Real-World Evidence Mounts for Rivaroxaban

A steady stream of follow-up research suggests that the novel oral anticoagulant (NOAC) rivaroxaban will fulfill the promise it showed in trials and provide a superior combination of stroke prevention, safety, and convenience for patients with nonvalvular atrial fibrillation (AF) and a wide variety of comorbidities, such as type 2 diabetes mellitus (T2DM).

Subgroup analysis indicates that rivaroxaban compares as well to war-farin (in terms of both safety and ef-ficacy) in small patient segments as it compares to the older drug in AF patients as a whole.¹

Studies of clinical usage, moreover, have demonstrated an advantage that trials did not: the relative ease of riva-roxaban use, compared with warfarin, reduces the percentage of patients who give up on anticoagulation therapy and use less effective stroke prevention strategies.²

These same studies have raised some issues that should be noted by physicians who treat both AF and T2DM. Overall, however, they contain good news for the many patients who have both conditions. (Estimates of co-morbidity vary, but research suggests that T2DM may double a patient’s odds of developing AF,³ and that about 17% of patients with AF have diabetes.⁴

“Substudies have shown that the beneficial effects of rivaroxaban are consistent with the results of the over-all study, irrespective of the history of previous stroke or transient ischemic attack, heart failure, myocardial infarc-tion, diabetes or moderate renal dysfunction,” wrote the authors of a recent article in Expert Review of Cardiovascular Therapy. “Moreover, recent data have confirmed the efficacy and safety of ri-varoxaban in real-life practice.”⁵

Such findings have helped NOACs like rivaroxaban take market share from warfarin, a vitamin K antagonist that has long been a mainstay of AF treat-ment because it is a very potent anti-thrombotic agent.

The efficacy of warfarin does vary, not only among different types of AF patients with different comorbidities, but also among different individual pa-tients who appear medically relevant. That said, a meta-analysis of studies with more than 28,000 patients calculated that the drug reduced stroke risk by an average of 64%.⁶

Unfortunately, warfarin is a famously difficult medicine to use. Its narrow therapeutic window offers patients little protection against stroke at inter-national normalized ratios (INRs) below 2.0, and produces unacceptable bleed-ing risks at INRs above 3.0. Worse, the dose needed to keep patients inside this narrow therapeutic window varies from patient to patient, and the dose needed to keep any given patient within this range varies from time to time. The only way to keep patients in the therapeutic zone is to perform repeated blood tests throughout the patient’s life and make adjustments as needed.

Patients must submit not only to this testing regime but also to the dietary and medical restrictions needed to prevent interactions between warfarin and vari-ous other drugs and foods. Indeed, there is some evidence that warfarin interacts with α-glucosidase inhibitors that are sometimes used to treat diabetes.⁷

These drawbacks, along with the fear of intracranial hemorrhages and other major bleeds, have always led many patients to refuse warfarin treatment and many others to abandon the drug after using it for a short period. Estimates vary, but some suggest that half of all patients who would benefit from warfarin never try it⁸ and that half of those who try it discontinue treatment within 5 years.⁹

Such decisions often prove fatal. Even in the absence of significant comor-bidities, AF is associated with a 5-fold increase in the risk of ischemic stroke. Certain common comorbidities increase the risk further still: prior stroke/tran-sient ischemic attack (relative risk [RR],

2.5; 95% CI, 1.8-3.5), hypertension (RR, 2.0; 95% CI, 1.6-2.5), diabetes mellitus (RR, 1.7; 95% CI, 1.4-2.0), and increasing age (RR, 1.5 per decade; 95% CI, 1.3-1.7).

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These numbers illustrate the lifesaving potential of any drug that could match (or exceed) the efficacy and safe-ty of warfarin without all the difficul-ties that discourage patient adherence. The phase 3 trial that led the FDA to ap-prove rivaroxaban in late 2011 indicated that the newcomer had the potential to be just such a drug.

