77, 95% CI 0.70 to 0.84) and a 31% reduction in colorectal cancer-specific mortality in favor of the sigmoidoscopy group (HR 0.69, 95% CI 0.59 to 0.82).

A per-protocol analysis adjusted for self-selection bias in the intervention group showed even larger benefits associated with screening sigmoidoscopy: a 33% reduction in colorectal cancer incidence (HR 0.67, 95% CI 0.60 to 0.76) and a 43% reduction in colorectal cancer mortality (HR 0.57, 95% CI 0.45 to 0.72).

Investigators determined that 191 patients would have to be screened to prevent one colorectal cancer diagnosis and 489 to prevent one colorectal cancer death.

The results are consistent with screening guidelines of the American Cancer Society and the U.S. Preventive Services Task Force, both of which recommend sigmoidoscopy every five years as a screening option, said Durado Brooks, MD, director of prostate and colorectal cancer for the ACS.

“The American Cancer Society sees this trial as significant,” Brooks said in an interview. “Its findings support our current guidelines that include flexible sigmoidoscopy as one of several options. Perhaps most important is the study’s reinforcement that the benefits of colorectal screening are not in doubt.”

A clinical spokesperson for the American Society of Clinical Oncology agreed with Brooks that the trial proves that screening prevents cancer and saves lives. However, the trial left several issues unresolved.

“I don’t think it applies to our guidelines because it doesn’t compare [sigmoidoscopy] to colonoscopy, and it doesn’t tell us whether one examination is better than examinations over time at a longer interval, Jennifer Obel, MD, of NorthShore Health System in Chicago, said in an interview.

“The trial validates that we can prevent colon cancer, and I think that’s the take-home message of this study, she added.

The authors reported no disclosures.

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Wrongful ICD Jolts Not Just a Nuisance

Inappropriate shocks from an implantable cardioverter-defibrillator (ICD) are common in real-world practice and are associated with an increase in mortality risk, Dutch researchers affirmed.

A single wrongful jolt was associated with a 1.6-fold elevated risk of death from any cause after adjustment for other factors (P=0.01) and each additional shock boosted the risk, up to 3.7-fold after five inappropriate shocks, Martin J. Schalij, MD, PhD, of Leiden University Medical Center in the Netherlands, and colleagues found in their single center registry.

The proportion of ICD patients who got at least one inappropriate shock rose over time to 18% at five years, the group reported in the Feb. 1 issue of the Journal of the American College of Cardiology.

These results add to similar findings from the 13% rate of inappropriate shocks at 41 months of follow-up in the study, as reported at the American College of Cardiology meeting last spring.

ICDs have also come under scrutiny recently for a high rate of potentially inappropriate implantation and a federal probe into ICD prescribing practices.

Although it’s unlikely that the shocks themselves are killing people, Schalij’s group cautioned, the results show that wrongful ICD discharge is not as benign as commonly thought.

“These inappropriate shocks are painful, psychologically disturbing, and potentially arrhythmogenic,” the researchers noted in their JACC report.

Although the observational study couldn’t determine causality, the researchers speculated that the association was most likely the result of cardiac injury from the high-voltage electrical discharge, which, in turn, lead to deterioration of left ventricular ejection fraction.

Other possible explanations, they added, are increased anxiety and depression or that the inappropriate shocks are a marker for atrial fibrillation, which is a leading mechanism for inappropriate shocks and is also linked to mortality.

The researchers looked at outcomes for all 1,544 patients (79% male, mean age 61) who received an ICD with data storage capability from 1996 to 2006 at their institution.

The majority of the devices (56%) were inserted for primary prevention, typically because of ischemic heart disease (64%).

There was an increase over time in the rate of inappropriate shocks — defined as episodes starting with a shock not delivered for ventricular tachycardia or ventricular fibrillation and ending if sinus rhythm was redetected by the ICD, and including multiple shocks if delivered within five minutes of the initial episode.

For first events, the cumulative rate was 7% at one year, 13% at three years, and 18% at five years.

