Spotlight on VTE Prevention

For years, venous thromboembolism (VTE) has been a thorn in the side of many hospitals; despite the fact that VTE is preventable, a large number of patients still don’t receive adequate prophylaxis. But now, financial incentives from CMS, along with the emergence of a new class of agents, are casting VTE into the forefront—and making prevention a top priority for hospitals.

By Kate Huvane Gamble

VTE, a condition that manifests as deep vein thrombosis (DVT) and/or pulmonary embolism (PE), is a common cause of hospitalization, morbidity, and mortality in the US. More than 200,000 new cases present each year, and the outlook for those patients is poor. According to data published in a Circulation study, approximately 30% of patients with VTE die within 30 days, 20% suffer sudden death due to PE, and 30% develop recurrent VTE within 10 years (http://hcp.lv/cWrzwf).

The economic impact of VTE is also substantial, with annual costs estimated at nearly $500 million (Pharmacotherapy, http://hcp.lv/bFcjZe). It’s a cost that many hospitals can no longer afford, particularly since DVT and PE events resulting from hip or knee replacement surgery are no longer covered under Medicare (Journal of Patient Safety, http://hcp.lv/9WuCVi).

As a result, interest in VTE prevention has grown over the past few years, according to David Rosenberg, MD, MPH, head of hospital medicine at North Shore University Hospital, Manhasset, NY. He says, “it has become one of the highest level priorities in the hospital setting,” adding that many organizations view VTE prevention as an “essential component of a quality improvement program.”

Adding further credence to the discussion are the recently updated core measure requirements from the Joint Commission (http://hcp.lv/aCBaa0), three of which focus on prevention, notes Michael P. Gulseth, PharmD, program director for anticoagulation services at Sanford USD Medical Center, Sioux Falls, SD. “Aside from the obvious morbidity and mortality factors, what’s driving a lot of the interest are the new core measures—and the possibility that they will be mandated in the future as part of pay-for-performance programs.”

Put simply, hospitals need to make VTE prevention a priority. There are, however, significant barriers. Findings from two large-scale studies looking at the use of evidence-based prophylaxis in patients at risk for VTE suggest that adherence to guidelines from the American College of Chest Physicians (ACCP) is poor. The IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) trial found that only 52% of patients in the US who meet the criteria for prophylaxis are receiving it (Chest, http://hcp.lv/9yvQY0), while the ENDORSE (Venous thromboembolism risk and prophylaxis in the acute hospital care setting) study found that just 59% of surgical patients and 40% of patients at risk for VTE were receiving the recommended therapy (The Lancet, http://hcp.lv/9Ftrcp).

The Institute of Medicine echoed this sentiment, stating that “too few health care professionals are aware of the evidence-based practices for identifying high-risk patients and providing preventive, diagnostic, or therapeutic services” (http://hcp.lv/cZ91WF). The American Public Health Association took it a step further, adding that the “disconnect between evidence and execution as it relates to DVT prevention amounts to a public health crisis” (http://hcp.lv/a0wOs9).

Identifying at-risk patients

So, why is there a disconnect? In a study analyzing VTE prevention efforts, Greg Maynard, MD, and Jason Stein, MD, pinpointed “the lack of a validated VTE risk assessment model” as a key factor in why some programs fall short (Journal of Thrombosis and Thrombolysis, http://hcp.lv/aagUQR). In the Surgeon General’s Call to Action to Prevention of Deep Vein Thrombosis and Pulmonary Embolism (http://hcp.lv/cZ91WF), former Secretary of Health & Human Services Michael Leavitt wrote that diagnosis of VTE is “easy to overlook because the signs and symptoms are often difficult to recognize.”

Identifying at-risk patients doesn’t have to be so difficult, says Rosenberg, who believes that the key to helping clinicians recognize patients who might develop VTE events is in realizing that most critically ill patients exhibit multiple risk factors, many of which predate admission to the ICU.

Once a patient is identified to be at risk, says Rosenberg, prophylaxis should be administered. It is important to note that the ACCP guidelines support a group-specific approach to prophylaxis, as not only is it difficult to confidently identify patients who don’t require prophylaxis and to “predict how risk factors combine to position an individual patient along the spectrum of thromboembolic risk,” but individualizing prophylaxis is complex and may be associated with poor compliance (http://hcp.lv/c98Nhm).

Pharmacologic prophylaxis—now and in the future

The ACCP recommends that every hospital develop a formal strategy that incorporates routine VTE risk assessments for all patients admitted to the ICU—most of whom will need to receive prophylaxis (http://hcp.lv/9Ox7YD).

The guidelines for pharmacologic prophylaxis are as follows:

• Low-molecular weight heparin (LMWH) or low-dose unfractionated heparin (LDUH) for critical care patients who are at moderate risk for VTE (medically ill or postoperative general surgery patients);
• LMWH prophylaxis for critical care patients who are at higher risk (following major trauma or orthopedic surgery);
• LMWH, fondaparinux, warfarin, or LDUH for patients undergoing hip fracture surgery (HFS); thromboprophylaxis for a minimum of 10 days in patients undergoing hip or knee arthroplasty or HFS, and for up to 35 days in hip arthroplasty and HFS patients;
• For critical care patients at high risk for bleeding, use of mechanical thromboprophylaxis with graduated compression stockings and/or intermittent pneumatic compression, at least until the bleeding risk decreases; once high bleeding risk decreases, pharmacologic prophylaxis should be substituted or added to it.