Researchers who randomized 14,264 AF patients between the 2 drugs and followed them for an average of 707 days found that the rates of stroke or systemic embolism in the intention to treat analysis were 2.1% per year for ri-varoxaban and 2.4% per year for warfa-rin (hazard ratio [HR], 0.88; 95% CI, 0.74-1.03; P <.001 for non-inferiority, P = .12 for superiority).¹¹

Rivaroxaban also boasted several other obvious advantages over the older medication. It came in just 2 doses 15 mg for people with impaired kidney function and 20 mg for everyone else and thus required no monitoring or dose adjustments. It placed no restric-tions on what patients could eat or what other medications they could use. It was even associated with a far lower risk of intracranial hemorrhage (HR, 0.67; 95% CI, 0.47-0.93; P = .02).¹¹

Yet despite all those advantages, the trial indicated that patients were just as likely to stop taking rivaroxaban as they were to stop taking warfarin. Discontinuation rates were 23.7% for rivaroxaban and 22.2% for warfarin.¹¹

Now, a large study of real-world rivaroxaban use concludes that the discontinuation rates reported by the phase 3 trial says more about trial design than actual patient behavior.

That study which took data from an ongoing, prospective, noninterventional registry that is following more than 1204 rivaroxaban users in Germany found that about 15% of patients discontinued rivaroxaban at some point in the first year of treatment and only about 3% of pa-tients discontinued it at any subsequent point.² This compares very favorably to tients (as opposed to those in clinical trials), which have found first-year discontinuation rates as high as 30% and 3-year discontinuation rates of 50%.^9,11

Another recent study a retrospective matched-cohort study of American patients found that treatment persistence at 6 months was 81.5% for rivaroxaban and just 68.3% for warfarin.

“Even more importantly, the persistence rates for rivaroxaban reported by Laliberte ́ et al, and confirmed in our study, are substantially higher than those re-ported for [vitamin K antagonists] in daily care settings,” wrote the authors of the German study in Europace.

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Dramatically higher persistent rates could translate into substantially fewer strokes overall, and the persistence figures were not significantly different for most of the subgroups the German researchers broke out from the total cohort. Patients with renal impairments, prior strokes, arterial hypertension, and prior discontinuation of warfarin were about as likely as the general population to stick with rivaroxaban.

The only subgroup that was significantly less likely than average to discontinue treatment consisted of patients with unusually low body mass index (HR, 0.74; 95% CI, 0.55-0.99; P = .04).

The only 2 subgroups that were sig-nificantly more likely than average to discontinue treatment consisted of pa-tients with diabetes (HR, 1.35; 95% CI, 1.03-1.77; P = .03) and patients with transient ischemic attack, stroke, or system-ic embolism (HR, 1.41; 95% CI, 1.08-1.85; P = .01). The most common reasons for rivaroxaban discontinuation among the cohort as a whole were bleeding (30%), other side effects (24.2%), and resump-tion of sinus rhythm (9.9%).

The paper’s lead author, Jan Beyer-Westendorf, MD, declined to specify why patients with diabetes were more likely than others to stop taking rivaroxaban, but future papers from his study group should help physicians decide whether to try such patients on rivaroxaban or some alternative. “We are planning to look at several subgroups including diabetic pa-tients,” he wrote in an e-mail. “However, we are still in the follow-up phase [of the Dresden NOAC study] and perform only a few interim analyses. Therefore, we do not have answers at present.”

The years since rivaroxaban’s initial approval have also brought a steady stream of information about its safety and effica-cy in AF patients with various comorbidities. Most of that information has been mined from the drug’s phase 3 trial data, and most of it has been encouraging.

To start with the 2 populations that were unusually likely to discontinue rivaroxaban in the German study those with diabetes and those with a history of stroke analyses suggested that both groups might fare marginally better with rivaroxaban than warfarin. The risk of stroke or systemic embolism was very nearly (but not quite) significantly lower among diabetic AF patients who took ri-varoxaban rather than warfarin (HR, 0.74; 95% CI, 0.54-1.01; P = .055) and overall bleeding risks were nearly identical.¹³

In patients with prior strokes, rivaroxaban performed slightly better than warfarin but, again, it was close enough that it may have been by chance (HR, 0.94; 95% CI, 0.77-1.16). The same was true when researchers calculated the risk of intracranial hemorrhage (HR, 0.74; 95% CI, 0.47-1.15) and fatal bleed-ing (HR, 0.54; 95% CI, 0.29-1.00).

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Results were very similar among AF patients who had suffered heart fail-ure,16 ischemic cardiovascular events,

and peripheral artery disease,

as well as patients over and under 75 years of age.

