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Rivaroxaban expected to have ‘huge impact’ on management of DVT, PE
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In early November, the FDA expanded the approved use of rivaroxaban to include the treatment of deep vein thrombosis and pulmonary embolism.
Many clinicians in the United States say rivaroxaban (Xarelto, Janssen Pharmaceuticals) will be a welcome addition to their armamentarium for treating individuals with thromboembolic conditions, and some believe the approval could be the next step in a paradigm shift in the care of these patients.
“This is a good drug that is easy to use,” Stephan Moll, MD, associate professor in the division of hematology-oncology at the University of North Carolina School of Medicine, said in an interview. “It will have a huge impact on how we manage DVT and PE.”
In July 2011, the FDA approved rivaroxaban to prevent venous thromboembolic events in patients who undergo knee or hip replacement surgery. This past summer, the agency assigned priority review designation to Janssen’s request for new indications to treat all patients with DVT and PE, as well as to prevent recurrences of both conditions.
The FDA based its approval — announced Nov. 2 — largely on the results of the global EINSTEIN research, a series of three trials that evaluated rivaroxaban’s safety and effectiveness.
HemOnc Today spoke with several clinicians who treat DVT and PE to learn more about how rivaroxaban and other novel therapies, including half-dose thrombolysis, may alter treatment and improve patient outcomes.
Standard ‘nightmare’
DVT and PE occur in at least 300,000 Americans annually, and some estimates suggest at least 100,000 deaths are attributable to the conditions each year, according to the CDC.
PE, which occurs in about one-third of DVT patients, is the third most common cause of hospital-related death in the United States. Sudden death is the first symptom in about 25% of patients with PE, and up to 30% die within a month of diagnosis, according to CDC. One-third of patients with DVT/PE will have a recurrence within 10 years, the CDC reported.
Standard therapy — low-molecular–weight heparin (LMWH) followed by vitamin K antagonists — has been used for most patients during the past several decades. It is effective but complex, requiring the need for injection and regular dose adjustments based on laboratory monitoring.
“If you give standard treatment the right way, it’s a perfectly effective drug with almost 90% reduction in recurrent thrombosis, but it has to be well controlled,” said Harry R. Büller, MD, PhD, professor of vascular medicine at Academic Medical Center in Amsterdam, the Netherlands, and lead investigator of EINSTEIN-PE, the final trial in the EINSTEIN series. “The reason that people look for alternatives is that [standard treatment is] a nightmare to give. Our major aim was to show that [rivaroxaban is] at least as good as standard care.”
The most recent recommendation for initial treatment of acute DVT or PE with rivaroxaban calls for a dose of 15 mg twice daily for the first 3 weeks followed by 20 mg once a day. A similar treatment schedule is recommended to prevent risk of recurrence of DVT or PE.
For most clinicians, the oral therapy is critical to the appeal of rivaroxaban.
The subcutaneous injections and regular dose adjustments were a cumbersome aspect to standard therapy for the initial and long-term treatment of PE.
“The lack of subcutaneous injections with rivaroxaban makes it easier for both health care professionals and patients,” Moll said. “However, education and follow-up are required.”
EINSTEIN-PE
The EINSTEIN-PE trial — a randomized, open-label investigation conducted from March 2007 to March 2011 — evaluated rivaroxaban in individuals with PE.
The findings of this trial, published earlier this year in The New England Journal of Medicine, showed a fixed-dose regimen oral rivaroxaban is comparable to standard therapy for initial and long-term treatment. Results also suggested rivaroxaban is associated with significant reductions in major bleeding and a potentially improved benefit–risk profile.
Samuel Z. Goldhaber, MD, professor of medicine at Harvard Medical School and director of the Brigham and Women’s Hospital Venous Thromboembolism Research Group, called the EINSTEIN-PE trial one of the most important studies ever undertaken related to pulmonary embolism.
Source: Photo courtesy of Samuel Z. Goldhaber, MD, reprinted with permission.
“This is one of the most important studies in pulmonary embolism that has ever been undertaken,” Samuel Z. Goldhaber, MD, professor of medicine at Harvard Medical School and director of the Brigham and Women’s Hospital Venous Thromboembolism Research Group, told HemOnc Today. “This trial is going to change the way we manage acute pulmonary embolism.”
The study included 4,832 patients at 263 sites in 38 countries.
The researchers assigned 2,419 patients to an oral rivaroxaban regimen of 15 mg twice a day for 3 weeks, followed by 20 mg once a day.
The investigators assigned 2,413 patients to standard treatment that consisted of enoxaparin 1 mg/kg of body weight twice daily, plus a vitamin K antagonist — either warfarin or acenocoumarol — that was initiated within 48 hours of randomization.
