Venous thromboembolism guidelines aim to clarify proper care in areas with ‘a lot of uncertainty’

Venous thromboembolism — which includes deep vein thrombosis and pulmonary embolism — causes up to 100,000 deaths annually in the United States and affects patients in numerous health care settings, regardless of age.

Although innately a hematologic condition, physicians in many different fields may be responsible for the prevention or treatment of VTE.

To better equip physicians across specialties with the tools and knowledge to manage patients with or at risk for VTE, ASH collaborated with the McMaster University GRADE Centre to develop Clinical Practice Guidelines on Venous Thromboembolism. The guidelines — the first six chapters of which were published in November — include more than 200 recommendations on VTE formulated by 10 panels of more than 100 thrombosis experts.

“This began with a group [of medical professionals] prioritizing questions about VTE we thought should be answered,” Adam Cuker, MD, MS, clinical director of Penn Blood Disorders Center, director of Penn Comprehensive Thrombosis Program, assistant professor of medicine and of pathology and laboratory medicine at University of Pennsylvania, overall chairman of the ASH VTE guidelines panel and the panel on heparin-induced thrombocytopenia (HIT), told HemOnc Today. “These are questions that we chose because we feel they are important for practicing clinicians, but also because they didn’t have a clear answer and there existed opportunities for improvement in clinical practice.”

The first six chapters address VTE diagnosis, prophylaxis for medical patients, management of anticoagulation therapy, HIT, pediatric treatment and VTE in the context of pregnancy. Four more chapters that cover VTE treatment, VTE management among patients with cancer, thrombophilia and prophylaxis for surgical patients are in development and will be published later this year or next.

“This was a fairly long process that took [3 years] because there were so many chapters,” Wendy Lim, MD, MSc, FRCPC, professor of medicine at McMaster University and chairwoman of the diagnosis panel, told HemOnc Today. “This was ASH’s first foray into guidelines that had multiple chapters, and a policy is being worked on to update these guidelines at appropriate times.”

HemOnc Today spoke with panel members and hematologists about the complex management involved with the prophylaxis and treatment of VTE, the need for guidance in light of the scant published data on specific patient populations, and the most important recommendations from the guidelines.

VTE prophylaxis

VTE is the third most common vascular disease in the world, with medical inpatients, long-term care patients, long-distance travelers and patients with injuries having increased risk.

The chapter on VTE prophylaxis — which included 19 recommendations — strongly recommended pharmacological VTE prophylaxis for acutely or critically ill inpatients at increased VTE risk and with acceptable bleeding risk and mechanical prophylaxis when bleeding risk is unacceptable.

The guidelines also strongly recommended against direct oral anticoagulants (DOACs) during hospitalization and extending pharmacological prophylaxis after hospital discharge.

“Understanding who is at most risk is really important,” Mary Cushman, MD, panel chairwoman and medical director of the thrombosis and hemostasis program, hematologist and professor of medicine and pathology at Larner College of Medicine, told HemOnc Today. “The idea is that when a person is admitted, you evaluate their risk for VTE so you can decide if their situation warrants prophylaxis. We have tools for this, and clinicians also need to consider bleeding risk when deciding who should get prophylaxis.”

“Clinicians must think about the risks of overprescribing anticoagulants, even if they are just at a low dose,” Cushman said. “In some hospitals, providers just don’t do this. In others, they do weigh the risks, which is the right thing to do because it’s the wrong policy to just give everyone who comes in a low-dose anticoagulant. If you do that, you’re overtreating, spending resources and opening them up to the risk for bleeding. We did point out that much more research is needed in the area of optimal patient selection for treatment.”

The panel conditionally recommended against routine VTE prophylaxis for long-term care patients or outpatients with minor VTE risk factors.

The use of graduated compression stockings or low-molecular-weight heparin (LMWH) for long-distance travelers at high risk for VTE received a conditional recommendation.

About 3.4 billion passengers travel by air every year worldwide.

Traveling by plane increases the risk for DVT or PE 2.8 times (95% CI, 2.1-4.2) compared with travel by other means.

“These were very difficult recommendations to make because the literature is scant, but there are there a lot of people who travel, and many are concerned about VTE so it was important to address,” Cushman said. “We spent a lot of time considering this recommendation.”

The estimated absolute risk for symptomatic DVT for people who travel by plane is approximately 0.05% (95% CI, 0.01-0.19). The estimated absolute risk for asymptomatic DVT with air travel is 2.6% for a 4-hour flight and 3.6% for a 7-hour-or-longer flight. Overall, the risk is about one case per 4,600 flights.