These recommendations, however, may change in the near future. In the recent RECORD trials, rivaroxaban—an oral factor Xa inihibitor approved for hip and knee replacement thromboprophylaxis in Europe and Canada—was shown to be safe and effective in the prevention of VTE following orthopedic surgery (http://hcp.lv/9QM94i).

A key factor in these findings is the ease of use offered by rivaroxaban—a once-daily oral agent that produces a predictable anticoagulant response that requires no monitoring—particularly compared to vitamin K antagonists such as warfarin, which for more than a half-century have been the only oral anticoagulants available. In an editorial published in The Lancet, authors John W. Eikelboom and Jeffrey I. Weitz wrote that although they are effective, “these drugs are challenging to use,” with unpredictable anticoagulant responses necessitating monitoring and frequent dose adjustments. In this regard, oral factor Xa inhibitors can provide a simplified course of treatment for patients (http://hcp.lv/9xn6hT).

But is the answer to VTE prophylaxis really that simple? Rosenberg believes it’s still too early to tell. “In some studies, they are seeing benefits of the new agents, but it’s not clear how much of a game-changer it’s going to be in the medically ill patient. Beyond the simplicity of a pill versus an injection—which is certainly a benefit—do the oral anticoagulants reduce the rates of VTE more than currently available agents? Do they have less bleeding than the currently available agents? We don’t have these answers yet.”

In areas such as stroke prevention and atrial fibrillation, oral anti-coagulants can have a significant impact as an alternative to warfarin, which is associated with “major complications and major difficulties,” notes Rosenberg. “It will be a great improvement in our ability to manage patients. And maybe in treatment of DVT and pulmonary embolism, these oral agents will offer benefit over currently available medication. But in terms of the prophylaxis, that’s yet to be determined.”

The only data available on prophylaxis stems from studies evaluating the administration of dabigatran etexilate, rivoraxaban, and apixaban for the prevention of DVT and PE in orthopedic surgery patients, according to Gulseth. The findings are as follows:

• Dabigatran: Trial results are generally positive; however, in the RE-MOBILIZE trial (Journal of Thrombosis and Haemostasis, http://hcp.lv/boDA3X), it was found to be not non-inferior to enoxaparin 30mg every 12 hours in the total knee arthroplasty population. So far, the company only appears to have applied for approval for atrial fibrillation stroke prophylaxis. However, Gulseth thinks that if the company does apply for an orthopedic indication, the drug will likely achieve an FDA indication for total hip arthroplasty patients, but not knee arthroplasty.
• Rivaroxaban: Generally positive results were achieved in the RECORD- 1 and 2-trials for total hip arthroplasty and the RECORD-3 and-4 trials for total knee arthroplasty; it was found to be superior to enoxaparin in all of the studies, including in the RECORD-4 trial (30mg twice a day of enoxaparin). However, it was associated with a slightly increased bleeding rate, which was not statistically significant, but is still of note to orthopedic surgeons, according to Gulseth.
• Apixaban: In the ADVANCE-1 trial (knee arthroplasty), in which it was compared to enoxaparin 30mg twice a day, apixaban failed to meet the non-inferiority criteria. But it did seem to have a benefit on bleeding profile compared to enoxaparin every 12 hours. It did have positive results versus enoxaparin 40mg sc daily in the ADVANCE-2 trial.

“It’s kind of a murky, gray world in that market,” says Gulseth. “In orthopedics in general, while we certainly need to prevent VTE and PE in that population, it is also one of the highest bleeding risk populations that physicians regularly deal with on a day-to-day basis. And the complications from bleeding are quite substantial.”

In addition to the heightened risk of bleeding, another critical issue is duration of prophylaxis. In a number of clinical trials, patients were administered medication for the initial course of prophylaxis for a 7-10 day period, according to Rosenberg. However, the typical hospital stay is only 5-6 days. “We’re beginning to raise the question of whether just because patients are going home on day 5, does that mean they have received enough prophylaxis at that point, or should that prophylaxis be continued, even after they’ve left the hospital,” he says. Just as patients continue to take antibiotics after being discharged to complete the therapy, some experts believe that VTE prophylaxis should be prolonged as well to prevent thromboembolic events.

And finally, Rosenberg says, “we need to determine whether that initial course of therapy is sufficient, or are there patients who need to receive an extended course of prophylaxis.” Evidence has suggested that certain groups of patients—including those who have undergone knee and hip arthroplasty or cancer surgery—may also benefit from extended prophylaxis. Rosenberg says this is an area that clearly warrants further exploration.

Although there are still many question marks, the progress being made in advancing VTE prophylaxis is nonetheless significant, and could turn out to be a game-changer. As clinical data continues to emerge, and the safety and effectiveness of new agents are further explored, the medical community can potentially take one step closer to being able to prevent DVT and PE on a larger scale.

Online Resources

• Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-based Clinical Practice Guidelines
• Quality Improvement in Managing Patients at Risk for Venous Thromboembolism
• Society of Hospital Medicine Venous Thromboembolism Resource Room
• Preventing Hospital-acquired Venous Thromboembolism: A Guide for Effective Quality Improvement