For second events, the cumulative rate was 28% at one-year follow-up, 49% at three-year follow-up, and 55% at five-year follow-up.

Misdiagnosis of supraventricular tachycardia caused most of the inappropriate shocks (76%).

Independent predictors of inappropriate device discharge were: Younger age (HR 1.8 for under 70, P=0.01) History of atrial fibrillation (HR 2.0, P<0.01) Interim appropriate shocks (HR 1.6, P=0.06) No statin use at baseline (HR 1.3, P=0.09)

Although newer generations of devices with advanced algorithms, multiple sensing leads, and better programing would have been expected to reduce inappropriate shocks, that’s not what the researchers found.

In the multivariate-adjusted analysis, patients who got their ICD after May 2004 actually tended to get more wrongful shocks than those who got devices earlier on (HR 1.3, P=0.05).

“The most plausible explanation for this paradox is found within the evolving guidelines,” the researchers noted in the paper.

As the guidelines have shifted the ICD patient population from mostly secondary prevention patients to mostly primary prevention patients, the addition of more patients in generally poor cardiac condition and at higher atrial fibrillation risk likely counteracted the effect of advanced ICD technology, Schalij’s group explained.

They cautioned that their study involved prospectively collected data but from a single center over a 10-year period with a potentially heterogeneous population due to evolving guidelines, device programming, and anti-arrhythmic drug treatment as well as possible residual confounding.

Schalij reported having received research grants from Biotronik, Medtronic, and Boston Scientific.

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FDA Panel Votes for No Change to ESA Label

ADELPHI, Md. — A panel of outside experts has voted 15-1, with one abstention, to recommend that the FDA allow continued use of darbepoetin alpha (Aranesp) for chronic kidney disease patients who are not on dialysis.

In a series of votes on Monday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee essentially endorsed the current prescribing guidelines for darbepoetin use among chronic kidney disease patients not on dialysis.

The FDA wanted the panel to revisit the safety and efficacy of darbepoetin, an erythropoiesis-stimulating agent (ESA), in light of a 2009 trial that found chronic kidney disease patients with type 2 diabetes and anemia who were not yet on dialysis failed to improve on most clinical outcomes when taking darbepoetin compared with the control arm. In addition, patients in the darbepoetin arm had nearly double the risk of stroke as those in the control arm.

FDA reviewers have estimated that five blood transfusions would be avoided in patients treated with darbepoetin alpha with the risk of one additional stroke per 100 patient years, compared with patients not receiving the drug.

Despite those negative safety findings, the advisory panel felt it would be too rigid to bar the use of darbepoetin in patients not yet on dialysis.

“There’s not compelling evidence it should be withdrawn,” said panelist Peter Kaboli, MD, an associate professor of internal medicine at the University of Iowa Carver College of Medicine.

“It seems like keeping this as an option available for the clinician is important,” said another panelist, James Gloor, MD, chairman of pediatric nephrology at the Mayo Clinic.

The trial that sparked the FDA’s call to revisit current darbepoetin recommendations was Amgen’s Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), which was designed to determine whether treating anemia associated with chronic kidney disease with darbepoetin to a target hemoglobin of 13g/dL would reduce the occurrence of either death, MI, stroke, or progression to end-stage renal disease.

The trial failed to meet its endpoint, but researchers determined that treatment with darbepoetin alfa resulted in a modest improvement in fatigue (P<0.001), in a reduction in cardiac revascularization (P=0.02), and a reduction in the need for red-cell transfusions (P<0.001).

However, darbepoetin significantly increased the risk of fatal or nonfatal stroke (5% versus 2.6%; HR 1.92, 95% CI 1.38 to 2.68).

There were 101 strokes in the darbepoetin group, and 53 strokes in the placebo group.

The TREAT trial results are already listed on the drug’s label, but the FDA wanted the panel’s advice on whether tougher warnings or restrictions were in order.