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Analysis of the effects of rivaroxaban in patients who were experienced with and naïve to vitamin K antagonists again showed comparable benefits, but it did suggest something that the authors of the clinical review thought cli-nicians should note: the possibility that patients are particularly susceptible to major bleeds when they are making the transition from one drug to the other^.1

Subgroup analysis of AF patients with mild renal failure (creatinine clearance between 30 and 49 mL/min) again found that such patients (who received 15 mg of rivaroxaban rather than 20 mg) suffered fewer strokes, embolisms, and bleeds than those who received warfarin but not consistently enough to demonstrate superiority.²⁰ This last finding should be of particular interest to physicians who treat patients with both AF and T2DM, for the latter disease ranks among the biggest causes of renal impairment.

AF patients with advanced kidney disease or on dialysis were not eligible for the trial, but subsequent retrospective analysis of real-world patient outcomes suggests that physicians should, at the very least, think twice before prescribing the medication for them.

Such prescriptions of rivaroxaban and dabigatran, for patients with advanced renal disease, currently do not have an FDA indication, partially because the drug is metabolized by the kidneys; how-ever, a recent study in Circulation²¹ found that doctors currently prescribe either rivaroxaban or dabigatran to 5.9% of all AF patients on hemodialysis who require anticoagulation. When the authors of the study compared outcomes of hemodial-ysis patients on rivaroxaban with those on warfarin, they found that rivaroxaban was associated with an increased risk of hospitalization or death from bleeding compared with warfarin (RR, 1.38; 95% CI, 1.03-1.83; P = .04).

“The challenge with all anticoagulants is to balance the reduction in stroke risk with the increase in bleeding risk. The equation is different in patients with renal failure, however, because they start off with a significantly elevated risk of significant bleeding,” said coauthor Franklin Maddux, MD, FACP, chief medical officer at Fresenius Medical Care North America, in an interview.

“In general, warfarin has a longer his-tory of use and we know much about its risks and characteristics of use, but it’s up to individual physicians to know their individual patients and the options for use of traditional or novel agents. In certain patients with rare clinical conditions that make them intolerant to warfarin, rivaroxaban might be a reasonable choice.”

Although the total number of AF patients who need hemodialysis is small (perhaps 50,000 patients in all), physi-cians should probably exercise sub-stantial caution when prescribing riva-roxaban or dabigatran to patients with advanced kidney disease. “Because the medication is cleared by the kidneys, a progressive loss of function over time could lead to increasing concentrations of the medication in the blood and in-creasing risk of serious bleeds,” said co-author Kevin E. Chan, MD, a nephrologist at Massachusetts General Hospital, in an interview. “When physicians prescribe ri-varoxaban to patients who are at risk of progressive failure, they should routinely monitor kidney function, and when they see signs of deterioration, they should check concentrations of medication in the blood. Subsequent research may show this to be unnecessary, but we don’t know yet.”

Follow-up studies have also investi-gated aspects of rivaroxaban that are not purely medical.

For example, a paper published in the American Journal of Cardiology²² used phase 3 trial data to determine the cost-effectiveness of the drug, which retails for about $380 a month, compared with warfarin, at roughly $15 a month.23 The study found that patients treated with rivaroxaban added an average of 10.03 quality-adjusted life years (QALYs) at a lifetime treatment cost of $94,456, while those receiving warfarin added an average of 9.81 QALYs and incurred costs of $88,544. The incremental cost-effectiveness ratio for rivaroxaban was $27,498 per QALY.

“Time horizon, Monte Carlo simula-tion demonstrated rivaroxaban was cost-effective in 80% and 91% of 10,000 iterations at willingness-to-pay thresh-olds of $50,000 and $100,000 per QALY, respectively,” the study authors wrote, referencing the business model used to predict risk. “In conclusion, this Markov model suggests that rivaroxaban thera-py may be a cost-effective alternative to adjusted-dose warfarin for stroke prevention in AF.”

Peter R. Kowey, MD, a researcher who also treats patients with AF, said in an interview that payers, who refused to cover rivaroxaban and other NOACs as first-line treatment when they hit the market, began rethinking their policy after the cost-effectiveness studies were published (and they reached pric-ing deals with drug makers).