However, those risks can vary based certain risk factors, including cancer, pregnancy, use of plastic casts, and use of oral contraceptives.

Pregnant women in general have an OR for VTE of 4.3 (95% CI, 0.9-19.8). Pregnant women who travel on a plane, however, have an OR for VTE of 14.3 (95% CI, 1.7-121).

“There are thresholds of risk for VTE. When people have more than one risk factor at the same time, they are going to have higher risk,” Cushman said. “With travel, a threefold increase in risk sounds like a lot, but it’s actually really tiny because the absolute risk for thrombosis is low for most people and only lasts a few weeks. However, if there are other factors — such as recent surgery, obesity, fracture, pregnancy and use of birth control pills — or if you have several of these factors simultaneously, you could get to the point where you cross that threshold of higher risk and actually get an event.”

For individuals with substantially increased risk for VTE when traveling by plane, the use of LMWH, aspirin or compression stockings may provide benefits that outweigh the risks.

The panel recommended against using any of these prevention methods in people who do not have an increased risk for VTE.

An outside letter written by a research group from Johns Hopkins University School of Medicine criticized the chapter on prophylaxis, arguing that it did not address the “widespread problem” of nonadministered doses of prescribed VTE prophylaxis to hospitalized patients.

“Although continuous efforts are being made to improve VTE prophylaxis prescription, these efforts are based on the implied assumption that appropriate VTE prophylaxis prescription guarantees its administration,” Oluwafemi P. Owodunni, MD, MPH, postdoctoral research fellow in the division of acute care surgery in the department of surgery at Johns Hopkins Hospital, and colleagues wrote. “Nonadministration of VTE prophylaxis can lead to preventable harm, and regrettably, it is endemic within hospitals. At our institution, we found that approximately 12% of prescribed doses of pharmacologic VTE prophylaxis were not administered to hospitalized patients. The most noteworthy finding of our investigation was that nearly 60% of nonadministered doses were due to patient or family member refusal.”

Cushman said that although the letter raises an important point, the issue of adherence is beyond the scope of the panel’s mandate to create guidelines for VTE prophylaxis.

“Our work in the guideline was to make recommendations on optimal treatment and did not cover implementation, per se, which is what the letter is about,” Cushman said. “We agree that the Hopkins program to promote patient adherence might have value.”

Diagnosis of VTE

Proper diagnosis of VTE is essential for timely management to reduce morbidity and mortality associated with the condition. However, diagnostic tests are subject to error and reliant upon population incidence estimates.

The panel tasked with creating strategies for properly diagnosing VTE — which released 10 recommendations that evaluated PE, DVT in lower and upper extremities, and recurrent VTE — developed optimal diagnostic strategies for suspected VTE based on prevalence of disease and the pretest probability of VTE. It also presented alternate diagnostic strategies to account for the variability in different practice settings.

Timely diagnosis of PE is especially important.

“PE is a potentially life-threatening diagnosis. Fortunately, for the vast majority of patients who present with PE, sudden death is rare,” Lim said. “Doctors like to get this diagnosed within 24 hours to confirm or exclude the diagnosis. If they cannot have a test done within 24 hours, it’s usually advised that the patient be treated as if they have a blood clot with anticoagulants before the tests are done.”

Recommendations include use of D-dimer as the initial test for patients with low-risk VTE, and imaging for patients with high-risk VTE. Ventilation-perfusion (VQ) scanning and CT pulmonary angiography (CTPA) are the most validated tests for PE diagnosis, and ultrasonography is appropriate for lower or upper extremity DVT diagnosis.

A decision to use the D-dimer test should come with confidence that the results will be available quickly and that the costs of running the test will be offset by avoiding unnecessary VQ or CTPA tests for patients who are at a low risk for PE.

“The D-dimer test is a blood test that is very sensitive but not very specific. It’s likely to be positive in a whole host of conditions,” Lim said. “If it’s positive, it doesn’t necessarily mean the patient has a blood clot [because] it doesn’t take an image. If the patient is in a low-risk population, a negative result is sufficient for excluding the diagnosis. But, if the patient is in a high-risk population, they probably should forego D-dimer testing and undergo imaging.”

The panel added that if a patient presents to the ED, the PE rule-out criteria, or PERC, may be used to determine if the D-dimer is necessary.

