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Low-dose anticoagulation shows promise beyond stroke, VTE prevention
Use of oral anticoagulants is expanding beyond stroke prevention in patients with atrial fibrillation and venous thromboembolism prevention to treatment in coronary and peripheral artery disease.
One particular study in a new population that received attention was COMPASS, published in The New England Journal of Medicine in 2017, which showed that patients with stable atherosclerotic vascular disease treated with 2.5 mg rivaroxaban (Xarelto, Janssen) twice per day plus aspirin had a decreased risk for CV death, stroke or MI compared with those treated with aspirin alone. This benefit, however, came with an increased risk for major bleeding events.
The lower dose of rivaroxaban is not yet approved for commercial use in the United States, but a supplemental new drug application to the FDA was filed by Janssen in December and a company spokesperson told Cardiology Today the agency is expected to make a decision sometime in the fourth quarter of 2018.
“This is exciting because even with secondary prevention, these patients with established stable atherosclerotic cardiovascular disease still remain at very high risk — up to 10% will have a recurrent event within 1 year,” Erin D. Michos, MD, MHS, associate director of preventive cardiology at the Ciccarone Center for the Prevention of Cardiovascular Disease, associate professor of medicine at Johns Hopkins University and Cardiology Today Next Gen Innovator, said in an interview. “That’s despite all of the aggressive standard prevention therapy that we have. Trying to find additional avenues to reduce risk is important, and it’s why this trial should hopefully shape guidelines and [the low dose should] get approved.”
Sonia Anand, MD, PhD, FRCP, professor in the division of cardiology and senior scientist at the Population Health Research Institute at McMaster University in Hamilton, Ontario, agreed.
“The implications are for patients who have chronic stable coronary artery disease or peripheral artery disease, and this new combination [of low-dose rivaroxaban plus aspirin] could replace using single antiplatelet agents such as aspirin on a daily basis,” she told Cardiology Today.
This could result in a new treatment option, but also a change in mentality for patients and clinicians.
“Many physicians still have this old-school version [where] they imagine cholesterol plaque building up and clogging arteries, but what we’re dealing with is a significant level of ongoing chronic inflammation of vessels and activation of the clotting cascade as well when we have these plaque ruptures,” Deborah Hornacek, MD, staff physician in the section of vascular medicine at Cleveland Clinic, said in an interview. “It’s a mindset shift for patients and physicians to be thinking of atherosclerosis as atherothrombosis.”
Benefits, drawbacks of anticoagulants
Data regarding patients with ACS assigned low-dose rivaroxaban are somewhat limited. In the GEMINI-ACS-1 trial published in The Lancet in 2017, patients with ACS who were assigned low-dose rivaroxaban and a second-generation P2Y12 inhibitor did not have an increased risk for bleeding, although they did not have superior outcomes compared with those assigned aspirin in DAPT.
“We looked at the safety, and we found that rivaroxaban in combination with an [adenosinediphosphate receptor] antagonist was actually safe, equally safe to dual antiplatelet therapy, which is what’s done now post-ACS,” E. Magnus Ohman, MD, professor of medicine at Duke University School of Medicine and member in the Duke Clinical Research Institute, told Cardiology Today. “It leads us to not knowing what’s the most efficacious approach. There’s more work that should probably be done.”
The risk for CV death, MI and stroke was reduced with low doses of rivaroxaban in patients with ACS in the ATLAS ACS trial that was published in NEJM in 2011.
The low 2.5-mg dose of rivaroxaban demonstrated benefit for patients with stable CAD and PAD in further substudies of COMPASS. In one study published in the Journal of the American College of Cardiology in March, patients with lower-extremity PAD treated with low-dose rivaroxaban plus aspirin had reduced incidence of major adverse limb events. Patients with stable CAD or PAD also had a reduction in ischemic stroke with low-dose rivaroxaban plus aspirin, according to results presented at the International Stroke Conference in January (see Table below).
Even with the benefits of rivaroxaban shown in the COMPASS trial and its substudies, especially in high-risk patients, these patients faced an increased risk for bleeding. In the COMPASS trial, 3.1% of patients assigned rivaroxaban with aspirin had major bleeding events compared with 1.9% of those assigned aspirin alone. Most bleeding events seen in the COMPASS trial were treatable events, such as those involving the gastrointestinal tract, experts said.
Although some clinicians see the risk for major bleeding as a concern, others said the risk is minimal.
“There is a small signal for bleeding, but it’s very small,” Ohman said in an interview. “It can’t really be completely said it’s nothing, but it was nowhere near where it was in the ATLAS trial with triple therapy. With dual therapy, it’s actually lower. That’s helpful because every add-on therapy has a bleeding risk.”
Experts said rivaroxaban has been shown to be successful in these patients because it focuses on two pathways: platelets and coagulation. Antiplatelet effects are often the major target in other combination therapies, but they often miss the anticoagulation aspect. Patients have better outcomes through blocking both the platelet and coagulation pathways. Through this low-dose factor Xa inhibitor, there is more benefit than risk.
