November 28th, 2011
Roundtable: Two Trials, Two Anticoagulants, Many Implications
After findings from the industry-funded ATLAS ACS 2–TIMI 51 and ADOPT trials were presented at AHA and published in the New England Journal of Medicine, CardioExchange asked three experts to weigh in.
The ATLAS ACS 2–TIMI 51 investigators randomized 15,526 patients within 7 days after hospital admission for an ACS to standard therapy plus either placebo or rivaroxaban in one of two doses (2.5 or 5 mg) twice daily. At a mean follow-up of 13 months, the rate of the composite primary endpoint (death, MI, and stroke) was significantly lower among rivaroxaban recipients (both dose groups combined) than among placebo recipients (8.9% vs. 10.7%). Compared with placebo, rivaroxaban at either dose was associated with significant increases in major bleeding (2.1% vs. 0.6%) and intracranial hemorrhage (0.6% vs. 0.2%). Rivaroxaban has been approved by the FDA, but (like other anticoagulants) not for ACS.
In ADOPT, 4495 hospitalized medical patients at risk for thromboembolism were randomized to receive apixaban for 30 days or enoxaparin for 6 to 14 days. After 30 days, the groups’ rates of thromboembolic events were similar, but major bleeds occurred twice as often with apixaban (0.47%) as with enoxaparin (0.19%). Apixaban is awaiting FDA approval.
Question to the Experts
Given the evidence to date, how quickly should rivaroxaban and, if it’s approved, apixaban be used in clinical practice — and for what patient populations?
The Experts Respond
Samuel Goldhaber, MD (principal investigator of ADOPT, focusing here on ATLAS)
The landmark ATLAS ACS 2 trial changes forever the way we’ll think about the pathophysiology of ACS and the way we’ll manage patients with STEMI, NSTEMI, or unstable angina. Now we can discard the notion that ACS depends solely upon quelling the platelet and preventing “white clot.” After all, rivaroxaban is the same anticoagulant used to prevent extension of “red thrombus” hiding in the left-atrial appendage or common femoral vein. (Conversely, pulmonary embolism pathophysiology abounds with activated platelets, but we’ll save that discussion for another day.) By my count, many ACS patients will be prescribed six core medications to prevent recurrent events: 1) aspirin; 2) clopidogrel/prasugrel/ticagrelor; 3) a statin; 4) a beta-blocker; 5) an ACE inhibitor or ARB; and 6) rivaroxaban 2.5 mg twice daily.
The TIMI investigators were courageous to test the tiny dose of rivaroxaban 2.5 mg twice daily. It’s only one quarter the dose used to prevent stroke in atrial fibrillation. And it’s only half the dose used to prevent DVT and pulmonary embolism in patients undergoing total-hip or -knee replacement. As cardiovascular clinicians, we’re used to prescribing ultra-low doses of some medications, such as baby aspirin at 81 mg once daily. And some have advised (with a bit of a smile) that the aspirin dose can be lowered even further so that we can instruct our patients to simply “lick an aspirin tablet once a day.” We might place rivaroxaban in the same ultra-low-dose category.
The concept of ultra-low-dose warfarin to manage coronary artery disease has been floating around for generations. Several decades ago, one of my patients who had undergone CABG was having recurrent angina but wasn’t a candidate for reoperation CABG or for PCI. I asked his cardiac surgeon for advice. This wise surgeon (now deceased) gave me a recommendation without any explanation or evidence: “Try warfarin 1 mg a day.” Sure enough, the angina abated and my patient lived another 12 years. Is rivaroxaban the modern-day version of licking a warfarin tablet?
I have some questions for the TIMI investigators who designed and executed ATLAS ACS 2, as well as for clinicians who blog on CardioExchange:
1) What insights can we gain about understanding the differences between ACS and atrial fibrillation, given the 4-fold difference in rivaroxaban dose to manage these two diseases?
2) If rivaroxaban 2.5 mg twice daily is superior to rivaroxaban 5 mg twice daily for preventing cardiovascular and all-cause mortality, might rivaroxaban 2.5 mg once daily yield even more striking results than rivaroxaban 2.5 mg twice daily?