“The PERC rule helps emergency department doctors judge the probability of PE and whether they need to proceed with testing,” Lim said. “Common signs of PE are fast heart rates, low oxygen levels in the blood, signs and symptoms of DVT in the leg, coughing up blood, risk factors for developing clots like previous PE or DVT, cancer, oral contraceptive use, etc. They also look at the age of the patient and then score them. Depending on the number of points, it puts the patient into a category that determines whether they should be tested.”

Anticoagulation

The chapter on optimal management of anticoagulation therapy includes 25 recommendations, some of which may challenge long-held physician practices, according to Daniel M. Witt, PharmD,FCCP, BCPS, panel chairman and pharmacist in the department of pharmacotherapy at The University of Utah.

“I’ve been taking care of people on anticoagulation therapy for over 20 years, and after that amount of time you get very comfortable with the decisions that you make and the conversations that you have with patients,” Witt told HemOnc Today. “This chapter is interesting because it challenges a lot of the evidence that supports aspects of anticoagulation providers feel very comfortable doing day in and day out. It became very challenging for the panel to put aside what they do in their normal practices vs. what the evidence actually suggests. There were very lively discussions among panel members. The recommendations were worded very carefully.”

For instance, the panel strongly recommended against periprocedural LMWH bridging therapy — a common practice — for patients with low-to-moderate risk for recurrent VTE who are undergoing an invasive procedure.

Bridge therapy generally involves stopping warfarin 5 days before surgery, with LMWH injections starting 3 days before the surgery and stopping the day prior. After surgery, the patient restarts warfarin but also receives LMWH injections until the warfarin is therapeutic, which could take several days.

Source: The University of Utah College of Pharmacy.

“Without a lot of good evidence to support it, this became the de facto standard of care,” Witt said. “There was observational evidence that showed pretty clearly that there is not a whole lot of benefit in terms of preventing clotting to using LMWH, and there was a significant risk for bleeding that outweighed the benefit.

“So, we made a strong recommendation against bridging with LMWH for patients who are at low-to-moderate risk for blood clotting,” he said. “That’s a pretty dramatic departure from what is normally done, but I think it’s going to prevent a lot of bleeding situations.”

The panel evaluated 2,000 cases to support this recommendation. Of them, only three patients experienced recurrent VTE without the bridge therapy.

On top of that, LMWH injections during bridge therapy can cause bleeding events. Overall, the risk for bleeding is about 10 times lower without bridge therapy.

“The risk was so high and the benefit so low, it just didn’t make any sense,” Witt said. “It’s a practice that has to be stopped in this patient population.”

Witt added that there is not a lot of information on bridge therapy for people with a high risk for recurrent VTE who require an invasive procedure.

However, the top invasive procedure that normally necessitates stopping vitamin K antagonist (VKA) therapy is colonoscopy. In those cases, if the patient is at a high risk for recurrent VTE, the best practice is to delay the colonoscopy until the risk is downgraded to low or moderate, Witt said.

To monitor warfarin dosing, the guidelines strongly recommended patient self-management with home point-of-care international normalized ratio monitoring.

Conditional recommendations in the chapter included basing treatment dosing of LMWH on actual body weight, not using antifactor Xa monitoring to guide LMWH dosing, using specialized anticoagulation management services, and resuming anticoagulation after episodes of life-threatening bleeding.

It may take time before the recommendations in this chapter are fully embraced because of the high costs of DOACs, Witt said.

“My own experience is that the reason people don’t choose DOACs is simply because they can’t afford them with their prescription drug coverage,” he said. “I think most clinicians are starting to favor DOACs over [VKA therapy] because they are so easy to use. In terms of effectiveness ... trials have shown that they are about equal, but there is lower bleeding risk with DOACs, so the advantage is really about safety.”

Balancing the risks and benefits is key to optimal use of anticoagulation therapy.

“In some cases, you are going to be in this tricky spot where the patient has a really high ongoing need for anticoagulation therapy but also a high risk for recurrent bleeding,” Witt said. “In that case, you have to have a conversation with the patient to figure out what is the most important thing for them to try to avoid. You then make a decision and move forward.”

Challenges of HIT

HIT — a prothrombotic adverse drug reaction to heparin — continues to vex clinicians when managing patients who require anticoagulation.

Of approximately 12 million patients in the U.S. who are exposed to heparin each year while in the hospital, less than 0.1% to 0.7% experience HIT, with incidence varying according to type of heparin, duration of use, and surgical vs. medical patient population.