Research on other anticoagulants has been performed since the 1960s with warfarin, which has been tested at different doses, experts said. The effects of low-dose warfarin with aspirin was assessed in the CARS trial, which was published in The Lancet in 1997. In this study, patients with MI who were assigned 1 mg or 3 mg warfarin with 80 mg aspirin did not have a greater clinical benefit than was achieved with 160 mg aspirin alone.
In the past 10 years, studies have focused on direct oral anticoagulants, which have been shown to have an established benefit in patients with AF.
Apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) is another anticoagulant that has previously been studied. In the APPRAISE-2 trial published in NEJM in 2011, patients who were high risk after ACS and were assigned full-dose apixaban (5 mg twice per day) in addition to antiplatelet therapy had an increased risk for major bleeding events without a significant reduction in recurrent ischemic events. This study was terminated early due to the increase in major bleeding events without a reduction in ischemic events. “The key difference in this study is the dose — where adding the full dose led to too much bleeding. In COMPASS, they added a quarter of the dose of the dual oral anticoagulant,” Christopher P. Cannon, MD, senior physician at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, said in an interview.
An alternate approach to improving secondary prevention is to add a second antiplatelet agent to aspirin, Cannon said. This was done in the PEGASUS-TIMI 54 trial published in the Journal of the American College of Cardiology in 2016, in which researchers analyzed the effects of ticagrelor (Brilinta, AstraZeneca), a P2Y12 receptor antagonist, in patients with a prior recent MI. A reduction in major adverse CV events was seen, with an increase in major bleeding. In a subgroup analysis of PAD, those assigned ticagrelor had an absolute risk reduction of 4.1% for major adverse CV events with a number needed to treat of 25. Patients who were assigned placebo had an increased risk for peripheral revascularization and acute limb ischemia. Even with this benefit, patients assigned ticagrelor had an increased risk for major bleeding, experts said.
“In COMPASS, you have a single low-dose antiplatelet — so just the aspirin — and then you’re adding a different strategy, a different type of drug,” Michos said. “You’re adding a low-dose antithrombotic that’s blocking the activity of the clotting factor Xa. Of note, PEGASUS didn’t show a reduction in all-cause mortality but COMPASS did. So the benefits may have been a little bit better with the dual strategy approach in COMPASS, though it’s hard to compare head to head because they’re slightly different patient populations, but with rivaroxaban being an effective factor Xa inhibitor, combined with aspirin, you’re coming at the thrombotic pathway from two different mechanisms as opposed to using dual antiplatelet therapies for secondary prevention.”
Potential availability in the U.S.
Low-dose rivaroxaban was approved in Europe in 2013 for treatment of patients after an ACS event, but is not yet available in the U.S. Based on accumulating data from the COMPASS trial, low-dose rivaroxaban has been shown to have a benefit in patients with CAD and PAD and can be a new therapeutic option for cardiologists, vascular medicine specialists and vascular surgeons, experts said.
“It adds one more tool for secondary prevention that we can think of, particularly for patients who have recurring issues or who have a higher risk,” Ohman said.
Patients with PAD may have the quickest impact with low-dose rivaroxaban because it is a more intensive therapy, experts said, noting it may eventually be approved for patients with ACS, although it would be on a selective basis.
“[PAD has] been for a long time a disease that has relatively few targeted therapies and targeted drugs,” Hornacek told Cardiology Today. “We’ve relied heavily on intervention and then cardiovascular risk factor modification, borrowing data from cardiology and cardiac studies. It is exciting to see something that potentially has more benefit for these PAD patients.”
However, experts said, it may be difficult to implement this treatment into common practice.
“We would look to use this, but the tricky thing in the stable population is that they’re stable,” Cannon said. “That is, you’re seeing them in the office, they’re generally doing fine in follow-up and they’re not hospitalized for something. That is a somewhat odd setting to clinically say, ‘I need to add this therapy because you’re going to do better, and it causes more bleeding.’ There’s a little bit of a difficulty in trying to introduce a therapy in that stable-type setting. The data are compelling, though, so we need to try.”
Other issues that clinicians may face once low-dose rivaroxaban is made available in the U.S. are cost and prior authorization from insurance companies, which is a major barrier for any new therapy in cardiology, experts said.
“Approval is one aspect; being used is another,” Ohman said. “That’s probably one of the weaker links right now. We have several therapies that have been found to be beneficial that are not used for cost reasons and health insurance reasons, among other things. There are a lot of other reasons, which is a shame because patients can do better with some of these therapies.”
Research continues
Although the COMPASS trial and its substudies have provided a wealth of information on the benefits of low-dose rivaroxaban in patients with CAD and PAD, more research is needed on patients with ACS.
The effects of low-dose rivaroxaban will also need to be investigated further in patients with PAD. The VOYAGER PAD study, which is currently being conducted, will focus on patients with PAD who underwent recent infrainguinal revascularization. Results from this study will be completed in 1 to 2 years, experts said. More information is needed on how to treat patients with PAD who had a major adverse CV event.
A comparison of antiplatelet therapy with a low-dose anticoagulant would be helpful, although a study of this kind may take 5 to 6 years to complete, Cannon said.
