guidelines

New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials

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New Project Aims to Set Effectiveness Guidelines for Hemophilia Gene Therapy Trials

An international team has joined efforts to establish guidelines for effectiveness and outcome measurements regarding gene therapies in hemophilia.

The CoreHEM project will be led by researchers from McMaster University in Ontario, Canada, in collaboration with the National Hemophilia Foundation (NHF) in the U.S. and the Green Park Collaborative — a major initiative of the Center for Medical Technology Policy (CMTP), based in Baltimore, Maryland.

“With a growing pipeline of gene therapy products for hemophilia, it is an ideal time for this work,” Sean Tunis, president and CEO of CMTP, said in a news release. “This effort will potentially serve as a model for achieving consensus around outcomes to demonstrate effectiveness and value for promising emerging therapies in many other clinical areas, as well as for other rare conditions.”

Hemophilia is caused by a genetic defect that leads to low levels or the total absence of clotting factors — factor VIII in hemophilia A and factor IX in hemophilia B — which are necessary for effective bleeding control. Hemophilia patients need to receive routine injections of the missing clotting factors to control symptoms of the disease. This demanding therapy schedule can have an extreme impact on patients’ quality of life.

Scientific advances have led to the development of new treatments that may have the potential to cure hemophilia A and B by replacing the damaged gene. Clinical trials on these new gene therapies should provide enough evidence demonstrating their effectiveness, but also substantial improvements in reducing or eliminating burdens of the disease.

The CoreHEM project aims to define a core outcome, set through a consensus process, which should be considered when evaluating the effectiveness of gene therapies in patients with hemophilia.

Taking into consideration input from patients, clinicians, researchers, product manufacturers, public and private payers, and U.S. and international government agencies, the team will create a list of potential outcome domains and measurement approaches that will be reviewed by a steering committee.

This list will go through an online Delphi voting process and an in-person consensus meeting to prioritize and condense the list into the final core outcome set.

“These breakthroughs have the potential to be life-changing,” said Val Bias, CEO of the National Hemophilia Foundation. “This collaborative effort will bring a much needed voice from our patients, and the important role they play in identifying outcomes that are vital to their health.”

The final results of the CoreHEM project, expected early in 2018, will be published in a peer-reviewed article providing recommendations for important patient outcomes in clinical studies focused on gene therapies for hemophilia. In addition, an “effectiveness guidance document” will also be published.

Implementing these outcome-defined measures will not only help patients and clinicians to make better treatment-related decisions, but will also potentially improve the way clinical trials are conducted and assessed.

“The enthusiasm from so many stakeholders to becoming part of the project speaks volumes to the potential of this initiative,” said Alfonso Iorio, co-principal investigator and associate professor of health research methods, evidence, and impact at McMaster University.

Creating a consensus for implementation early in the development of breakthrough technology is a key to success, he added.

Cholesterol Guidelines May Underestimate Cardiovascular Risk in HIV-Infected Patients – See more at: http://www.jwatch.org/na35651/2014/09/09/cholesterol-guidelines-may-underestimate-cardiovascular#sthash.fanWUptz.dpuf

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Although new guidelines recommend statin use in more HIV-infected patients, most of those with evidence of coronary plaque are still not flagged as needing therapy.

 Cholesterol guidelines released in 2013 recommend statin therapy for, among others, patients aged 40 to 75 with a 10-year atherosclerotic cardiovascular disease (CVD) risk ≥7.5%, as estimated by a new calculator. Whether this recent guideline, which was designed for the general population, is better than the 2004 Adult Treatment Panel III guidelines at predicting CVD — or at appropriately recommending statin use — in HIV-infected patients is not known. Now, investigators have examined the performance of the new and old guidelines in a cohort of HIV-infected patients.

A total of 108 patients without known CVD underwent coronary computed-tomography angiography (CCTA). The median age was 46 years, 50% were current smokers, and 20% were receiving antihypertensive medications. Despite the relatively low overall 10-year atherosclerotic CVD risk score (3.3%), 36% of participants had high-risk–morphology plaque detected on angiography. When the new and old guidelines were applied, several striking findings emerged:

  • In the overall study population, statins would be recommended for 21% by the 2013 guidelines versus 8% by the 2004 guidelines.

  • Among patients with high-risk–morphology coronary plaque, statins would be recommended for 26% by the 2013 guidelines and 10% by the 2004 guidelines.

  • Among patients without coronary plaque, statins would be recommended for 15% by the 2013 guidelines versus 5% by the 2004 guidelines.

COMMENT

The main limitation of this study is that detection of high-risk–morphology plaque on CCTA is not yet known to be predictive of CVD risk — or statin benefit — in HIV-infected patients. Nevertheless, the finding that 74% of HIV-infected patients with high-risk–morphology plaque would not qualify for statins even by the more-encompassing 2013 guidelines is alarming. Would HIV-infected patients who do not meet current guidelines benefit from statin use? A randomized clinical trial to address this question is in the offing.

