Tailoring anticoagulation more of a reality with DOACs

Direct oral anticoagulants have the potential to replace warfarin for the treatment of many patients with venous thromboembolism, but without a need for routine monitoring, good patient selection is key to their use.

After remaining fairly static for several decades, the care of patients diagnosed with venous thromboembolism (VTE) has evolved greatly in the past 10 years, with newer and more easily administered treatments now available.

One of the greatest changes in post-VTE care is the availability of direct oral anticoagulants (DOACs). Because they have rapid onset of action and can be given in fixed doses without the need for routine monitoring, DOACs have the potential to replace warfarin for the treatment of many patients with VTE, according to Michael B. Streiff, MD, FACP, medical director of the Johns Hopkins Hospital Anticoagulation Management Service in Baltimore.

Clinicians should follow patients for complications of deep venous thrombosis such as postthrombotic syndrome which can involve persistent feelings of pain and heaviness or can lead to a red or blue
Clinicians should follow patients for complications of deep venous thrombosis, such as postthrombotic syndrome, which can involve persistent feelings of pain and heaviness or can lead to a red or blue discoloration, new varicose veins, or abnormally thickened skin. Image by iStock

“While we have accumulated extensive experience using warfarin over the last 50 years, it is very labor intensive, requires careful monitoring, and has multiple drug and dietary interactions,” Dr. Streiff said. “With the DOACs, you get results at least as good as with warfarin, but you have fewer adverse effects and interactions.”

Since 2010, four direct oral anticoagulants have been approved for the treatment of VTE. Apixaban (Eliquis) and rivaroxaban (Xarelto) are selective factor Xa inhibitors approved for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). Dabigatran (Pradaxa) and edoxaban (Savaysa) are, respectively, a thrombin inhibitor and a factor Xa inhibitor approved for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for at least five days.

The ease of administration of DOACs means that more patients with VTE are able to be treated as outpatients, according to Jeffrey I. Weitz, MD, FACP, executive director of the Thrombosis and Atherosclerosis Research Institute at McMaster University in Hamilton, Ontario, Canada.

“Because these drugs can be given orally, that means that if someone is diagnosed with a DVT we rarely have to admit them anymore,” Dr. Weitz said. “They are only admitted if they have extensive DVT or if the patient has other associated conditions that necessitate hospitalization.”

Because DOACs do not require monitoring, Dr. Streiff stressed the importance of making sure each patient is a good candidate for the drugs. The easiest way to do that, he said, is to look at which patients were excluded or included in the clinical trials for each agent. Internists should pay close attention to kidney and liver function when prescribing DOACs and during each patient's course of therapy.

To monitor kidney function, Dr. Streiff calculates the Cockcroft-Gault creatinine clearance for each patient he is considering for DOAC therapy. The Cockcroft-Gault creatinine clearance should be greater than 25 mL/min for apixaban and greater than 30 mL/min for each of the other DOACs, he said. For liver function, a patient's aspartate aminotransferase and alanine aminotransferase levels should not be greater than two to three times the upper limit of normal, and the total bilirubin level should not be greater than 1.5 to 2 times the upper limit of normal, Dr. Streiff said. In addition, he orders a complete blood count and a comprehensive metabolic panel every three to six months as clinically indicated based on a patient's clinical status.

Duration of therapy

Another major advance in recent years is the understanding that up to half of cases of VTE are unprovoked, according to Dr. Weitz.

“Half of VTE are provoked by major transient risk factors like surgery, trauma, hospitalization, or immobilization for medical illness,” Dr. Weitz said. “If you treat these patients with an anticoagulant for three months and then stop, as long as the patient is back to their normal mobility, their risk for recurrence is very low.”

In contrast, patients with unprovoked VTE have no obvious risk factors for having developed the blood clot.

“In those patients, if you treat for three months and stop anticoagulation, the risk for recurrence is about 10% at one year and about 30% at five years,” Dr. Weitz said. “In these patients, VTE is a chronic disease and they require long-term treatment to prevent recurrence.”

Two studies have explored the use of a lower prophylactic dose of apixaban or rivaroxaban in patients in whom continued anticoagulation is being considered.

In the AMPLIFY extension study, funded by Bristol-Myers Squibb and Pfizer and published in the New England Journal of Medicine in 2013, a thromboprophylactic 2.5-mg twice-daily dose of apixaban was associated with a significantly reduced risk for recurrent VTE versus placebo without an increased rate of major bleeding in patients with VTE who had completed 6 to 12 months of anticoagulation. Similar results were seen in the EINSTEIN CHOICE study. Published in the New England Journal of Medicine in 2017 and funded by Bayer, this study showed that in patients who had completed 6 to 12 months of anticoagulation, those who continued treatment with a prophylactic dose of 10 mg of rivaroxaban once daily had a significantly lower risk for recurrent VTE than patients treated with aspirin, with no increase in major bleeding.