The committee voted that while the TREAT study failed to show a benefit for the patients taking darbepoetin, the trial also failed to show that darbepoetin should be ruled out as an option for patients not yet on dialysis, largely because the study lacked a true placebo group.

About half of the patients in the control group were eventually given a monthly darbepoetin injection because their hemoglobin levels fell below 9 g/dL.

Amgen argued that because the so-called “rescue” doses administered to the control group were about one-quarter of what the start dose was for the study group, the study does indeed have a placebo.

Some panelists said the trial sent a clear message that a low dose of darbepoetin is safer than a high dose in chronic kidney failure patients who aren’t on dialysis.

“TREAT and other trials suggest a high dose is not desirable,” said Allan Coukell, the consumer representative on the panel.

“I don’t think we know how best to use this drug in this population,” added Coukell, who is the director of the Pew Prescription Project. “That’s not to say there isn’t a population that would benefit, but we don’t know who they are.”

Panelist Judith Kramer, MD, a pediatrician at Duke University Medical Center, said that despite safety concerns, the TREAT trial was too narrow in its focus to be able to extrapolate the findings to the entire chronic kidney disease patient population not on dialysis.

“I’m concerned about safety, but we can’t jump from being concerned to having a rigid cutoff,” she said.

During the public comment portion of Monday’s meeting, the panel heard from patients and nephrologists who urged the FDA to keep darbepoetin available for kidney disease patients and to let physicians determine on a patient-by-patient basis whether the benefits of using the drug outweigh the stroke risk.

The panel was also asked to vote on whether the drug should not be given to patients who have had strokes in the past. In the TREAT trial, 12% of patients in the darbepoetin arm with a history of stroke had another stroke during the trial (compared with 4% of patients in the control arm who had a stroke in the past).

But the panel again didn’t want to place such cut-and-dry restrictions on the drug and voted 10-4 (with three members abstaining) to keep darbepoetin as an option for patients with a history of stroke.

“This should be one factor physicians and patients should consider,” said panelist Jeffrey Kopp, MD, a nephrologist at National Institutes of Health.

The panel suggested that future ESA trials study the drug class by using a true placebo group, and to also examine the safety and efficacy of using ESAs in patients who are very close to requiring dialysis.

Darbepoetin alpha was first approved in 2001 to treat anemia associated with chronic renal failure in patients, regardless of whether they are on dialysis. The approval was based on clinical trials that showed darbepoetin works in a similar way as epoetin alfa to raise hemoglobin level and reduce the need for red blood cell transfusions.

The FDA does not have to follow the advice of its advisory panels, but it often does. Amgen also manufacturers two similar drugs, the epoetin alfas Epogen and Procrit.

The FDA has been increasingly focusing on ESAs and their safety risks.

In March, the agency began implementing a formal strategy to reduce the risks posed to cancer patients who are taking ESAs to treat anemia caused by chemotherapy. The Risk Evaluation and Mitigation Strategy (REMS) requires doctors who prescribe the drugs for cancer patients to register with Amgen and enroll in a training program on use of the agents.

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ECTRIMS: Cancer Drug Wins in Early MS Trial

AMSTERDAM — A low-dose regimen of the leukemia drug alemtuzumab (Lemtrada) slashed annualized relapse rates in patients with newly diagnosed multiple sclerosis in a head-to-head trial against interferon-beta-1a (Rebif), a researcher reported here.
Patients taking alemtuzumab — first sold under the brand name Campath for treating B-cell chronic lymphocytic leukemia — had a mean annualized relapse rate of 0.18 during a two-year, phase III trial, compared with 0.39 for patients receiving the standard regimen of interferon (P<0.0001), said Alasdair Coles, PhD, of the University of Cambridge in England.

Coles reported findings from the 581-patient trial, dubbed CARE-MS I, during a late-breaking news session at the joint meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis.

Patients in the study had disease duration of no more than five years and EDSS disability scores of 3 or less, but had active disease on the basis of relapses during the previous two years. Patients who had received disease-modifying therapies previously were excluded.

