In November 2015, the American Society of Hematology (ASH) and the McMaster University GRADE Center announced a collaboration to develop clinical practice guidelines on the diagnosis and treatment of venous thromboembolism (VTE). ASH is the sponsoring organization providing all funding for the work, while the GRADE Center has offered expertise in systematic evidence review and guideline development methods. This project represents the first large-scale guideline development effort by ASH, undertaken as part of a larger Quality Initiative approved by the Society in 2014.
VTE was selected as the first condition for which ASH would develop guidelines because it is a commonly encountered clinical concern for hematologists and for other medical specialties and disciplines, including emergency medicine, internal medicine, surgery, oncology, and pharmacology.
To ensure that the guideline-development team adequately met the needs of all of these interests, ASH assembled a coordination panel and 10 expert panels. The panels comprised more than 100 U.S.-based and international hematologists, clinicians from other specialties, and scientists with expertise in evidence synthesis and appraisal and guideline development methodology.
Together, the panels are discussing a total of 237 relevant clinical questions in their respective areas, explained Adam Cuker, MD, MS, chair of the ASH VTE Guideline Coordination Panel.
“This is a truly comprehensive effort,” Dr. Cuker, who also is director of the Penn Comprehensive and Hemophilia Thrombosis Program at the University of Pennsylvania, said. “After several years of hard work, I am very pleased to announce that we expect recommendations from at least four of these panels to be published in 2018.”
According to Holger Schünemann, MD, PhD, MSc, chair of the Department of Health Research Methods, Evidence, and Impact at McMaster University in Ontario, the “goal was certainly to provide comprehensive guidelines on VTE, but we also wanted to gain knowledge on guideline development for future guideline projects on other topics. Another goal was to research new methods to make guidelines more transparent and efficient, both in the process and for the users.”
The finish line for releasing the complete guidelines is in sight, and at a Special Education session at the 2017 ASH Annual Meeting, the chairs of each of the 10 VTE guideline panels presented key recommendations from the upcoming chapters, providing an inside look at the guideline-development process.
In each presentation, representatives described the process for reaching a “strong” or “conditional” recommendation. Steps included:
- prioritizing and specifying clinical questions
- conducting a systematic review of available evidence for each question
- weighing the benefits and risks of intervention options
- considering the certainty of evidence
- accounting for resource use, acceptability, feasibility, and impact on health equity of each recommendation
Below are a few of the recommendations previewed at the meeting.
Diagnosis of VTE: Start With D-Dimer
Mark Crowther, MD, chair of the ASH Committee on Quality, which oversees the Society’s guideline development efforts, stepped in for panel chair Wendy Lim, MD, MSc, to discuss updates to the diagnosis of VTE. First, he recognized that VTE diagnosis is a problematic area: “We have a vast number of tests available to us, but they are expensive in some cases, difficult to administer, and have toxicity,” he said, adding that diagnostic strategies vary between hospitals.
“No diagnostic test is perfectly accurate,” he noted. “They all have true positives, true negatives, false positives, and false negatives, irrespective of the technique.”
Dr. Crowther focused his presentation on answering the following question: “In a patient population with a low clinical probability of pulmonary embolism (PE), what is the optimal diagnostic strategy to diagnose a first episode of PE?”
After omitting a diagnostic strategy that resulted in a large number of false positives, the remaining two choices (an initial D-dimer and a computed tomography pulmonary angiogram [CTPA]) produced similar rates of true positives. “Based on a comparison of these two strategies, the panel chose the strategy of an initial D-dimer, followed by a CTPA in patients with positive D-dimer results,” he reported.
However, because VTE diagnosis is based on pre-test probability (i.e., the clinical probability of VTE in the general population of interest prior to diagnostic testing), the recommendation changes as prevalence changes: “For low pre-test probability (5% instead of 50%), i.e., for patients with a low likelihood of the disease, the panel recommended starting with a D-dimer test, followed by additional testing if the D-dimer is positive,” Dr. Crowther explained. “For high pre-test probability, the strategies could start with a CTPA, followed by additional testing if the CTPA is negative.”
VTE Prophylaxis in Surgical Patients: No to IVC Filters
David R. Anderson, MD, from Dalhousie University in Halifax, Nova Scotia, discussed a recommendation for preventive anticoagulation in patients with VTE who require major surgery, specifically when and in whom inferior vena cava (IVC) filters should be used.
IVC filters might be considered as prophylaxis, rather than standard anticoagulation in patients undergoing major surgery, because “anticoagulation may be contraindicated because of bleeding risk, and mechanical prophylaxis may not be feasible because of injury,” he explained.