The regimen included a dose adjustment to maintain an international normalized ratio of 2 to 3. Standard treatment ran for at least 5 days and was discontinued when the INR was 2 or more for 2 consecutive days.
Eligibility criteria included a primary diagnosis of PE. One-quarter of patients from both groups also had DVT.
First recurrent VTE served as the primary efficacy outcome. Clinically relevant bleeding served as the principal safety outcome.
Treatments lasted for 3, 6 or 12 months and were assigned based on clinician recommendation. The average duration was 7 months.
“This was the first time we have seen completely oral anticoagulant therapy with a loading dose followed by a maintenance dose, without any intravenous or subcutaneous injection of any anticoagulant,” Goldhaber said in an interview.
Rivaroxaban demonstrated noninferiority for efficacy, with an HR of 1.12 (95% CI, 0.75-1.69). The investigators reported recurrence rates of 2.1% (50 events) among patients in the rivaroxaban group and 1.8% (44 events) among patients in the standard therapy group.
Rivaroxaban also demonstrated noninferiority for the principal safety outcome (HR=0.9; 95% CI, 0.76-1.07). Researchers observed major or clinically relevant bleeding in 10.3% of patients assigned to rivaroxaban compared with 11.4% of patients assigned to standard therapy.
“What struck me is that rivaroxaban was superior in terms of less major bleeding,” Goldhaber said.
Rivaroxaban demonstrated superiority in that comparison alone (1.1% vs. 2.2%; HR=0.49; 95% CI, 0.31-0.79).
The efficacy and safety results were consistent across demographic categories, including age, body weight, sex, kidney function, and the presence or absence of cancer at baseline, Büller said. The researchers observed no evidence of liver toxicity associated with rivaroxaban.
A paradigm shift
The EINSTEIN-PE findings may signify a paradigm shift in the treatment of patients with PE, said Moll, medical director of Clot Connect, an initiative that provides patients and health care professionals with clinical-practical information and support resources related to VTE, thrombophilia and anticoagulation.
“The results of this trial can lead to a significant change in the way patients with PE are treated in three ways,” Moll said. “Firstly, warfarin management is cumbersome for patients and health care professionals due to the need for regular INR testing, importance of a consistency of diet in respect to vitamin K intake and the many drug interactions that can influence the INR. Having an oral anticoagulant that does not require routine monitoring of its anticoagulant effect and that is not affected by vitamin K content of the diet is a huge advantage over warfarin.”
Second, rivaroxaban is active within 1 to 3 hours of oral intake, Moll said. He noted the drug was tested in trials in patients with acute DVT and PE immediately from the get-go, without bridging with a parenteral anticoagulant.
“This is huge,” Moll said. “There is no need for a subcutaneous injection when one starts this oral anticoagulant, as it leads to therapeutic anticoagulation within 3 hours of taking the first pill.”
Third, rivaroxaban has a relatively short half-life of 5 to 9 hours.
“Perioperative interruption of anticoagulant therapy is much simpler than with warfarin, as rivaroxaban’s anticoagulant effect is gone much faster,” Moll said. “Discontinuation of rivaroxaban 1 to 3 days prior to surgery — depending on renal function, as well as bleeding risk with the particular surgery — is all it takes for the anticoagulant effect to be gone, whereas warfarin’s effect takes 5 to 7 days to wear off.”
‘Real world’ data needed
EINSTEIN-PE was one of a series of large, international, phase 3 clinical trials that evaluated rivaroxaban. The others included EINSTEIN-DVT, which evaluated patients with DVT, and EINSTEIN-EXT, an extension study of patients with VTE.
Charles S. Abrams
The EINSTEIN-PE and EINSTEIN-DVT trials are significant in that they demonstrated treatment with an oral anticoagulant alone can be sufficient to treat thromboembolic disease, Charles S. Abrams, MD, associate chief of the hematology-oncology division and professor of medicine at the University of Pennsylvania, told HemOnc Today.
“Do these trials mean that standard therapy is dead? Not yet,” said Abrams, who also is secretary of the American Society of Hematology. “These studies report on impressive outcomes, but only in highly monitored patients enrolled in clinical trials. What remains to be seen are clinical outcomes in patients who are treated under real-world conditions.”
In a press release issued this spring when the results of EINSTEIN-PE were made public, Büller said researchers involved with the EINSTEIN studies were satisfied with the findings of the entire program.
“The patient populations were large enough and the data were convincing enough that we feel we have advanced the field,” Büller said. “Rivaroxaban is just as good as standard treatment for pulmonary embolism — these data are convincing.”