The difference in relapse rates meant the cancer drug met one of two primary endpoints in the study, which was intended to demonstrate alemtuzumab’s superiority to one of the mainstays of first-line MS therapy.

But alemtuzumab was no better than interferon in the other primary outcome measure, the proportion of patients showing sustained six-month accumulation of disability (8% for alemtuzumab, 11% for interferon, P=0.22).

Speaking with MedPage Today before his presentation, Coles said the study investigators had expected 20% of patients in the interferon arm to show disability progression. The much lower number seen in the study made it effectively impossible for alemtuzumab to demonstrate an advantage, he said.

Other key efficacy findings included the following: Pecentage of patients relapse-free during the study: 78% alemtuzumab, 59% interferon (P<0.0001) Percentage showing new or enlarging T2 hyperintense MRI lesions: 49% alemtuzumab, 58% interferon (P=0.035) Mean change in EDSS disability score: 0.14 for both alemtuzumab and interferon Percentage with new T1 hypointense lesions: 24% alemtuzumab, 31% interferon (P=0.05) Brain atrophy (change in parenchymal fraction): -0.87% alemtuzumab, -1.49% interferon (P<0.0001)

No new safety signals were seen with alemtuzumab in the trial, compared with the experience in earlier clinical trials and in leukemia and lymphoma patients.

Infections affecting the upper respiratory and urinary tracts, as well as oral herpes, were more common with the drug relative to interferon.

Also, 18% of alemtuzumab patients developed an autoimmune thyroid event and 0.8% developed immune thrombocytopenia.

Coles said these events were expected and were successfully managed with standard therapies.

Alemtuzumab targets the CD52 molecule, carried on certain T and B cells. It therefore alters immunoregulation in ways that apparently reduce autoimmune activity in MS — but can also induce other forms of autoimmunity.

In MS, its dosing schedule is unusual compared with those for other therapies. Patients in CARE-MS I received 12 mg/day intravenously for five days, with a second three-day course one year later (for treating leukemia, the standard dose is 30 mg three times weekly for up to 12 weeks).

Because its effects on immune regulation appear to be more or less permanent, no additional dosing is planned. Under long-term extensions of CARE-MS I and earlier trials, patients may receive another course if they show renewed disease activity.

With up to four years of follow-up, Coles told MedPage Today, no patient has received more than four courses. He said in his own clinic, with 29 patients participating in the extensions, only one has needed an additional course after completing the originally scheduled treatments.

Because the schedule does not require frequent, lifelong dosing — interferon requires three injections per week, glatiramer acetate (Copaxone) and oral medications are given daily — almemtuzumab may be attractive to many patients even apart from the possibility of enhanced efficacy, Coles said.

But another neurologist not involved with the study suggested that the drug’s safety profile remains a major concern.

Timothy Vollmer, MD, of the University of Colorado in Denver, said the extreme duration of alemtuzumab’s effects was itself a potential problem.

“[It] induces long-term if not permanent changes in immunoregulation; it also induces significant generalized immune suppression and disturbance of immunoregulatory circuits,” he observed.

As a result, said Vollmer, “once you treat a patient, you can’t take it back. Those patients are then at risk for infections and for development of autoimmune disease.”

He added that he considered these risks more worrisome than the potential for progressive multifocal leukoencephalopathy with natalizumab (Tysabri).

Coles said a companion phase III trial of alemtuzumab involving patients with more established, pretreated MS was still underway, with completion expected soon.

Those results would help inform patients and physicians about their treatment choices, he said.

The study was funded by sanofi-aventis and Genzyme.

Coles reported consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono and UCB-Celltech.