3) Does having one novel anticoagulant suffice for secondary prevention of ACS? Should dabigatran and apixaban be tested again with lower doses than previously used?
4) Should rivaroxaban be tested for lowering the rate of stent thrombosis outside the setting of ACS?
5) Will hospital formularies be tempted to stock only a single novel anticoagulant, one that can be used for SPAF, prevention and treatment of VTE, and ACS?
What an exciting time to be a practitioner of cardiovascular medicine! We’re gaining new insights and discovering new life-saving therapies at an impressively rapid pace.
Elaine Marie Hylek, MD, MPH (focusing on ATLAS)
ATLAS ACS 2 excluded patients with prior stroke or clinically significant gastrointestinal bleeding in the previous 12 months. The mean age was 62 years, 9% of participants were age 75 or older, and 75% of participants had a creatinine clearance of ≥68 mL/minute. Given these baseline characteristics, it would be difficult to extrapolate these trial results to older patients or to patients with renal impairment. Younger patients who have high risk for recurrent ischemic events and low baseline bleeding risk are likely to be those with the most favorable benefit-to-risk ratio.
The findings from ATLAS ACS 2 were perhaps the biggest surprise at AHA. The most interesting result was that the lower dose of rivaroxaban, 2.5 mg twice daily, demonstrated substantial reductions in CV and all-cause mortality that were not seen with the higher dose. One of the biggest questions fluttering around the convention hall was why this trial was positive when similar trials with novel anticoagulants, APPRIASE-2 (apixaban) and RUBY-1 (darexaban), had failed. The answer is dose.
After a robust phase 2 dose-ranging study, the investigators chose doses of rivaroxaban that were half (5 mg twice daily) and one quarter (2.5 mg twice daily) of the full anticoagulant dose used in AF (20 mg once daily). It may be that with respect to anticoagulant therapy in ACS, less is more. More-intensive antithrombotic therapy may attenuate the ischemic benefits by directly increasing severe and fatal bleeding or bleeding that results in discontinuation of important concomitant medical therapy. This may also help to explain the apparent paradoxical reduction in mortality with the “very low” dose of rivaroxaban, compared with the “low” dose. Some important questions remain:
1) What was the mechanism of the mortality reduction, as the substantial benefit was not accounted for by reductions in MI or stroke?
2) How do we reconcile these data with the impressive results in ACS with the potent antiplatelet drugs ticagrelor and prasugrel?
What’s clear is that ATLAS changes the landscape in ACS: Chronic treatment with an anticoagulant, at least at a very lose dose, offers the potential of substantial benefit. Nevertheless, the ideal combination of antiplatelet and anticoagulant regimens is yet to be determined, as is clinicians’ comfort with the higher rates of major bleeding, particularly intracranial hemorrhage.
ADOPT addressed the last frontier in VTE prophylaxis: hospitalized medically ill patients. Although a negative study, it offers two key lessons:
1. VTE prophylaxis trials should no longer include the soft endpoint of asymptomatic incidental DVTs picked up by ultrasounds, as they are not performed as part of routine care and distort the natural history of DVT. ADOPT showed a trend toward a significant reduction in the hard endpoint of symptomatic VTE and VTE-related deaths in the apixaban group, but this secondary endpoint was underpowered.
2. More important: ADOPT, along with complementary data from MAGELLAN with rivaroxaban in a similar population, illustrates that our entire paradigm of VTE prophylaxis in medically ill patients may need to be rethought. The event curves reveal that the rates of VTE continued to increase after the cessation of enoxaparin after 6 to 14 days, compared to extended treatment with apixaban. The risk for VTE appears to continue unabated in medically ill patients well after discharge, and patients may accrue risk after 30 days.
While factor Xa inhibitors’ role is clear for DVT prophylaxis in orthopedic patients and for stroke prevention in AF, further trials of extended prophylaxis are needed to further define the optimal regimen and treatment duration for VTE prophylaxis in medically ill patients. At least we’re beginning to ask the right questions.
How do you think factor Xa inhibitors will change clinical practice? Offer your perspective on ATLAS and ADOPT — and on our experts’ opinions.