Diagnosis of HIT is complicated because, although it occurs rarely, signs that alert physicians to the condition occur much more frequently. Thus, guidelines on the diagnosis and management of HIT made up the largest chapter of the six released, with 33 recommendations.

“The cardinal clinical feature of HIT is a fall in the platelet count in the setting of a proximate heparin exposure,” said Cuker, a HemOnc Today Next Gen Innovator. “That is an extremely nonspecific scenario for HIT, but it is ubiquitous for hospital patients. Many hospital patients receive heparin, and a substantial number develop thrombocytopenia. ... So, we should at least be thinking about the possibility of HIT whenever there is an intersection of the two.”

The recommendations specifically address screening of asymptomatic patients, diagnosis and initial management of suspected HIT, treatment of acute cases, and proper care in special situations of patients with acute HIT or a history of HIT.

Several of the strong recommendations revolve around the diagnosis and initial management of patients with suspected HIT.

For example, the panel strongly recommended the use of the 4Ts score — which differentiates HIT from other causes of thrombocytopenia based on severity of thrombocytopenia (platelet count fall), timing of platelet count fall, incidence of thrombosis or other sequelae, and other apparent causes of thrombocytopenia — rather than a Gestalt, or unstructured, nonstandardized, intuition-based, approach for estimating the pretest probability of HIT.

“The problem with the Gestalt approach is that ‘your Gestalt’ and ‘my Gestalt’ may bring us to entirely different conclusions,” Cuker said. “Gestalt approaches tend to be especially inaccurate when the clinician is not an expert in the disease. To help standardize the approach to clinical assessments, pretest scoring models like the 4Ts score ... can be used to make decent estimates of the probability of HIT.”

The panel also strongly recommended against HIT laboratory testing and empiric treatment of HIT in patients with a low-probability 4Ts score.

“I’m especially proud of the recommendations we made around the diagnostic approach to a patient with suspected HIT and that we created an evidence-based algorithm on the basis of our recommendation,” Cuker said. “Most previous guidelines have focused on the management of patients once they are diagnosed with HIT.”

The panel also conditionally recommended nonheparin anticoagulants for treatment of acute HIT, which Cuker said could be the most impactful recommendation moving forward.

“One of the practice-changing recommendations we made was the recommendation to use DOACs to treat patients with acute HIT,” Cuker said. “That’s never been recommended by a guideline before. It took the panel some time to arrive at that conclusion.

“DOACs are relatively new, and most of the evidence of their use to treat HIT was published while the panel was working on the recommendations,” he added. “When we met for the first time, a lot of that evidence wasn’t available.”

With the recent rise of DOACs and their ability to effectively anticoagulate with a lower risk for bleeding, some professionals have begun to speculate whether the use of heparin would decline significantly, thus reducing the overall rate of HIT.

Cuker, though, said he does not foresee heparin being completely replaced in the near future.

“There have been rumors of the demise of heparin for so long, but we still use it frequently,” he said. “There are still potential opportunities to replace heparin in some situations — like for surgical patients — but I think there are still certain situations where there exists no feasible alternative to heparin.”

Patients undergoing cardiac surgery who are put on a cardiopulmonary bypass machine are one example.

To prevent their blood from clotting in the circuit, they must be anticoagulated, and cardiac surgeons, anesthesiologists and perfusionists still prefer heparin because it’s short-acting, there’s a reversal agent, it’s inexpensive and it can be monitored in the operating room.

“I don’t think heparin is going away anytime soon,” Cuker said. “One thing I think everyone has to remember, too, is that DOACs are not a free ride, either, in terms of adverse events.”

Pregnancy and pediatrics

Management of VTE during pregnancy and in children are both areas that lack sufficient data to make strong recommendations.

Additionally, DOACs have not yet been approved for children, pregnant women or women who are breastfeeding, limiting their treatment options.

In both chapters focused on these patient groups, researchers used data from women who were not pregnant to make some of their recommendations.

“There just is very little data on DOACs. The concern is that we know DOACs cross the placenta and we are not sure of the risk to the fetus,” Anita Rajasekhar, MD, panel member and clinician at University of Florida Health, told HemOnc Today. “DOACs also cross into breast milk, so they are not recommended for women who are breastfeeding. My sense is that it will be quite some time before we have data on use of DOACs with pregnancy. ... So, I don’t think [the guidelines] will change soon. For now, it’s best to avoid these agents.”