Researchers intend to conduct a subgroup analysis of the 8,200 patients in the EINSTEIN-PE and EINSTEIN-DVT trials to determine whether they can identify a risk profile for patients who are likely to have bleeding problems when assigned to rivaroxaban or standard treatment.
Potential limitations
In the EINSTEIN-PE trial, just 5% to 6% of patients in the study population had malignancies, said Menno Huisman, MD, PhD, an associate professor in the department of medicine at Leiden University Medical Center in the Netherlands, whose primary research interests include the diagnosis and treatment of venous and arterial thromboembolism.
Also, investigators used vitamin K antagonists — not grade 1A LMWH — for patients who had malignancy and presented with acute PE.
“The outcomes of the study have to be seen in the light of these two limitations,” Huisman said. “Nevertheless, the outcomes in the relatively small number of patients with malignancy treated with rivaroxaban — although they may have been a favorable, selected group of patients — were comparable to those without malignancy.”
Moll said he would consider giving rivaroxaban to patients with newly diagnosed DVT or PE, provided they understood it was off-label, and that it has no known reversal agent or established management strategy should major bleeding occur.
Huisman echoed that concern.
“There is no specific antidote for rivaroxaban,” he said. “Although in a recent study in volunteers, who were treated with rivaroxaban, prothrombin complex concentrate shortened the prolonged prothrombin time. We do not know whether these concentrates will also work when a patient on rivaroxaban presents at the ED with major, life-threatening bleeding. This is an important caveat.”
LMWH and vitamin K antagonists remain the standard of care in many patient populations, as the rivaroxaban regimen is not approved for patients with cancer or those with renal complications.
Because the FDA approval of rivaroxaban is so recent, clinicians are just beginning to debate whether the drug should be given to patients with malignancies.
“At this point, I would not use rivaroxaban in cancer patients with DVT or PE, but rather stick to the established low-molecular–weight heparin treatment until further data on the performance of rivaroxaban in cancer patients with DVT or PE become available,” Moll said.
Further testing is necessary, particularly among patients with malignancies, Abrams said.
“The true toxicity of these agents will need to be established in the community through the use of drug safety and surveillance programs,” Abrams said.
Huisman suggested future studies compare rivaroxaban and low-molecular–weight heparin in unselected patients with VTE and malignancy.
“I would suggest that both treatments should be given for at least 6 months,” Huisman said.
There may be an economic component to this argument, Moll said.
“Many people in the United States who can’t afford low-molecular–weight heparin can be treated with Coumadin,” he said. “It is possible to argue that if they are not getting low-molecular–weight heparin, then there may be an argument for Coumadin or Xarelto. It could play a fair role in oncology. However, we are not there yet.”
Other recent advances
Another alternative approach highlighted in recent data is the effectiveness of half-dose thrombolysis as an acute treatment for moderate PE.
The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial included 121 patients.
Investigators assigned 60 patients to a standard regimen, which consisted of enoxaparin for 80% of patients and heparin for about 20%. Researchers assigned the other 61 patients to “safe-dose” thrombolysis.
Patients who weighed ≥50 kg received 10 mg in 1 minute followed by 40 mg in 2 hours, while patients who weighed <50 kg received 0.5 mg/kg total dose, 10 mg in 1 minute followed by the remainder in 2 hours. All patients assigned to safe-dose thrombolysis also received concomitant anticoagulation with about a 20% to 30% reduced dose of enoxaparin or heparin.
Pulmonary hypertension at the last follow-up — which occurred at 28 months — served as the primary endpoint. Investigators used echocardiography to determine pulmonary artery pressure.
Secondary outcome measures included the development of bleeding and the duration of hospitalization.
At 28 months of follow-up, 16% of patients in the thrombolytic group developed pulmonary hypertension vs. 57% of the control group (P<.001), Mohsen Sharifi, MD, adjunct professor of medicine at A.T. Still University and director of Arizona Cardiovascular Consultants in Mesa, Ariz., said during a press conference when the findings were released.
The study also included a composite endpoint of pulmonary hypertension and recurrent PE at the last follow-up.
“The composite endpoint was 16% in the thrombolytic group vs. 63% in the control group,” Sharifi said.
Half-dose thrombolysis also was associated with a significant reduction in hospitalization, Sharifi said. The average stay was 2.2 days for patients in the thrombolytic group vs. 4.9 days for patients in the control group (P<.001).
Sharifi said the studied dose of thrombolysis may serve as a form of “pulmonary stress test” and post-therapy risk stratification tool. Patients who have pulmonary infarction and begin to experience chest pain with thrombolysis may stay longer.