Vollmer reported serving on scientific advisory boards for Teva Neuroscience, Acorda, Biogen Idec, Hoffman LaRoche, and Novartis and has been a consultant for Xenoport, Guidepoint Global, PRIME Education, Global Prairie, Daiichi Sankyo, Projects in Knowledge, Teva Neuroscience, Lilly USA, Medical Logix, MSDx, Esai Pharma, Schering- Plough Biopharma, as well as grants or pending grants payable to his institution from Teva Neuroscience, Biogen Idec, Lilly Research Laboratories, Genzyme, Ono Pharmaceuticals, Elan Pharmaceuticals, Acorda Therapeutics, Novartis, sanofi-aventis, Pfizer, NIH, PDL Biopharma, Biosite, EMD Serono, Genentech, and Daiichi Sankyo. At ECTRIMS, he presented phase III data for an investigational drug that may compete with alemtuzumab.

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ATS: Automated Nagging Increases Drug Adherence

SAN DIEGO, May 21 — Automated phone reminders may increase the likelihood patients will take medication for chronic conditions, a researcher said here.

In a randomized, controlled trial, asthma patients who received calls increased adherence to inhaled corticosteroids by about two percentage points compared with patients who weren’t nagged, according to William Vollmer, Ph.D., of the Kaiser Permanente Center for Health Research in Portland, Ore.

On an individual basis, such an increase may seem small, Dr. Vollmer said at the annual meeting of the American Thoracic Society.

But he noted that “even a small change in adherence can potentially produce a big public health benefit, especially when the disease is as prevalent as asthma,” he said.

He cautioned that he and colleagues have yet to crunch the numbers on how automated phone reminders may affect healthcare costs or quality of life. “We don’t know yet what the clinical significance is,” he said.

The study involved 8,600 members of Kaiser Permanente’s northwest region who were prescribed inhaled corticosteroids, including 1,600 who were newly diagnosed.

They were randomly assigned to get automated calls or usual care over an 18-month period. Adherence was measured using medical and dispensing records, Dr. Vollmer said.

The system itself was interactive and allowed participants to respond to questions about barriers to adherence and to ask to have their prescription refilled.

“The technology is pretty cool,” Dr. Vollmer said.

Over the 18 months, he said, adherence was 38% in the control group, but 40% in the intervention arm, a difference that was significant at P<0.01.

“We got what we hoped to get,” he said, “a modest but statistically significant effect.”

The increase was higher in men than women (at 3% versus 1%) and was greatest (at 4%) in those over 60.

People whose baseline adherence was in the middle range improved the most, up 3%, Dr. Vollmer said. That compared to 1% improvement for those at the high and low end of the range.

Dr. Vollmer said those at the high end of the adherence scale may simply have little room to improve, while for those at the low end, “this may be too mild an intervention.”

Similar systems with live callers have proven useful in smoking cessation, said Dennis Doherty, M.D., of the Lexington Veterans Affairs Medical Center in Kentucky, who wasn’t involved in the Vollmer study but moderated a press conference at which it was discussed.

He noted that automated calls are not always well-tolerated by patients, and said that other media — such as the Internet or text messaging — might also be used.

But such automated systems “are going to take a culture change” before they’re widely used, he said.

The study was supported by the NIH.

Dr. Vollmer is an employee of Kaiser Permanente.

Primary source: American Thoracic Society

Source reference:
Vollmer VM, et al “Use of automated phone calls to support inhaled corticosteroid (ICS) adherence” Am J Respir Crit Care Med 2009; 179: Abstract 1089.

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Breast Tumors More Aggressive in African-American Women

HOUSTON, Oct. 23 — The poorer breast cancer survival rates for African-American women can be attributed to unfavorable tumor cell biology, not just socioeconomic factors, researchers here reported.

African-American women were more likely to have estrogen-receptor-negative disease and high-grade tumors, and to be diagnosed with more advanced disease, Wendy Woodward, M.D., Ph.D., of the University of Texas M.D. Anderson Cancer Center here, and colleagues, reported online in the Dec.1 issue of Cancer.

These conclusions were derived from a review of 2,140 patients with locally advanced, nonmetastatic breast cancer treated from 1975 to 2000 in two sequential prospective clinical trials at M.D. Anderson.

