The Doctor's Channel - Family Medicine

Thyroid hormone analogue shows promise for statin-treated dyslipidemia

2010-03-12T21:09:30+00:00

NEW YORK (Reuters Health) – When statins alone can’t reverse dyslipidemia, the thyroid hormone analogue eprotirome may be helpful, new research suggests.

In a 12-week study of 189 dyslipidemic, statin-treated patients, eprotirome safely reduced the levels of various atherogenic lipoproteins, the investigators report in The New England Journal of Medicine for March 11.

In the study, subjects continued to receive simvastatin or atorvastatin and were randomized to receive eprotirome (25, 50, or 100 micrograms/day) or placebo.

With the 25, 50, and 100 microgram doses of eprotirome, mean low density lipoprotein (LDL) cholesterol levels fell by 22%, 28%, and 32%, respectively, from a baseline value of 141 mg/dL. By contrast, placebo produced a mean reduction of just 7%. Eprotirome had a similar effect on levels of serum apolipoprotein B, triglycerides, and Lp(a) lipoprotein.

Eprotirome was generally well tolerated, with no adverse cardiac or bone effects. Although thyroxine levels fell in patients receiving the drug, serum levels of thyrotropin and triiodothyronine did not change.

“This randomized, placebo-controlled, double-blind trial showed that eprotirome is associated with further reductions in serum LDL cholesterol levels in patients who are already receiving statins,” the authors conclude. “Eprotirome also has potent properties for lower levels of apolipoprotein B, triglycerides, and Lp(a) lipoprotein.”

The study was supported, in part, by Kara Bio, the company developing eprotirome.

Reference:
N Engl J Med 2010;362:906-916.

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Long-term abatacept safe, usually effective for juvenile idiopathic arthritis

2010-03-12T21:01:30+00:00

NEW YORK (Reuters Health) - Four out of five children with juvenile idiopathic arthritis had a good clinical response to abatacept during a long-term open-label extension trial. The safety profile was good, and the level of response often increased as treatment went on, the researchers report.

Lead author Dr. Nicolino Ruperto, from Universita di Genova, Italy, and associates report these findings in Arthritis & Rheumatism published online February 26th.

Abatacept is a soluble fusion protein that selectively modulates the costimulatory signal required for full T cell activation, the authors explain.

Their trial had three phases: a 4-month open-label lead-in in which all patients took abatacept; a 6-month randomized, double-blind, placebo-controlled withdrawal phase (in which patients with a flare discontinued treatment); and the open-label long-term extension that's the focus of the current report.

The researchers enrolled 153 children from Europe, Latin America, and the U.S. who ranged in age from 6 to 17 years. Their median disease duration was 4.1 years. In addition to abatacept 10 mg/kg (maximum, 1000 mg) given every 28 days, the children could also receive oral or intra-articular steroids and methotrexate.

For the efficacy analysis at day 589 of the open extension, the investigators divided patients into three groups:
-- 51 children continuously treated with abatacept during all three phases -- 47 children randomized to placebo who resumed treatment with abatacept during the extension phase
-- 22 children without an ACR (American College of Rheumatology) Pedi 30 response during the open-label lead-in who continued treatment with abatacept in the extension phase.

Total treatment time ranged from 21 to 52 months.

Among the 51 children who took abatacept for all three phases, 88% achieved at least an ACR Pedi 50, 57% achieved at least an ACR Pedi 90, and 43% achieved inactive disease status.

Among the 47 placebo-group children who resumed abatacept in the extension phase, 83% achieved an ACR Pedi 50, 40% an ACR Pedi 90 and 23% achieved inactive disease.

Finally, among the children who could not achieve ACR Pedi 30 in the lead phase, 64% had an ACR Pedi 50 in the extension phase, and 18% had an ACR Pedi 90. One child (2.8%) achieved inactive disease status.

Given that most patients who did not respond during the lead-in phase did respond during the extension, the authors suggest that 4 months may not be a sufficient therapeutic trial with abatacept for some patients.

"The clinical benefit of abatacept treatment is maintained or progressively improves with time," and treatment is safe and well tolerated, the researchers conclude. There were no cases of tuberculosis, opportunistic infections, or malignancies during open-label treatment, although one 12-year-old boy developed multiple sclerosis.

Furthermore, interruptions in therapy were well tolerated and not associated with adverse events or infusion reactions when therapy was re-introduced. Seventeen patients developed anti-abatacept or anti-CTLA-4 antibodies, which did not affect efficacy or elicit safety concerns.

However, the authors note, the number of patients and extent of treatment was not sufficient to detect rare safety events, so they plan to continue following this cohort and to establish a registry.