Of 31 total recommendations regarding VTE in pregnancy, strong recommendations included LMWH over unfractionated heparin for acute VTE and antepartum anticoagulant prophylaxis for those with a history of unprovoked or hormonally associated VTE.

However, the panel conditionally recommended against antepartum anticoagulant prophylaxis for those with prior VTE associated with a resolved nonhormonal-provoking risk factor.

Another conditional recommendation — albeit with very low certainty of evidence — was to schedule delivery for pregnant women receiving therapeutic-dose LMWH for the management of VTE, with discontinuation of anticoagulant therapy before the delivery. This may reduce major bleeding risks and allow for access to neuraxial anesthesia.

“Most anesthesiologists, based on current North American and European guidelines, will not place an epidural catheter if a woman has had LMWH at therapeutic doses in the last 24 hours.” Rajasekhar said.

For pregnant women receiving prophylactic-dose LMWH, however, the panel recommended against scheduled delivery and stopping prophylactic therapy. Instead, women should stop the therapy when they go into labor spontaneously.

“Prophylactic doses are associated with a lower risk for postpartum hemorrhage, which guided this recommendation,” Rajasekhar said. “There is always a risk for bleeding with any dose, but we believed this risk low enough that it did not require stopping the drug and scheduling delivery.

“Because of its lower dose, many anesthesiologists will allow a shorter time frame before placing an epidural as opposed to therapeutic doses,” she added. “Stopping LMWH at the time of spontaneous labor will allow most women to receive an epidural catheter if they choose.”

Diagnosing and treating VTE in children also is difficult to address due to the lack of studies in this area, leading to the panel releasing mostly conditional recommendations.

A few of the strong recommendations, however, included not using thrombolysis followed by standard anticoagulation for patients with nonlife-threatening renal vein thrombosis. Instead, anticoagulation should be used alone.

For children with life-threatening renal vein thrombosis, the panel suggests using thrombolysis.

“The use of thrombolysis was based on a balance of a risk/benefit ratio,” Paul Monagle, MD, professor of pediatrics at University of Melbourne and a pediatric hematologist at Royal Children’s Hospital, told HemOnc Today. “The data around thrombolysis suggests the bleeding rates in children are relatively high, and the benefits ... just didn’t seem to be there in the context of the bleeding risk.

“Pediatrics is a population where many children who get thrombosis are treated by nonhematologists because there aren’t that many pediatric hematologists around,” he added.

Although these guidelines did not have many strong recommendations, they do represent the first full document to quantify how much data were extrapolated from adults, Monagle said.

“I don’t think [conditional recommendations] invalidate or make the chapter any less important because, in the areas where there are a lot of data and randomized trials, you don’t need someone to write guidelines for you; everyone already knows what to do,” Monagle said. “In situations where there aren’t much data and a lot of uncertainty about what to do ... that’s where people are really looking for guidance.” – by John DeRosier

Click here to read the , “Will heparin eventually be phased out with expanded use of DOACs for VTE?”

References:

Cuker A et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018024489.

Witt DM, et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018024893.

Lim W, et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018024828.

Schünemann HJ, et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018022954.

Bates SM, et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018024802.

Monagle P, et al. Blood Adv. 2018;doi:10.1182/bloodadvances.2018024786.

For more information:

Adam Cuker, MD, MS, can be reached at Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104; email: adam.cuker@uphs.upenn.edu.

Mary Cushman, MD, can be reached at The University of Vermont Larner College of Medicine, 360 South Park Drive, Colchester, VT 05446; email: mary.cushman@uvm.edu.

Wendy Lim, MD, MSc, FRCPC, can be reached at McMaster University, 50 E. Charlton Ave., Hamilton, ON L8N 4A6; email: limwp@mcmaster.ca.

Paul Monagle, MD, can be reached at The University of Melbourne Academic Centre, Royal Children’s Hospital 50 Flemington Road, Parkville Victoria 3052 Australia; email: paul.monagle@rch.org.au.

Anita Rajasekhar, MD, can be reached at University of Florida Medical Plaza, 2000 SW Archer Road, 3rd Floor, Gainesville, FL 32608; email: anita.rajasekhar@medicine.ufl.edu.

Daniel M. Witt, PharmD, FCCP, BCPS, can be reached at The University of Utah L.S. Skaggs Pharmacy Institute, Room 4323, 30 S. Campus Drive, Salt Lake City, UT 84112; email: dan.witt@pharm.utah.edu.

Disclosures: Cuker, Cushman, Lim, Monagle, Rajasekhar and Witt report no relevant financial disclosures.