“Those who do well and are ambulatory without symptoms may be discharged in a matter of 1 or 2 days,” Sharifi said.
Half-dose thrombolysis
Prior research has suggested that only about 5% of PE cases are considered severe enough to warrant administration of thrombolytic agents at full dose. Although these drugs have proved effective, they are associated with a 2% to 6% increased risk for intracranial hemorrhage.
MOPETT is the first trial to show that using a lower dose of drug tissue plasminogen activator (t-PA) and anticoagulants can be safe and effective for this patient population, the researchers concluded.
“Pulmonary embolism can be more aggressively — and above all, safely — managed with what we call ‘safe-dose thrombolysis,’” Sharifi said. “Over 70% of pulmonary embolism patients would benefit from this treatment.”
Stavros V. Konstantinides, MD, FESC, professor of clinical trials in the Center for Thrombosis and Hemostasis at the Johannes Gutenberg University of Mainz, Germany, told HemOnc Today the idea of half-dose thrombolysis is intriguing, yet he expressed caution.
“This is an interesting idea, with potentially interesting results, but at the moment, it is only valuable for generation of hypotheses regarding future regimens of thrombolysis,” Konstantinides said.
He said he looks forward to seeing the full results of MOPETT published in a peer-reviewed journal.
Konstantinides’ research group is studying the same topic in the Pulmonary Embolism Thrombolysis (PEITHO) study, which includes 1,000 normotensive patients with PE who are randomly assigned to thrombolysis vs. placebo. Data should be available by the end of this year.
“Maybe then we will know more on the subject,” Konstantinides said. – by Rob Volansky
References:
Büller H. Late-breaking clinical trials III. Presented at: the American College of Cardiology 61st Scientific Sessions & Expo; March 24-27, 2012; Chicago.
CDC. Deep Vein Thrombosis/Pulmonary Embolism Data & Statistics. Available at: www.cdc.gov/ncbddd/dvt/data.html. Accessed Oct. 17, 2012.
EINSTEIN-PE investigators. N Engl J Med. 2012;366:1287-1297.
Guyatt GH. Chest. 2012;141(2 Suppl):7S-47S.
Patient Information Guide: Deep Vein Thrombosis and Pulmonary Embolism. 2012. Clot Connect patient education program. University of North Carolina Hemophilia and Thrombosis Center. Available at: http://files.www.clotconnect.org/DVT_and_PE.pdf. Accessed Oct. 18, 2012.
Sharifi M. Joint ACC/Journal of the American Medical Association late-breaking clinical trials. Presented at: the American College of Cardiology 61st Scientific Sessions & Expo; March 24-27, 2012; Chicago.
For more information:
Charles Abrams, MD, may be reached at 912 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104; email: abrams@mail.med.upenn.edu.
Harry R. Büller, MD, PhD, may be reached at Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam; email: h.r.buller@amc.uva.nl.
Samuel Z. Goldhaber, MD, may be reached at Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115; email: sgoldhaber@partners.org.
Menno Huisman, MD, PhD, may be reached at Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Building 1, P.O. Box 9600, 2300 RC Leiden, the Netherlands; email: m.v.huisman@lumc.nl.
Stavros V. Konstantinides, MD, FESC, may be reached at Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstrabe 1, 55131 Mainz; email: stavros.konstantinides@unimedizin-mainz.de.
Stephan Moll, MD, may be reached at UNC Hemophilia and Thrombosis Center, 170 Manning Drive, 3rd Floor Physicians Office Building, Campus Box 7016, Chapel Hill, NC 27599-7016; email: smoll@med.unc.edu.
Mohsen Sharifi, MD, may be reached at Arizona Cardiovascular Consultants, 5440 E. Southern Ave. #104, Mesa, AZ 85206.
Disclosures: Abrams, Huisman and Konstantinides report no relevant financial disclosures. Büller reports research support, consulting work and advisory board roles with Bayer HealthCare, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Isis, Pfizer, Roche, Sanofi-Aventis and Thrombogenics. Goldhaber serves as a consultant for Janssen, and his research group receives support from Johnson & Johnson. Moll reports consulting with Bayer, Boehringer-Ingelheim, Daiichi and Johnson & Johnson. Sharifi reports consulting with Covidien.
The potential is there.
Keith McCrae
Rivaroxaban (Xarelto, Janssen) and dabigatran (Pradaxa, Boehringer Ingelheim) have the potential to change the paradigm in thrombosis. The EINSTEIN trials were convincing and well done. They were carefully controlled clinical trials, but accrual was limited to patients who were not at high risk of bleeding complications. This led to a low incidence of bleeding during the trials, which was comparable to that seen with warfarin (Coumadin, Bristol-Myers Squibb). Whether the same low risk will be observed in the community without strict selection guidelines of a clinical trial is unknown.