Understanding which patients are at the highest risk for bleeding with these therapies would be critical, Anand said in an interview.
Clinicians can benefit from the development of a risk score to determine which patients would have more benefit than risk with low-dose rivaroxaban, experts said.
“We need some better way to figure out who’s going to benefit most from the antithrombotic effects vs. who’s going to be harmed by bleeding because there’s really a balance,” Michos told Cardiology Today. “You have a reduction of thrombosis and ischemia on one side and you have increased risk of bleeding on the other.”
Some novel calculators have tried to adapt this concept, including the DAPT score and the Precise DAPT score, which does not involve angiographic data and is based on clinical factors. A risk calculator may be able to be developed from the COMPASS trial data, experts said.
Other patient populations that need more research include women and Asian individuals. Both groups had low representation in the COMPASS trial. Although there were no significant sex differences in the trial, it is difficult to determine whether that is because of the low number of women in the cohort. Asian adults typically have a greater risk for hemorrhagic stroke, although this could not be thoroughly assessed in COMPASS due to its low enrollment of Asian patients.
In addition to other patients, other anticoagulants must also be studied further.
“It would be nice to see if this concept applies to other factor Xa or IIa inhibitors,” Cannon said. “Would it be possible to do so in a similar type population with low-dose apixaban or lower-dose dabigatran (Pradaxa, Boehringer Ingelheim)?”
Cost analyses are also required to factor in the cost of 2.5 mg rivaroxaban twice per day in the reduction of the direct costs of procedures and hospitalizations for major CV events. The issue is that the drug currently does not have a price associated with it because it is not available in the U.S., experts said.
The combination of the research needed in this area can help progress the treatment of these patient populations.
“It’s important that we actually study these patients and these multi-distribution vascular disease patients because we need to learn more how to best apply this therapy,” Ohman said in an interview. “That would be the most helpful thing that we can do because ... it’s a little bit more complicated than patients that have just one coronary lesion that’s stented and otherwise doing fine.”
Importance of dose, patient selection
One important factor of low-dose rivaroxaban is dosing, especially since incorrect dosing can lead to unsuccessful prevention of a blood clot and an increased risk for stroke, experts said.
“Under-dosing patients who should be getting full-dose anticoagulation is a fear that I have because it’s happening now even before this trial and strategy is approved for use with other agents,” Cannon said in an interview. “Dose is a key factor in getting the right antithrombotic mix for patients. The confusion between needing anticoagulation for AF or a venous indication vs. this arterial indication may lead to confusion in inappropriate dosing.”
If the FDA approves low-dose rivaroxaban in these patients, a caveat on patient selection would be warranted to avoid major bleeding events, experts said.
“If it was approved, I don’t think that I would necessarily apply rivaroxaban broadly across all secondary prevention patients, but I would think carefully,” Michos told Cardiology Today. “I would definitely be interested in patients with a history of PAD because they’re very high risk as long as they’re not at increased risk of bleeding, the higher-risk patients with coronary disease and certain other subgroups as long as their bleeding risk is very low. A lot of thought has to go into patient selection. I don’t think it’s a slam dunk. We need to think carefully about which patients we use this on.”
Even with new prevention options, clinicians still need to focus on the basic treatment options that are effective.
“We get excited when these new therapies are coming out and do genuinely show good promise, but we need to not forget the other things that we already know work for these patients, emphasizing at least being on aspirin, at least having that glycemic control and at least having the lipids and the statins being under control and appropriately treated as well,” Hornacek said. – by Darlene Dobkowski
- References:
- Alexander JH, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1105819.
- Anand SS, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.03.008.
- Bonaca M, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.03.524.
- Eikelboom JW, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1709118.
- Fuster V, et al. Lancet. 1997;doi:10.1016/S0140-6736(97)01180-X.
- Mega JL, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa1112277.
- Ohman EM, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)30751-1.
- Sharma M, et al. LB7. Presented at: International Stroke Conference; Jan. 23-26, 2018; Los Angeles.
- For more information:
- Sonia Anand, MD, PhD, FRCP, can be reached at 1280 Main St. West, Hamilton, Ontario L8S 4K1; email: anands@mcmaster.ca.
- Christopher P. Cannon, MD, can be reached at Brigham and Women’s Hospital, Cardiovascular, 75 Francis St., Boston, MA 02115; email: cpcannon@bwh.harvard.edu.
- Deborah Hornacek, MD, can be reached at Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195; email: hornacd@ccf.org.
- Erin D. Michos, MD, MHS, can be reached at 600 N. Wolfe St., Baltimore, MD 21287; email: edonnell@jhmi.edu.
- E. Magnus Ohman, MD, can be reached at 2301 Erwin Road, 8678A HAFS Building, Durham, NC 27710; email: ohman001@mc.duke.edu.
Disclosures: Anand reports she received speaker fees and consultant fees from Bayer Pharmaceuticals. Cannon reports he received research grants from Amgen, Arisaph, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck and Takeda and consultant fees from Alnylam, Amgen, Amarin, Arisaph, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi and Takeda. Hornacek, Michos and Ohman report no relevant financial disclosures.