The retrospective record review of these two independent trials made it possible to control for access bias, the investigators said. The patients were treated with Adriamycin (doxorubicin)-based adjuvant or neoadjuvant therapy, with or without tamoxifen, and mastectomy.

The adjuvant chemotherapy cohort included 1,456 patients: 1,142 Caucasian, 186 Hispanic, and 128 African-American women.

The smaller neoadjuvant chemotherapy cohort included 684 patients: 448 Caucasian, 114 Hispanic, and 122 African-American patients.

In both groups, African-American patients had larger and later-stage tumors (IIIA) (adjuvant P=0.017; neoadjuvant P=0.051) and a higher rate of estrogen receptor-negative disease (adjuvant P=0.054; neoadjuvant P=0.039).

In line with epidemiology studies, which have shown lower overall survival for African-American breast cancer patients, the 10-year actuarial overall survival rate for African-American patients in this study was worse than the rates for the Caucasian or Hispanic patients. In the adjuvant group, the rates were 52%, 62%, and 62%, respectively (P=0.009). In the neoadjuvant group, the rates were 40%, 50%, and 56%, respectively, (P=0.015).

In multivariate analyses to control for confounding factors, the researchers reported that African-American race remained independently associated with an almost 40% poorer overall survival rate in both treatment group: 39% in the adjuvant group (hazard ratio=1.39, P=0.018) and 37% in the neoadjuvant group (hazard ratio=1.37, P=0.02).

In the adjuvant chemo group, 24% of the African-American women were diagnosed with stage III or supraclavicular nodal disease, compared with 16% of the Caucasian patients. Of the African-American women, 22% had tumors larger than 5 cm compared with 13% of the Caucasian women. In the neoadjuvant group, the findings were similar.

These patients had more advanced clinical-stage disease, larger primary tumors, and higher rates of estrogen receptor-negative disease, the researchers wrote.

In neither cohort was there a statistically significant difference in age at diagnosis between the African-American and the Caucasian women. Median age in the adjuvant cohort was 50 (range 15 to 79), while the median age in the neoadjuvant group was similar.

African-American patients received as many chemotherapy cycles as other women in the studies, making it highly unlikely that noncompliance with treatment led to poorer survival rates.

In addition, the researchers said that in the greater Houston area where these studies were conducted, Hispanic and African-American women have similar socioeconomic status. Thus the Hispanic patients, whose survival rates were much better, served as an important comparison group for the African-American patients.

For these reasons, Dr. Woodward said, they have interpreted the data as suggesting that intrinsic biologic differences in the disease and response to treatment among the racial groups contributed to the poorer survival rates for the African-American patients.

It is clear, Dr. Woodward wrote, that because those who report themselves as African American or black represent a genetically and culturally diverse group, explaining how race is associated with biologically aggressive breast cancer will be difficult.

One avenue for future research would be to study whether some African-American women have genetic polymorphisms involved in estrogen regulation. It is also possible that epigenetic phenomena, such as an increased likelihood of being exposed to a carcinogen, might contribute to the formation of more virulent breast cancer.

It is also possible, the researchers suggested, that in an era of targeted therapy, it is not inherent baseline differences in biology that drive the outcomes, but rather imbalances in the biological factors that determine response to new therapy and to which newer therapies are targeted. The findings of this study, they said, suggest that additional work aimed at explaining these mechanisms is warranted.

Discussing the study’s limitations, the researchers noted that national statistics show that poorer survival rates among African American patients are also in part due to socioeconomic variables, including less frequent screening, less aggressive treatment, and failure to seek medical care.

In addition, they wrote “African-American patients had more advanced disease at the time of treatment. We were not able to determine whether this was due to less access to healthcare, neglect in seeking healthcare, or intrinsic differences in tumor biology.”

However, they said, because this study included only patients treated in clinical trials, some of these potentially confounding variables were minimized. Although the role of socioeconomic factors was not studied directly, the investigators said it was unlikely that it would completely explain the overall poorer survival rate in the study.