Compared with the limited data from randomized clinical trials, observational studies provided “considerably more information on this recommendation,” according to Dr. Anderson. “Overall mortality was actually higher in patients, or observed to be higher in patients, who had IVC filters,” he said, “with a 1.5 percent absolute increased risk of death.”
Unprovoked VTE: Patient and Provider Choice
Thomas L. Ortel, MD, PhD, of Duke University in Durham, North Carolina, discussed a recommendation for the treatment of patients with an unprovoked VTE who have completed an initial course of therapy (≥3-6 months). In this setting, “the question is, if you are going to use a direct oral anticoagulant (DOAC) for indefinite therapy, would a lower dose be better or equivalent to a standard dose?” Dr. Ortel explained.
To answer this question, panelists reviewed evidence from two randomized clinical trials comparing DOACs against aspirin for extended anticoagulation. “When you look at the anticipated absolute effect of a lower-dose DOAC, the risks with the standard dose are comparatively fairly low for each of our outcomes of interest,” Dr. Ortel reported. The risks of mortality and deep vein thrombosis were slightly lower in the lower-dose group, but the risk of non-fatal PE was higher.”
Given the small observed differences between low- and standard-dose DOACs, the panel allowed for more flexibility in this recommendation. In its eventual, conditional recommendation, the panel suggested using either dose for indefinite therapy, based on patients’ and providers’ values and preferences.
Cancer-Associated VTE: No Routine Thromboprophylaxis
Gary H. Lyman, MD, MPH, from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, tackled a complicated issue: whether ambulatory patients with cancer who are receiving chemotherapy should also receive VTE prophylaxis.
This was one of the clinical areas in which panelists were granted abundant clinical trial data to consider, including 17 randomized, controlled trials published in the past decade. “For all patients across the trials, we observed an average VTE risk of 6 to 7 percent in the control group,” Dr. Lyman reported, “whereas risk in the low-molecular-weight heparin (LMWH) group was about half of that, for a relative risk of 0.55.”
However, he added, absolute risk difference was less clear-cut, based on the low baseline risk of VTE among the study populations. This risk also varies according to cancer subtype, he noted.
After reviewing the available evidence, the panel recommended against routine thromboprophylaxis for most patients in this setting, but with important exceptions. “This is a strong recommendation for patients who are considered to be at low risk for VTE, a conditional recommendation against the routine prophylaxis in those at intermediate risk, and a conditional recommendation for LMWH thromboprophylaxis in those at high risk,” Dr. Lyman said, “with a caveat that patients should have no major bleeding risk or other contraindication to anticoagulation.”
The Future of VTE Guidelines
As new information and evidence is released, ASH and McMaster’s primary goal will be to make sure that these guidelines stay relevant to clinical practice. That starts with ensuring that clinicians are aware of them because, as Dr. Cuker noted, “a guideline, no matter how good the recommendation, is completely useless if it does not affect practice.”
All stakeholders share the continued goal of creating guidelines that “meet the highest standards for rigor and credibility, that would be useful for and used by clinicians and – most importantly – that would improve the quality of care received by our patients,” Dr. Schünemann added.
Prevention of VTE in surgical patients
Panel Chair: David Anderson, MD, Department of Medicine, Dalhousie University, Halifax, NS, Canada
Prevention of VTE in nonsurgical patients
Panel Chair: Mary Cushman, MD, University of Vermont, Burlington, VT
Diagnosis of VTE
Panel Chair: Wendy Lim, MD, MSc, McMaster University, Hamilton, ON, Canada
Panel Chair: Saskia Middeldorp, MD, PhD, Academic Medical Center, Amsterdam, Netherlands
Treatment of VTE (deep vein thrombosis and pulmonary embolism)
Panel Chair: Thomas L. Ortel, MD, PhD, Duke University Medical Center, Durham, NC
Optimal management of anticoagulation therapy
Panel Chair: Daniel M. Witt, PharmD, Department of Pharmacotherapy, University of Utah College of Pharmacy, Salt Lake City, UT
Panel Chair: Adam Cuker, MD, MS, University of Pennsylvania, Philadelphia, PA
Prevention and treatment of VTE in patients with cancer
Panel Chair: Gary H. Lyman, MD, MPH, Fred Hutchinson Cancer Research Center, Seattle, WA
VTE in the context of pregnancy
Panel Chair: Shannon Marie Bates, MD, McMaster University, Hamilton, Canada
VTE in pediatric populations
Panel Chair: Sarah O’Brien, MD, MSc, Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, OH