Bristol-Myers Squibb, which manufactures abatacept under the brand name Orencia, provided funds for the study.

Reference:
Arthritis Rheum 2010.

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3-pronged treatment improves outcomes in neonatal post-bleeding ventricular dilatation

2010-03-12T20:56:51+00:00

NEW YORK (Reuters Health) - A treatment called DRIFT (Drainage, Irrigation, and Fibrinolytic Therapy) may improve developmental outcomes and survival in preterm infants with posthemorrhagic cerebral ventricular dilatation, new research suggests.

Definitive conclusions can't be drawn as the trial was stopped early, partly due to a higher risk of secondary intraventricular bleeding with DRIFT. But clinically speaking, infants treated with DRIFT were better off two years later than those given standard therapy.

"Premature infants with posthemorrhagic ventricular dilatation have a high rate of severe cognitive and motor disabilities, but no intervention has been shown to improve outcome," lead author Dr. Andrew Whitelaw, from the University of Bristol Medical School, U.K., and colleagues note.

"Secondary cerebral injury may be caused by free radicals, inflammation, and pressure," the authors explain. Drainage, irrigation, and fibrinolysis address all these mechanisms and could potentially improve patient outcomes.

As they report in the April issue of Pediatrics, the researchers randomized 77 preterm infants with posthemorrhagic ventricular dilatation to receive DRIFT (n = 39) or standard treatment (n = 38), which included drainage of cerebrospinal fluid to control ventricular expansion.

By two years of corrected age, 3 children in the DRIFT group and 5 in the control group had died, and 18 and 22 in the DRIFT and control groups, respectively, were severely disabled.

Therefore, rates of the primary endpoint - death or severe disability - were 54% with DRIFT versus 71% with standard care (adjusted OR, 0.25).

"Severe cognitive disability was nearly halved" with DRIFT, the authors report. Specifically, 11 survivors in the DRIFT group (31%) had severe cognitive impairment, versus 19 of 33 (58%) in the control group (aOR, 0.17), as measured by the Bayley Mental Development Index. The median Mental Development Index score in the DRIFT group was also better: 68 vs. <50.

DRIFT did not improve rates of sensorimotor disability, however.

The research team comments that their results "raise a difficult dilemma in trial management." Given that the interim analysis showed increased intracerebral bleeding and no decrease in the need for shunts with DRIFT, "few would have taken responsibility in 2007 for continuing to recruit" to this trial. But today, the authors continue, the two study groups have a difference of more than 18 points on the Mental Development Index score, "which most families and clinicians would rate as important."

With the caveat that their population was small and the trial was stopped early, the researchers still conclude: "Despite an increase in secondary intraventricular bleeding, DRIFT reduced severe cognitive disability in survivors and overall death or severe disability."

Reference:
Pediatrics 2010;125:e852-e858.

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Cardiac catheterization has low diagnostic yield

2010-03-11T22:49:39+00:00

NEW YORK (Reuters Health) – Just 38% of patients with suspected cardiac disease are found to have obstructive coronary disease on elective cardiac catheterization, new research shows. This low diagnostic yield suggests that clinical assessments and noninvasive tests are not doing their job in selecting patients for cardiac catheterization.

“Guidelines recommend continued observation in the case of patients who are at very low risk, noninvasive stress testing to determine the need for cardiac catheterization in the case of patients at intermediate risk, and direct referral for catheterization in the case of patients at high risk,” lead author Dr. Manesh R. Patel and colleagues note.

But whether these recommendations help limit the number of patients without coronary disease who undergo cardiac catheterization was unclear, according to the report in The New England Journal of Medicine for March 11.

To investigate, Dr. Patel, from Duke University Medical Center, Durham, North Carolina, and colleagues analyzed national registry data on nearly 400,000 patients without known coronary disease who had elective cardiac catheterization at 663 hospitals in the U.S.

Obstructive coronary disease was defined as stenosis of at least 50% of the diameter of the left main coronary artery or stenosis of at least 70% of the diameter of a major epicardial vessel.

The median patient age was 61 years and 52.7% of patients were male. Twenty-six percent of subjects had diabetes and 69.6% had hypertension. Roughly 84% had noninvasive tests before cardiac catheterization.

Only 37.6% of patients had obstructive coronary disease at catheterization, the report indicates. Moreover, 39.2% of patients had no coronary disease (stenosis <20% in all vessels).

A positive noninvasive test result slightly increased the likelihood of finding obstructive disease: 41.0% vs. 35.0% (adjusted odds ratio, 1.28, p < 0.001).