Tumor grade, with its well-recognized association with outcome, was not included in the multivariate analysis due to missing data, they said.

And lastly, they said, database demographics indicate that a greater proportion of African American women are less than age 50 at the time of diagnosis compared with Caucasian women. The fact that age did not differ in this study may demonstrate variation between the demographics of this study and the general U.S. population.

Summing up, Dr. Woodward’s team wrote that there have been significant efforts over the past decade to increase breast cancer awareness and screening. However, the investigators said, it is equally important to determine whether differences in tumor biology between races also contribute to the noted disparity in outcome.

Ideally, they said, these differences would be best studied in randomized clinical trials that prospectively stratify patients according to socioeconomic factors that may also affect cancer outcome.

Primary source: Cancer

Source reference:
Woodward, WA, et al “African-American Race is Associated With a Poorer Overall Survival Rate for Breast Cancer Patients Treated With Mastectomy and Doxorubicin-Based Chemotherapy” Cancer 2006;107: doi 10.1002/cncr.22281.

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Organizational Restructuring, Employee Stress and Health

Former Los Angeles Lakers basketball team coach Rudy Tomjanovich helped call attention to what some consider America’s number one health problem: job-related stress. Early in February he quit his job “just 43 games into a five-year, $30-million contract” saying that the “‘wear and tear of doing this business’ was making him anxious, wrecking his diet and wearing down his immune system,” according to The Los Angeles Times.

Mr. Tomjanovich was fortunate to have recognized the effect job stress was having on his health and to have taken action. But his high-ranking position in the ultra-competitive world of professional sports, where no job is secure, increasingly has parallels in the corporate world, where many professionals today likely suffer the same ill-health effects.

Indeed, a 2002 report by the National Institute for Occupational Safety and Health (NIOSH) said that “Organizational practices have changed dramatically in the new economy. To compete more effectively, many companies have restructured themselves and downsized their workforces, increased their reliance on nontraditional employment practices that depend on temporary workers and contractor-supplied labor, and adopted more flexible and lean production technologies.”

Looking into how one factor mentioned by the NIOSH report, downsizing, might affect employee health, a 7.5-year Finnish study published in the British Medical Journal focused on 5,909 male and 16,521 female municipal workers, “aged 19-62 years, who kept their jobs” following downsizing campaigns by their employers.

Among other things the study found that there was an increase in sickness absence associated with major downsizing (>18% reduction) and “The extent of downsizing was…associated with cardiovascular deaths but not with deaths from other causes.” There was a 5.1 (95% CI, 1.4 – 19.3) times increase in cardiovascular mortality during the first four years after major downsizing

More recently, an October 2004 Australian study published in the Journal of Occupational Health Psychology looked at two possible components of workplace stress that can result as companies adapt to a competitive economic environment: job strain and job insecurity. Specifically, the study focused on 1,188 middle-aged managers and professionals and found that “Those reporting both strain and insecurity showed markedly higher odds for mental and physical health problems.”

Aggregate figures on employee stress, meanwhile, strongly suggest that the subject deserves the attention of physicians, policy makers and employers. Workers who say they are stressed have 46% higher annual health costs, while all told, on-the-job stress costs the US economy $300 billion annually, The Los Angeles Times noted, citing figures from the National Institute for Occupational Health and Safety and the American Institute of Stress respectively.

However, the ramifications of stress brought on specifically by downsizing and similar adaptive moves by companies still may not be fully understood. As the NIOSH report noted, “Revolutionary changes in the organization of work have far outpaced our knowledge about the implications of these changes for the quality of working life and for safety and health on the job.”

Primary source: British Medical Journal

Source reference:

BMJ, doi:10.1136/bmj.37972.496262.0D (published 23 February 2004)

Additional source: Journal of Occupational Health Psychology

Source reference:

J Occup Health Psychol. 2004; 9(4):296-305.

Additional source: National Institute for Occupational Health and Safety

Source reference:

The Changing Organization of Work and the Safety and Health of Working People, Publication No. 2002-116, April 2002

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