Off Orbit? ROCKET AF: Rivaroxaban Noninferior, But Not Superior, to Warfarin in ITT Analysis

November 15, 2010

Updated November 15, 2010 (Chicago, Illinois) — The ROCKET AF trial, launched when warfarin was the lone available oral anticoagulant, landed on earth this week during a high-profile presentation at the American Heart Association (AHA) 2010 Scientific Sessions. As reported earlier by heartwire , the pivotal trial for the new oral factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson) met its primary end point, with investigators showing the drug was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non–central nervous system (CNS) embolism.

The question of superiority over warfarin, however, is less clear, with two analyses showing disparate findings, at least in terms of statistical significance. In the intention-to-treat superiority analysis, investigators failed to show the drug had an advantage, statistically, over warfarin for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation. In the intention-to-treat analysis, 269 patients treated with rivaroxaban had a stroke or embolization, compared with 306 patients treated with warfarin (p=0.117).

In an on-treatment analysis addressing the superiority question, however, rivaroxaban fared better, with investigators showing that rivaroxaban significantly reduced the risk of stroke or non-CNS embolization by 21% compared with warfarin.

Dr Robert Califf

On the whole, investigators view the study in a positive light, regardless of how the superiority analysis is performed, intention-to-treat vs on-treatment, with most in agreement about the success of rivaroxaban given that it was noninferior to warfarin without an increase in major bleeding. Speaking during the morning press conference, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), a co–principal investigator of the ROCKET-AF trial, said the group wanted to first show rivaroxaban was equivalent to warfarin, a drug that was like a "battered old boxer that you'd think had had its day" but that kept on faring well against newer and newer drugs.

The results of ROCKET-AF, however, show that rivaroxaban is a "proven alternative" to warfarin in moderate- or high-risk patients with atrial fibrillation, say investigators.

Speaking with heartwire , Dr Douglas Zipes (Krannert Institute of Cardiology, Indianapolis, IN), who was not affiliated with the trial, said he was impressed with the data.

"If you take away only the conclusion of noninferiority, that's a step up," said Zipes. "Warfarin is a very difficult drug to use. Patients don't like the repeated [international normalized ratio] INR checks, and it's very difficult to maintain control. I have several patients with INRs all over the map, so to have another substitute for that is welcome. However, the on-treatment analysis shows superiority over warfarin, and while that's not the gold standard--call it the silver standard--I'm very impressed with the results. I've already started to switch some patients over to dabigatran [Pradaxa, Boehringer-Ingelheim], and if rivaroxaban gets approved, it would give us another choice."

Flight Launch: The ROCKET-AF Trial

ROCKET-AF is a double-blind, double-dummy phase 3 study in more than 14 000 patients with atrial fibrillation. Patients were randomized to 20-mg rivaroxaban once daily (or 15 mg in patients with moderate renal impairment at screening) or to dose-adjusted warfarin (titrated to an INR of 2.5). Patients in the trial were considered high risk, with 55% having had a prior stroke and 90% having hypertension. In addition, 90% of the patients had a CHADS2 score of 3 or higher, much higher than scores of patients enrolled in four comparable studies: Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY), ACTIVE W, AMADEUS, and SPORTIF V.

Overall, rivaroxaban was noninferior to warfarin in terms of the primary end point, a composite of stroke and non–CNS embolism, and as noted, was superior to warfarin when investigators analyzed the risk of stroke and non-CNS embolism in patients who remained on treatment over the course of the 40-month trial. It was not superior to warfarin in the stricter intention-to-treat analysis.

ROCKET-AF: Primary Efficacy Outcome

Stroke and non-CNS embolism Rivaroxaban (n=7081) Warfarin (n=7090) Hazard ratio (95% CI) p
Primary end point, noninferiority 1.71 2.16 0.79 (0.66–0.96) <0.001
Primary end point, on-treatment superiority 1.70 2.15 0.79 (0.65–0.95) 0.015
Primary end point, intention-to-treat superiority 2.12 2.42x 0.88 (0.74–1.03) 0.117
Vascular death, stroke, embolism 3.11 3.63 0.86 90.74–0.99) 0.034
Hemorrhagic stroke 0.26 0.44 0.59 (0.37–0.93) 0.024
Ischemic stroke 1.34 1.42 0.94 (0.75–1.17) 0.581
Unknown stroke 0.06 0.10 0.65 (0.25–1.67) 0.366

In terms of bleeding, the rates of the composite major and nonmajor clinically relevant bleeding were comparable in the rivaroxaban- and warfarin-treatment arms, with less fatal bleeding and intracranial hemorrhage observed among those treated with the new anticoagulant. Major bleeding occurred in 395 patients, at a rate of 3.60 per 100 patient-years, in the warfarin-treated patients, and in 386 patients, or at a rate of 3.45 per 100 patient-years, in rivaroxaban-treated patients (p=0.576).