In an editorial, Dr. David J. Brenner from Columbia University Medical Center in New York agrees with the authors that a better “gatekeeper” test is needed to select the best candidate for cardiac catheterization. “Ironically,” he notes, “there is evidence that, in many situations, a better gatekeeper test may be yet another radiographic imaging technique—namely, multidetector-row computed-tomographic angiography.”

Reference:
N Engl J Med 2010;362:886-895,943-945.

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Endoscopic resection for Barrett's esophagus usually avoids surgery

2010-03-11T22:47:25+00:00

NEW YORK (Reuters Health) - In patients with Barrett's high-grade dysplasia or early esophageal adenocarcinoma, endoscopic resection improves staging and "dramatically" reduces esophagectomy rates, Australian physicians report.

Esophagectomy, the standard of care, produces high morbidity, and mortality from the procedure ranges from 4% to 20%, according to the researchers. Moreover, the surgery is often done on the basis of biopsy results alone, but biopsy staging is not very accurate.

For these reasons, endoscopic resection is becoming more popular for staging and management, Dr. Michael J. Bourke, from Westmead Hospital in Sydney, and his colleagues say in their article, published online on February 23rd by the American Journal of Gastroenterology.

The researchers studied 75 consecutive patients (ages 45 to 87) who underwent endoscopic resection for biopsy-proven Barrett's high-grade dysplasia or esophageal adenocarcinoma. The mean follow-up was 31 months.

Barrett's mucosa ranged in length from 1 to 16 cm, with a mean of 3.6 cm. In 35 otherwise healthy patients younger than 75, with Barrett's segments no longer than 3 cm, the authors attempted complete excision by 2- to 3-stage radical mucosectomy - which was successful in 33 cases (94%). One patient required esophagectomy; in another, comorbidities interfered.

Among the remaining 40 patients, 8 developed metachronous lesions. Another 5 had esophagectomy because resection revealed submucosal invasion, but there was no recurrence at endoscopic resection sites. Four patients (ages 81 to 92 years) died, but none of the deaths was due to adenocarcinoma.

The authors staged the resections over at least two sessions six weeks apart to minimize the risk of strictures. The number of sessions ranged from one to five per patient, with a median of two resections at the index procedure.

Overall, histologic findings led to changes in grade or stage in nearly half of patients, with lesions downgraded/staged in 21 patients and upgraded/staged in 15. Diagnoses "included the full spectrum of pathology," the authors report, ranging from no dysplasia to submucosal invasive adenocarcinoma. Seventeen patients had only low-grade dysplasia or none at all.

"Nearly one in four patients would have undergone unnecessary esophagectomy if surgery based on biopsy alone was the first-line therapy" in their series, the authors point out.

Unlike biopsy, endoscopic resection also adds data on breadth, depth, and areas of more advanced pathology. Furthermore, because mucosal lesions have a very low rate of nodal involvement, endoscopic resection is likely to be curative, the investigators note.

The absence of serious procedure-related complications in this series "further enhances" the potential utility of endoscopic resection "as a low-risk definitive dysplasia grading and local T-staging tool," Dr. Bourke and associates write.

In conclusion, they say, "We believe it is no longer acceptable to refer patients with early disease for esophagectomy without including endoscopic resection in the preoperative staging strategy."

Reference:
Am J Gastroenterol 2010.

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Women benefit as much as men from statins for primary prevention of CVD

2010-03-11T22:44:28+00:00

NEW YORK (Reuters Health) - Statin use by women cuts their risk of primary cardiovascular disease (CVD) events by roughly a third, which is similar to the risk reduction seen in men, research shows.

"Statin therapy in women without CVD is controversial, given the insufficient evidence of benefit," Dr. Samia Mora, from Brigham and Women's Hospital, Boston, and colleagues note in the March 9th issue of Circulation.

Dr. Mora and colleagues analyzed gender-specific outcomes from the randomized JUPITER trial and performed a meta-analysis of statin trials that focused on women.

JUPITER included 6801 women at least 60 years of age, and 11,001 men at least 50 years of age. All had high C-reactive protein levels (at least 2 mg/L) and normal to low levels of low density lipoprotein cholesterol (no higher than 130 mg/dL). Participants took either rosuvastatin or placebo daily.

The meta-analysis included 7 primary prevention trials, with 13,154 women who had 240 CVD events and 216 deaths.

Compared to the men in the JUPITER trial, the women had lower absolute CVD rates per 100 person-years (0.57 vs. 0.88 for rosuvastatin groups and 1.04 vs. 1.54 for placebo groups) - but both genders had relative risk reductions of roughly 44%.

