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Novel therapies introduce next generation of PE treatment
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Data from the recently published EINSTEIN-PE trial provide evidence of a new treatment option for acute pulmonary embolism, generating excitement among physicians who care for patients with this condition.
Pulmonary embolism (PE) is the third most common cause of hospital-related death in the United States, and the US Surgeon General estimates that there are 100,000 to 180,000 deaths attributed to PE per year.
At the American College of Cardiology’s 61st Scientific Sessions in March, Harry R. Büller, MD, PhD, presented results of the EINSTEIN-PE trial, which showed that a fixed-dose regimen of the oral anticoagulant rivaroxaban was noninferior to standard therapy for the initial and long-term treatment of PE. Data demonstrate the novel therapy was also associated with significant reductions in major bleeding and a potentially improved benefit-risk profile. The data were published simultaneously in The New England Journal of Medicine.
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Samuel Z. Goldhaber, MD, of Brigham and Women’s Hospital, is a leader in PE research. Reprinted with permission from:
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“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, told Cardiology Today during a discussion of the EINSTEIN-PE results. “This trial is going to change the way we manage acute pulmonary embolism.”
EINSTEIN-PE
Rivaroxaban (Xarelto, Janssen Pharmaceuticals) is FDA approved for the prevention of venous thromboembolism in patients who have undergone knee or hip replacement.
“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. The reason that people look for alternatives is that [standard treatment is] a nightmare to give,” Büller, professor of vascular medicine at Academic Medical Center, Amsterdam, the Netherlands, said in a press release issued at the ACC Scientific Sessions. “Our major aim was to show that [rivaroxaban is] at least as good as standard care.”
EINSTEIN-PE was a randomized, open-label trial. From March 2007 to March 2011, researchers enrolled 4,832 patients at 263 sites in 38 countries. It is, by far, the largest such trial undertaken. The researchers assigned 2,419 patients to an oral rivaroxaban regimen and 2,414 patients to standard treatment. The rivaroxaban regimen was 15 mg twice a day for 3 weeks followed by 20 mg once a day. The standard regimen was enoxaparin 1 mg/kg of body weight twice daily plus a vitamin K antagonist that was initiated within 48 hours of randomization, and included a dose adjustment to maintain an INR 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 deep vein thrombosis (DVT). The primary efficacy outcome was the first recurrent VTE. The first major or nonmajor clinically relevant bleeding comprised the key safety outcomes. 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 recurrence rate was 2.1% (50 events) in the rivaroxaban group and 1.8% (44 events) in the standard therapy group.
For the principal safety outcome, rivaroxaban was linked to noninferiority compared with standard therapy (HR=0.9; 95% CI, 0.76-1.07). Major or clinically relevant bleeding was 10.3% in the rivaroxaban group compared with 11.4% in the standard therapy group. Rivaroxaban demonstrated superiority in major bleeding alone, 1.1% vs. 2.2% (HR=0.49; 95% CI, 0.31-0.79). According to the researchers, this was the most astonishing finding from the trial.
“What struck me is that rivaroxaban was superior in terms of less major bleeding,” Goldhaber said.
Büller said the efficacy and safety results were consistent across demographic categories, including age, body weight, sex, kidney function and cancer. There was no evidence of liver toxicity associated with rivaroxaban.
A paradigm shift
Findings from the EINSTEIN-PE trial may signify a paradigm shift in the treatment of patients with PE, many experts said.
Goldhaber said further validation will probably not be necessary. “Cardiologists are conservative by nature, but these results are compelling,” he said.
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Büller had a similar inclination: “Now it depends on the FDA.”
EINSTEIN-PE is one of a series of large, international, phase 3 clinical trials of rivaroxaban to treat VTE or prevent a recurrence in patients with acute PE or DVT.
“We are satisfied with the results of the entire EINSTEIN program,” Büller said, referring also to the earlier trials, EINSTEIN-DVT (for patients with DVT) and EINSTEIN-EXT (an extension study in patients with VTE). “The patient populations were large enough and the data were convincing enough that we feel we have advanced the field.
“Rivaroxaban is just as good as standard treatment for pulmonary embolism — these data are pretty convincing — and this is an oral-only approach, which makes it very simple,” Büller said in a press release.
Researchers will 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 on standard treatment or the new drug.
Other recent advances in PE
Alternative approaches to treat PE were the topic of another late-breaking clinical trial session presented at the ACC’s 61st Scientific Sessions.
The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial was conducted to determine whether half the standard dose of thrombolysis is effective as an acute treatment for moderate PE. The study included 121 patients. Sixty were assigned the standard anticoagulant, which consisted of enoxaparin for most cases and heparin for approximately 20% of patients; 61 patients were assigned “safe-dose” thrombolysis. The safe dose was defined as half-dose thrombolysis (for those >50 kg, 10 mg in 1 minute followed by 40 mg in 2 hours; for those <50 kg, 0.5 mg/kg total dose, 10 mg in 1 minute followed by the remainder in 2 hours) and concomitant anticoagulation with around a 20% to 30% reduced dose of enoxaparin or heparin.
The primary endpoint was development of pulmonary hypertension at the last follow-up, which occurred at 28 months. Echocardiography was used to determine pulmonary artery pressure. The study also included a composite endpoint of pulmonary hypertension and recurrent PE at the last follow-up. Secondary outcome measures included the development of bleeding and the duration of hospitalization.
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“At 28 months of follow-up, only 16% of the thrombolytic group developed pulmonary hypertension vs. 57% of the control group,” Mohsen Sharifi, MD, adjunct professor of medicine at A.T. Still University and director of Arizona Cardiovascular Consultants in Mesa, Ariz., reported at a press conference. “The composite endpoint was 16% in the thrombolytic group vs. 63% in the control group.”
The duration of hospitalization was reduced dramatically, Sharifi said. Average stay was 2.2 days in the thrombolytic group and 4.9 days in the control group. He noted that 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.
Currently, only about 5% of PE cases are considered severe enough to be given thrombolytic agents at full dose. Although these drugs have been 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.”
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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 Cardiology Today that the idea of half-dose thrombolysis appears interesting. However, he also expressed reservations.
“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 PEITHO study. Data on 1,000 randomized normotensive patients with PE assigned thrombolysis vs. placebo will be available by the end of 2012 and likely presented at the ACC’s Scientific Sessions next year.
“Maybe then, we will know more on the subject,” he said. – by Rob Volansky
For more information:
- Büller H. Late-breaking clinical trials III. Presented at: the American College of Cardiology 61st Scientific Sessions & Expo; March 24-27, 2012; Chicago.
- EINSTEIN-PE investigators. N Engl J Med. 2012;366:1287-1297.
- 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.
Disclosures:
- Dr. Büller has received research support, been a principal investigator, consulted and served on the scientific advisory boards for Bayer HealthCare, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Isis, Pfizer, Roche, Sanofi-Aventis and Thrombogenics. Dr. Goldhaber is a consultant for Janssen and his research group receives support from Johnson & Johnson. Dr. Konstantinides is chair of the steering committee for the PEITHO trial. Dr. Sharifi reports consulting for Covidien.