ROCKET-AF: Bleeding Outcomes

Stroke and non-CNS embolism Rivaroxaban (n=7081) Warfarin (n=7090) Hazard ratio (95% CI) p
Major and nonmajor bleeding 14.91 14.52 1.03 (0.96–1.11) 0.442
Major bleeding 3.60 3.45 1.04 (0.90–1.20) 0.576
>2 g/dL hemoglobin drop 2.77 2.26 1.22 (1.03–1.44) 0.019
Transfusion 1.65 1.32 1.25 (1.01–1.55) 0.044
Critical organ bleeding 0.82 1.18 0.69 (0.53–0.91) 0.007
Bleeding causing death 0.24 0.48 0.50 (0.31–0.79) 0.003
Intracranial hemorrhage 0.49 0.74 0.67 (0.47–0.94) 0.019

Dr Elaine Hylek

Speaking during a morning press conference, Dr Elaine Hylek (Boston University, MA), who was not affiliated with the ROCKET-AF trial, said the results must be placed in the right context, with physicians, as well as media, interpreting the data in light of the "incredibly complex" patients included in the study. These patients, average age 73 years old, would have been expected to be at a higher risk of stroke, intracranial hemorrhage, major hemorrhage, and increased INR variability, said Hylek.

That said, however, she raised the issue of interpreting the data in light of the lack of superiority in the intention-to-treat analysis, noting that once noninferiority is evident in a clinical trial, superiority, which was prespecified in ROCKET-AF, is best assessed with an intention-to-treat analysis. She said the difference between the on-treatment and intention-to-treat analyses is likely due to poor adherence with rivaroxaban, thus raising concerns about the relevance of the per-protocol analysis to real-world clinical practice.

"The issue here with the per-protocol analysis is that when you create a threshold for adherence with a drug that has a short half-life, that is prescribed just once a day, you're probably increasing the performance of it compared with a drug that's going to have a lasting effect over three to five days, like warfarin, so that there might be a bit of an imbalance there," she told the media. "I'm not negating the importance of the per-protocol analysis. It's important to get at the biological effect of the drug. It just doesn't necessarily give you a lot of assurance in a real-world setting, where people take their drugs 50% of the time."

Hylek added that a conclusion stating noninferiority compared with warfarin is the safest, most conservative interpretation of the trial, and Califf agreed. "I think it's totally fair to say that the trial did not demonstrate superiority by the high standard, according to the usual rules of clinical trials," he said. He added that based on the "texture of the data," however, clinicians will be able to assess the risks and benefits of rivaroxaban compared with warfarin and make a decision, likely in favor of the novel factor Xa inhibitor.

Dr Gordon Tomaselli (Johns Hopkins University School of Medicine, Baltimore, MD), who was not affiliated with ROCKET-AF, told heartwire that the questions surrounding superiority aren't too concerning to him as a clinician. The most important end point in the trial, he said, was noninferiority, as it shows doctors that there is a safe and effective alternative to warfarin, and "at the end of the day, for many patients, rivaroxaban becomes a superior drug" simply because they can't tolerate warfarin or are unable to be therapeutically managed with the notoriously difficult older drug.

In the ROCKET-AF trial, warfarin-treated patients spent 57.8% of time in the therapeutic range, slightly lower than in other clinical trials with warfarin, a likely reflection of the high-risk patients included in the trial. "This was an impressive trial because the patients were so sick," said Tomaselli.

Comparing ROCKET-AF With RE-LY

The results of ROCKET-AF contrast with data from the RE-LY trial, a study also reported by heartwire . In that trial, dabigatran prescribed at 150 mg twice a day reduced the risk of stroke/peripheral embolic events by 34% (p<0.001) and the risk of hemorrhagic stroke by 74% (p<0.001) compared with warfarin and was equal in terms of bleeding. On October 20, 2010, the Food and Drug Administration approved dabigatran 150 mg twice daily and, for a small subset with severe renal impairment, 75 mg twice daily, for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Dr Kenneth Mahaffey

Speaking during the late-breaking clinical-trials session, Zipes asked Dr Kenneth Mahaffey (Duke Clinical Research Institute), who presented the data to the AHA audience, about the inevitable comparison between dabigatran and rivaroxaban. After stating the difficulties in comparing two trials, with different designs and patients, Mahaffey said the only way to compare the two drugs would be in a head-to-head comparative study. Zipes asked Mahaffey, jokingly, if he were running for election, saying, "I said it was an unfair question and you avoided it entirely."

Califf tackled the dabigatran/rivaroxaban comparison a little more directly. He said there is no scientifically valid way to compare the two drugs, and that any physician who claims to make a science-based decision of one drug over the other is not telling the truth. He said that if rivaroxaban is approved, a study comparing the relative safety and effectiveness of the two drugs would be welcome and might be possible given the US government's push for more comparative-effectiveness trials. Califf said his 84-year-old mother dislikes taking warfarin and he has already had discussions with her about switching her off it, likely to dabigatran. Califf pointed out that his mother can afford the new direct thrombin inhbitor, highlighting the cost issue that is going to factor into the decision-making process with any new anticoagulant.

Bayer and Johnson & Johnson Pharmaceutical provided financial support for the ROCKET-AF study. Califf reports research grants from Amylin, Johnson & Johnson, Eli Lilly, Merck, Novartis, and Schering Plough and consulting fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline,, Kowa , Medtornic, Merck, Novartis, Sanofi-Aventis, and XOMA. Hylek reports research support from the National Institutes of Health, Bristol-Myers Squibb, and Ortho-McNeil and serving on the advisory boards of Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Medtronic, Merck, Pfizer, and Sanofi-Aventis. Mahaffey reports research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, Portola, Regado, Sanofi-Aventis, and the Medicines Company and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, Novartis, and Sanofi-Aventis.