“As things continue to evolve, I think that more and more VTE patients are going to get anticoagulation extended,” Dr. Weitz said. “Patients will get a stepped approach where they get more intense treatment after diagnosis to prevent recurrence in the first month when the risk is highest, then a treatment dose for three to six months, and then a prevention dose to prevent recurrence in those who remain at risk.”

Long-term care

In addition to considering long-term anticoagulation, clinicians must take care to follow patients for complications of VTE, such as the postthrombotic syndrome (PTS), a chronic condition that typically occurs in the leg after a DVT. Instead of the leg returning to normal, a patient is left with persistent feelings of pain and heaviness and the leg often looks different, explained ACP Member Susan R. Kahn, MD, MSc, director of the Centre of Excellence in Thrombosis and Anticoagulation Care at Jewish General Hospital in Montreal. For example, she said, the leg may appear swollen or have a red or blue discoloration. The patient may develop new varicose veins in the affected leg, or the skin may be abnormally thickened. In severe cases, the patients can develop an ulcer in the affected leg, she noted.

Regular follow-up of patients after acute DVT is recommended so they can be educated about and monitored for development of PTS, so treatment can be initiated, and so severe manifestations such as ulcers can be avoided, Dr. Kahn said. Cornerstones of PTS treatment include initiating elastic compression therapy, avoiding recurrent DVT, and providing good skin care to avoid dryness and ulceration.

Patients with a history of PE are also at risk for developing chronic thromboembolic pulmonary hypertension, said Geno J. Merli, MD, MACP, co-director of the Jefferson Vascular Center at Jefferson Health in Philadelphia.

“In patients with a history of clots in the lung, I ask, ‘Do you have shortness of breath? Can you do a flight of stairs without getting winded? Do you get winded with only minimal activity?’” Dr. Merli said. “If an internist suspects chronic PE with hypertension, they should send their patient to a lung specialist to be evaluated.”

Patients with cancer

Treatment of VTE among patients with active cancer, who are at higher risk for the condition, has also begun to evolve, according to Dr. Weitz. Current guidelines from the American College of Chest Physicians, the American Society of Clinical Oncology, and the European Society for Medical Oncology recommend that patients with VTE associated with active cancer receive low-molecular-weight heparin, which requires a daily injection.

However, the HOKUSAI VTE Cancer study, published in the New England Journal of Medicine and funded by Daiichi Sankyo, found that oral edoxaban was noninferior to low-molecular-weight heparin for the composite endpoint of recurrent VTE or major bleeding. Specifically, edoxaban was more effective for recurrent VTE but was associated with an increased risk for bleeding.

The SELECT-D study, presented at the 2017 American Society of Hematology Annual Meeting & Exposition and funded by Bayer, compared low-molecular-weight heparin and rivaroxaban for the treatment of VTE in patients with cancer. Treatment with rivaroxaban also reduced VTE recurrence rates at six months by more than one-half compared with low-molecular-weight heparin but was associated with more bleeding.

Based on the results of these two papers and those of several observational studies, Dr. Weitz said that he “would imagine that we will soon begin to see a doing away with low-molecular-weight heparin in many VTE patients with cancer and more use of DOACs.”

Antidote availability

A major concern with DOACs has been the lack of available reversal agents, which can be needed in cases of life-threatening bleeding or emergency surgery.

One reversal agent, idarucizumab, was approved by the FDA in October 2015 for emergency reversal in patients taking dabigatran. It was approved based on the results of the RE-VERSE AD study, funded by Boehringer Ingelheim, which showed an immediate reversal of dabigatran's anticoagulant effects in patients who presented with life-threatening bleeding or required urgent surgery.

However, idarucizumab cannot be used to reverse the effects of rivaroxaban and apixaban, which are the more commonly used agents in patients with VTE, according to Dr. Merli. Andexanet alfa (Portola) is under FDA review as a reversal agent for these drugs but has not yet been approved.

Instead, nonspecific agents, such as prothrombin complex concentrates, have been used broadly. Prothrombin complex concentrates contain clotting factors in varying amounts, and several studies have shown their efficacy in reversing vitamin K antagonists in emergency cases.

“It is important for physicians and patients to know that there are reversing agents for these drugs as well,” Dr. Merli noted.