Further analysis showed that statin therapy significantly reduced revascularization and unstable angina in women, but did not affect other CVD events.

In the meta-analysis, statin use by women cut primary CVD events by 37% (p < 0.001), but did not significantly affect total mortality.

When the results of JUPITER and the meta-analysis are taken together, the researchers conclude, "statin therapy resulted in about a one-third relative reduction in primary CVD in women, a benefit similar to that seen in previous meta-analyses of men."

Reference:
Circulation 2010;121:1069-1077.

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Continuous intraperitoneal insulin linked with better quality of life

2010-03-10T16:36:00+00:00

NEW YORK (Reuters Health) - Patients report higher quality of life with continuous intraperitoneal versus subcutaneous insulin, Dutch investigators have found.

The researchers had previously reported that continuous intraperitoneal insulin allows better glycemic control compared to intensified subcutaneous insulin therapy (see Reuters Health story, August 11, 2009).

Their new paper reports on health-related quality of life outcomes and treatment satisfaction in 23 adults with type 1 diabetes who enrolled in a randomized cross-over trial of the two approaches. Patients had 6 months of intensive subcutaneous insulin followed by 6 months of peritoneal infusion, or vice versa. The subcutaneous insulin was given either continuously or via injection - whatever the patient was doing before enrollment.

In their article, published online February 25th in Diabetes Care, lead author Dr. Susan J. Logtenberg, from Isala Clinics, Zwolle, and colleagues write that scores on six subscales of the 36-item Short-Form Health Survey were significantly higher with peritoneal infusion. The only exceptions were in the social functioning and bodily pain domains.

On the World Health Organization-Five Well-Being Index, significantly fewer patients had a score below 50 -- an indication of poor emotional well-being - after peritoneal treatment (6 vs 13, p = 0.02).

Moreover, patients perceived significantly fewer hypoglycemic and hyperglycemic events during their peritoneal infusion phase, leading to greater treatment satisfaction.

As the authors point out, patients preferred the peritoneal approach despite the fact that it requires hospital admission and surgery to insert the pump. It also costs more than twice as much as continuous subcutaneous insulin infusion.

"Continuous intraperitoneal insulin infusion should be (re)considered as a treatment option, at least when satisfactory results of treatment are not reached with subcutaneous intensive insulin treatment regimens," Dr. Logtenberg's team concludes.

Medtronic Europe, which sells insulin pumps, provided an unrestricted grant to the authors.

Reference:
Diabetes Care 2010.

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Melamine-related kidney stones can be managed conservatively

2010-03-10T16:32:38+00:00

NEW YORK (Reuters Health) - Kidney stones linked to melamine-tainted infant milk formula can usually be managed conservatively, Chinese authors report. For infants with renal failure, hemodialysis without surgery was usually adequate.

In August 2008, Chinese officials reported that melamine had been illegally added to some milk-based formulas to increase the protein content. Since then, several young children who drank the tainted milk have died and thousands have developed kidney stones. (See Reuters Health reports September 12 and December 2, 2008.)

In a paper scheduled for publication in the April Journal of Urology, Dr. Jian Guo Wen and colleagues at the First Affiliated Hospital of Zhengzhou University report that in their region, more than 3,000 children came for free medical evaluations after ingesting melamine-tainted formula. In 165, the researchers diagnosed melamine related urinary stones. Fifty children (mean age 23.4 months) had bilateral stones.

The children in this subgroup drank the formula for an average of roughly one year, the authors said. Thirty-one had symptoms, including altered frequency of urination, crying at urination or unexplained crying, and oliguria or anuria. Twenty-eight had mildly acidic urine (pH 6 or less), and 11 had renal failure.

Thirty-three patients had stones ranging from 4-10 mm in diameter (based on ultrasound findings); the other youngsters had smaller calculi. The stones - mainly uric acid and melamine -- were radiolucent on plain x-ray but clearly visible on CT.

Management consisted of hydration, IV sodium bicarbonate 5% to raise urine pH, and an antispasmodic drug (anisodamine 0.1-0.3 mg/kg or atropine 0.1-0.2 mg/kg) to help the stones pass.

Eight of the 11 children with renal failure received up to four sessions of hemodialysis. One patient required ureteral catheterization for a week to drain the renal pelvis.

Children remained in the hospital for an average of 8 days; by discharge, all clinical symptoms resolved. No patient died. Within a month, 33 children passed their stones; in the other 17 youngsters, the stones became smaller.

Despite the good outcomes, the authors advise that "these children need to be monitored for long-term effects of melamine-tainted mild formula consumption."