The generally positive findings from most follow-up research into the en-tire class of medications has increased acceptance and answered many ques-tions that clinical trials never did.

There is, however, a major question that research is unlikely to answer at any point in the future: how the NOACs compare against each other in terms of efficacy and safety.

“Assuming the differences among them are not so large that they could be demonstrated conclusively via retroac

tive analysis of patient records and there’s no reason to think the difference is that large the only thing that would answer that question is a massive randomized trial that pitted them against each other,” said Kowey, who is the director of the Center for Clinical Cardiology at the Lankenau Institute for Medical Research.

“That, of course, would be very expensive and there is no incentive what-soever for any company to foot the bill, so we’ll probably never know for sure which anticoagulant to prescribe for which patient. Still, we can say, with a fair amount of confidence at this point, that this class of medication has sub-stantial advantages over warfarin, and that’s a step forward.”

1. Martinez-Rubio A, Dan GA, Kaski JC. Rivaroxa-ban and stroke prevention in patients with atrial fibrillation: new evidence. Expert Rev Cardiovasc Ther. 2014;12(8)933-947.

2. Beyer-Westendorf J, Forster K, Ebertz F, et al. Drug persistence with rivaroxaban therapy in atrial fibrillation patients—results from the Dresden non-interventional oral anticoagulation registry. Europace. 2015;17(4):530-538.

3. Sun Y, Hu D. The link between diabetes and atrial fibrillation: cause or correlation? J Cardio-vasc Dis Res. 2010;1(1):10-11.

4. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Fac-tors in Atrial Fibrillation (ATRIA) study. JAMA.2001;285(18):2370-2375.

5. Baron-Esquivias G, Fernandez-Aviles F, Atienza F, Pastor Puevo P, Toro R, Sanmartin Fernandez M. Efficacy and safety of rivaroxaban in real-life patients with atrial fibrillation. Expert Rev Cardio-vasc Ther. 2015;13(4):341-353.

6. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in pa-tients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.

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8. De Breucker S, Herzog G, Pepersack T. Could geriatric characteristics explain the underprescription of anticoagulation therapy for older patients admitted with atrial fibrillation? a retrospective observation study. Drugs Aging. 2010;27(10):807-813.

9. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689-2696.

10. Aguilar MI, Hart R, Pearce LA. Oral antico-agulants versus antiplatelet therapy for prevent-ing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database Syst Rev. 2007;18(3):CD006186.

11. Patel MR, Mahaffey KW, Garg J, et al. Rivar-oxaban versus warfarin in nonvalvular atrial fibril-lation. N Engl J Med. 2011;365:883-891. 12. Gallagher AM, Rietbrock S, Plumb J, van Staaa TP. Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibril-lation in general practice: do the appropriate patients receive stroke prophylaxis? J Thromb Haemost. 2008;6(9):1500-1506.

13. Halperin JL, Bloomgarden Z, Hellkamp A, et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and diabetes: a sub-group analysis of the ROCKET AF trial. Circulation. 2012;126:A15544.

14. Laliberte F, Cloutier M, Nelson WW, etal. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin.

2014;30(7):1317-1325. 15. Hankey GJ, Patel MR, Stevens SR et al. Riva-roxaban compared with warfarin in patietns with atrial fibrillation and previous stroke or transicent ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012;11(4):315-322.

16. van Diepen S, Hellkamp AS, Patel MR, et al. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrilla-tion: insights from ROCKET AF. Circ Heart Fail. 2013;6(4):740-747.

17. Mahaffey KW, Stevens SR, White HD, et al. Ischaemic cardiac outcomes in patients with atri-al fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J. 2014;35(4):233-241.

18. Schuyler-Jones W. Hellkamp AS, Halperin J, et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF [published online December 3, 2013]. Eur Heart J. doi:10.1093/eurheartj/ eht492.

19. Halperin JL, Hankey GJ, Wojdyla DM, et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014;130:138-146.

20. Fox KA, Piccini JP, Wojdyla D, et al. Preven-tion of stroke and systemic embolism with rivar-oxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394. 21. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015;131(11):972-979.

22. Lee S, Anglade MW, Pham D, Pisacane R, Kluger J, Coleman CI. Cost-effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012; 110(6):845-851.

23. GoodRx website. http://www.goodrx.com/. Accessed April 25, 2015.

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