There is no easy way to reverse bleeding due to the new oral anticoagulants. With warfarin, plasma can be used to reverse bleeding relatively quickly. Plasma does not reliably reverse bleeding caused by the newer oral anticoagulant drugs. Similar concerns apply to other agents, such as recombinant Factor VIIa or vitamin K complex concentrates, particularly the three factor concentrates currently available in the United States.
Speaking specifically of cancer, the same concerns apply.
Having said that, I do think these drugs have the potential to change the paradigm, but much more needs to be done to establish safety. An FDA press release suggests that bleeding risks associated with dabigatran do not appear to be greater than those expected from Coumadin, but most of this data applies to patients with atrial fibrillation. Whether this will apply to patients with venous or arterial thrombosis, particularly those with cancer, is uncertain.
We need studies specifically targeted toward patients with malignancies. There were not enough patients with cancer in the EINSTEIN studies to draw firm conclusions, and I presume they were probably not patients with advanced malignancies. We need specific studies looking at patients with all different types of neoplasms to determine the safety and efficacy profile of these drugs in patients with cancer.
Keith McCrae, MD, is a member of the staff in hematologic oncology and blood disorders at Cleveland Clinic’s Taussig Cancer Institute. He may be reached at Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave., Cleveland, OH 44195; email: mccraek@ccf.org. Disclosure: McCrae reports no relevant financial disclosures.
There are insufficient data to make a determination at this time.
Geno J. Merli
The EINSTEIN trials enrolled a large population of patients with venous thromboembolism. They demonstrated the efficacy and safety of rivaroxaban vs. low-molecular– weight heparin bridged to warfarin therapy.
Unfortunately, this important breakthrough in care really cannot yet be correlated to the cancer patient population with venous thromboembolism. The reason is that the cancer population enrolled was very small in both trials. In addition, rivaroxaban is an oral agent which — in a cancer population receiving chemotherapy — may become problematic with the nausea and vomiting associated with treatment.
Another concern for this population would be the non-reversibility of rivaroxaban should major bleeding develop during treatment.
I do believe that rivaroxaban is worth studying in patients with cancer and thrombosis. I am sure clinical trials will be developed to study this question in such a high-risk population.
Geno J. Merli, MD, is co-director of the Jefferson Vascular Center and clinical professor at Jefferson University Hospitals. He may be reached at Gibbon Building, Suite 6270, 111 S. 11th St., Philadelphia, PA 19107; email: geno.merli@jefferson.edu. Disclosure: Merli reports no relevant financial disclosures.
Perspective
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Harry S. Jacob, MD, FRCPath(Hon)
Recently, two studies demonstrated significant prophylactic efficacy of aspirin following anticoagulant treatment in first-episode DVT/PE. Thus, we now may be able to treat many DVT/PE patients without ever exhibiting a needle. Amazing — if these results hold up in the future.Perspective
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A. Koneti Rao, MD, FACP
Rivaroxaban represents a major advance in the area of antithrombotic therapy for venous thromboembolism. The recent approval by the FDA of rivaroxaban for the treatment of patients with DVT or PE — and to prevent recurrences — is likely to impact the field in a major way for a number of reasons.First, a single agent given by the oral route and without the need for either subcutaneous injections or intravenous administration is driving the entire management of DVT and PE. Second, this is further enhanced by the absence of a need for repeated laboratory monitoring, which has been a cumbersome and costly issue with warfarin. Third, the rapid onset of action and short half-life both allow it to be instituted and discontinued with greater ease, particularly in the context of surgical procedures, as compared with warfarin. This obviates the issue of bridging with a parenteral agent, as is the case currently.
Although the benefit-risk evaluation has been very gratifying with rivaroxaban in the large multicenter trials, these represent carefully screened and monitored populations who may be sometimes younger than those encountered in clinical practice. The studies to date need to be followed up with information on this agent, and other oral antithrombotic agents, when they are used in the real-world setting.
There are areas where of the efficacy of rivaroxaban needs to be established, such as in the context of patients with VTE and malignancies. Another need is the development of appropriate therapeutic strategies to manage patients with bleeding complications while on rivaroxaban because there is no antidote. Future studies would need to address the relative efficacy of oral selective factor Xa inhibitors and thrombin inhibitors.
That said, rivaroxaban and its approval for treatment of VTE represents a welcome addition to an armamentarium that has remained limited and static for decades. It clearly fills a major need in the management of an entity that is associated with substantial morbidity and mortality.
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