– See more at: http://www.jwatch.org/na35651/2014/09/09/cholesterol-guidelines-may-underestimate-cardiovascular#sthash.fanWUptz.dpuf

2014 Top Stories in Urology: AUA Urotrauma Guidelines

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Practicing urologists have always played an integral role in the evaluation and treatment of acute genitourinary organ injury. Well-established criteria for imaging of blunt trauma, originally pioneered by McAninch and colleagues, have been incorporated in most trauma center protocols. Although trauma surgeons may manage life-threatening renal hemorrhage with nephrectomy, urologist input remains critical when deciding appropriate intervention for all other urinary tract and genital injuries.

The field of genitourinary trauma and reconstruction received a major push toward dissemination of evidence-based best practices with the introduction of the AUA Guideline on Urotrauma.1 Guidelines drive education, policy, and changes in practice patterns that may be adopted worldwide. In addition, gaps in knowledge identified by the evidence review define opportunities for future research.

Urologists can expect two diverging outcomes of the introduction of guidelines. Trauma systems will look to the guidelines to ensure adherence with evidence-based recommendations. This will likely create greater demand for urological consultation and involvement during and after hospitalization. Conversely, if urologists are not willing to provide prompt engagement and collaboration with trauma teams, it is possible that other practitioners will take over decision-making and care of patients with genitourinary injuries.

Key takeaways from the AUA Urotrauma Guidelines include the following:

  1. The surgical team must perform immediate surgery (or angioembolization in selected situations) in hemodynamically unstable patients with no or transient response to resuscitation.
  2. Follow-up imaging is necessary for high-grade renal injuries, although the particular lesions and how to follow them remains unknown.
  3. Ureteral injury should be explored and repaired immediately; if diagnosis is delayed, use a drain-and-wait approach.
  4. Intraperitoneal bladder rupture should always be repaired after blunt trauma.
  5. Extraperitoneal bladder rupture can be classified into complicated and uncomplicated. Complicated injuries require exploration and repair, whereas uncomplicated injuries can be managed with catheter drainage.
  6. Suprapubic tubes may be used in the face of orthopedic hardware as determined by expert opinion; it must be acknowledged that there is little evidence to support the guideline recommendation.
  7. Primary urethral realignment is an option for pelvic fracture urethral injury. Suprapubic cystostomy is almost always the best initial choice for urinary drainage in the acute setting of a pelvic fracture urethral injury. Primary realignment will reduce stricture rates, but prolonged efforts at realignment should be avoided.
  8. Genital injuries require early exploration using correct approaches at the local hospital level based on the mechanism and severity of injury. An exception to this is penile replantation, which should be referred to centers of excellence for microvascular repair.

New guidelines uphold levothyroxine as standard of care for hypothyroidism

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Levothyroxine (L-T4) should remain as the standard of care for treating hypothyroidism, according to a new hypothyroidism guidelines released by the American Thyroid Association (ATA).

“Our guidelines offer reassurance to physicians and their patients [that] no changes are needed in the current standard of care for hypothyroidism in the majority of patients,” said Dr. Jacqueline Jonklaas, chair of the task force that reviewed the latest clinical data on hypothyroidism therapeutics and an associate professor at Georgetown University Medical Center in Washington, DC, US.

The taskforce was convened to determine whether the current standard of care for hypothyroidism should be revised, and if warranted, to identify potential therapeutic alternatives to L-T4 monotherapy. [Thyroid 2014;doi:10.1089/thy.2014.0028]

L-T4 is a synthetic form of the hormone thyroxine (T4) that is converted to triiodothyronine (T3) in the body. While L-T4 is effective in most patients, some feel unwell when taking the drug, which is a cause for concern among physicians.

Although some studies suggested combination therapies may be a valid approach for patients with hypothyroidism, the taskforce concluded there was no robust evidence to recommend a change in the current standard of care.

“We found no consistently strong evidence for the superiority of alternative preparations [eg, levothyroxine-liothyronine combination therapy, or thyroid extract therapy] over monotherapy with L-T4 in improving health outcomes. However, some patients, particularly those with a polymorphism or genetic variation in the deiodinase enzyme that converts L-T4 [to T3], may benefit from combination treatments,” Jonklaas said.

Future research, she said, should focus on the development of superior biomarkers of euthyroidism to supplement thyroid stimulating hormone (TSH) measurements, mechanistic research on serum T3 levels (including effects of age and disease status, relationship with tissue concentrations, and potential therapeutic targeting), and clinical trials evaluating the long-term effects of different combination therapies or thyroid extracts.

Dr. Hossein Gharib, ATA president and professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota, US said while some questions remain unanswered, the new guidelines provide useful up-to-date information for endocrinologists and physicians on who to treat, why to treat, including subclinical disease, and how to treat hypothyroidism.

Pharmacists for their part can encourage patients to adhere with their medication unless advised otherwise by their physician and to report any adverse effects associated with excessive amounts of thyroid hormone such as palpitations, rapid weight loss, restlessness, sweating, and insomnia.