In a short editorial comment, Dr. John C. Pop at Vanderbilt Children's Hospital, Nashville, Tennessee, disagrees with using hemodialysis to treat renal failure in these children. Instead, he advocates "stenting to relieve the obstruction, followed by conservative treatment" until the stones resolve. He would reserve hemodialysis for patients whose renal insufficiency persists.

Dr. Wen's team defends its management decisions, noting that not all the hemodialysis patients had significant ureteral obstruction. "Hemodialysis was performed according to the regimen issued by the Ministry of Health," and parents of the patients opted for this treatment instead of stenting.

Reference:
J Urol 2010;183:1533-1538.

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Fertility-conserving surgery safe for early cervical cancer

2010-03-09T16:57:54+00:00

NEW YORK (Reuters Health) – In young women with stage IA1 cervical cancer, a fertility-preserving conization does not reduce survival compared to hysterectomy, researchers report in the March Obstetrics and Gynecology.

With either procedure, 5-year survival is excellent, approaching 100%, the findings indicate.

Small series and case control studies have suggested that conization is safe, but large studies comparing conization and hysterectomy for stage IA1 cervical cancer have been lacking until now, according to lead author Dr. Jason D. Wright, from Columbia University College of Physician and Surgeons, New York, and colleagues.

For the current analysis, the researchers used data from the Surveillance, Epidemiology, and End Results database from 1988 to 2005. They identified 1409 women, age 40 or younger, with stage IA1 cervical cancer; 841 had hysterectomy and 568 underwent conization.

On logistic regression analysis, predictors of conization included Asian ethnicity, single status, diagnosis later in the study period, and residence in the eastern United States. In addition, women younger than 30 had a 78% higher likelihood of conization compared to women above 35.

At 5 years, 98% of those treated with conization and 99% treated with hysterectomy were alive.

“Our study suggests that fertility-conserving surgery is safe for young women with stage IA1 squamous cell carcinoma of the cervix,” the authors conclude. “Young women with microinvasive cervical tumors should weigh the risks and benefits of conization in the context of individual preferences and tumor characteristics.”

Reference:
Obstet Gynecol 2010;115:585-590.

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Tenofovir-related renal dysfunction can't always be reversed

2010-03-09T16:55:19+00:00

NEW YORK (Reuters Health) - Tenofovir nephrotoxicity can't always be fully reversed in HIV-infected men, according to a new study.

Up to 2% of patients have adverse renal effects from the nucleotide reverse transcriptase inhibitor, and reportedly, kidney function rapidly normalizes when tenofovir is stopped. But "because of the few cases, limited follow-up and the insensitive measure used" (serum creatinine) in the previous reports, it's not known how reversible the nephrotoxicity really is, note senior author Dr. Andrew Carr, from St. Vincent's Hospital, Sydney, Australia, and colleagues.

In a paper published online February 19th in the Journal of Acquired Immune Deficiency Syndromes, Dr. Carr and his associates describe 24 men who discontinued tenofovir because their estimated glomerular filtration rate (eGFR) was less than 60 ml/minute/1.73 m2.

During a median of 30 months between start of tenofovir and drug cessation, median eGFR fell from 74 to 51 ml/min/1.73 m2 - a reduction about 10 times greater than expected with normal aging.

During the median period of 13 months after tenofovir discontinuation, eGFR rose by a median of 19 ml/min/1.73 m2. Most improvement occurred in the first month.

In only 10 (42%) patients did eGFR return to pre-tenofovir levels, and only two exceeded 90 ml/min/1.73 m2.

Twelve patients had eGFR increases above the median; this group had a more rapid monthly decline while on tenofovir compared to those with less improvement (1.9 vs 0.7 ml/min/1.73 m2, p = 0.009) and a shorter duration of tenofovir therapy (21 vs 51 months, p = 0.08), suggesting that "more acute renal damage is less likely to be permanent."

These patients were also more likely to have received protease inhibitors (100% vs 54%, p = 0.02). The authors explain that protease inhibitors can increase tenofovir levels in plasma and renal tubular epithelium. Therefore, the greater improvement was likely due to cessation of higher tenofovir exposure.

The single-center study was retrospective, relatively small and had a variable duration of follow-up, and so prospective validation in a larger, more heterogeneous population is needed, the researchers say.

Nevertheless, they conclude, earlier discontinuation of tenofovir might have led to greater improvements in renal function, "which underlines the importance of regular assessment and perhaps of earlier intervention."

Specifically, they advise, even gradual deterioration in eGFR to levels above 60 ml/min/1.73 m2 might be cause enough to discontinue tenofovir.

Reference:
J Acquir Immune Defic Syndr 2010.

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