May 29, 2013
When we have a standard therapy for a disease, in this case vitamin K antagonists (VKA) for deep venous thrombosis (DVT), and a new therapy comes out, what do we want to know about the new drug? Is it at least as effective as the old therapy? Because if it’s not, that ends the conversation. If it’s at least as effective, that opens the door to further discussion. We also want know if the new therapy is safe, or at least no more dangerous that what we’re already using. Then we want to know the cost, because new therapies aren’t cheap. Bringing a drug to market costs a lot of money and who gets to cover that cost? The people buying the medication: patients, insurance companies, the government.
Let's take a look at rivaroxaban for treatment of DVT and see if it's something we should add to our treatment quiver or a case of 'the enemy of good is better'.
Who was studied?
The main study looking at rivaroxaban treatment for DVT study was by the EINSTEIN group published in NEJM 2010. There was a follow-up study using the same drug for PE but for now, we’ll stick to DVT. About 3500 patients with acute symptomatic DVT were split into two groups. Group one got standard therapy with LMWH and an oral vitamin K antagonist. Group two got rivaroxaban 15 mg/kg bid for three weeks and then 20 mg per day for the duration of therapy- 3, 6 or 12 months. One thing I don’t like about this study is that it was funded Bayer (the company that makes the drug) but that’s the reality with almost all large drug trials. An upside of the trial is that there was a good representation of the different causes of DVT- unprovoked, surgery, trauma, immobilization, estrogen, cancer, previous VTE.
Efficacy and safety
The primary efficacy outcome was recurrent venous thromboembolism. Both groups were statistically the same: 2.1% for rivaroxaban and 3% for standard therapy. The primary safety outcome, major bleeding or what was dubbed ‘clinically relevant non-major bleeding’, was the same for both groups : 8.1%.
Major bleed rates were around 1% for both groups, and that held up in the follow-up study looking at rivaroxaban for PE. But what is a major bleed? It may mean something different to you than your colleagues. In these trials, a major bleed was defined as: clinically overt with at least a 2g/dL hemoglobin drop, bleeding that led to at least a 2 units blood transfusion, intracranial or retroperitoneal or critical site bleed, or bleeding that contributed to death.
A meta-analysis in BMJ 2012 looked at the available data on new anticoagulants (for multiple indications, not just DVT) and found similar results as the NEJM study, but came to the conclusion that rivaroxaban was associated with a reduced risk of bleeding. Click here for an in-depth analysis by Professor Simon Carley.
The BMJ meta-analysis showed that rivaroxaban had non-inferior efficacy and decreased bleeding rates compared to VKAs. I don't agree with the argument that this drug has superiority because of fewer bleeding compications. The rate of serious bleeding was 1% for both rivaroxaban and VKAs. If you put lipstick on a pig, it’s still a pig. Bleeding happens and the new stuff is just as bleedy or just as not bleedy, which ever way you want to slice it.
A footnote to all of this data is that in the two main NEJM rivaroxaban studies on VTE and PE, INR was therapeutic about 50-60% of the time. If INR was therapeutic 100% of the time, would rivaroxaban have looked so good? We’ll probably never know because that’s the problem with warfarin and one of the selling points of this new drug: VKA metabolism is erratic. A 2011 Swedish study found INR in therapeutic range 76% in 18,000 patients on VKAs. How would rivaroxaban have fared against this cohort?
Should warfarin be voted out of office?
If the new therapy is no better and no worse than the old therapy as far as recurrent VTE and bleeding, why would we vote the incumbent out of office? If this were politics, how would you campaign against each candidate? Warfarin has a long track record and we can bring out a lot of its dirty laundry.
Compared to the other drugs your patients are taking, warfarin is a great drug and a horrible drug. It’s great because it thins the blood and it’s horrible because it makes patients bleed, has variable and erratic metabolism, needs frequent monitoring and patients have dietary restrictions. In the 2010 EINSTEIN NEJM study, INR was therapeutic (2.0-3.0) just over half the time and low about a quarter of the time (and this was in a clinical trial where you would expect tight control). Let’s face it, warfarin is a fussy drug and your patient will need to give themselves LMWH shots until goal INR is reached. Self administration of LMWH can be a barrier to treatment. It’s expensive and, if treatment becomes prolonged, REALLY expensive.
The new stuff, rivaroxaban, is no worse than the old stuff as far as efficacy and bleeding. So how is it better? It’s orally dosed so no shots are needed. It has more reliable metabolism, less drug interaction, no dietary restrictions, no monitoring. But like any new drug, you know it’s not going to be cheap and then there’s the problem of reversibility - the Achilles heel of the new anticoagulants. Let’s take a look at these two issues. First, cost.
My local pharmacy prices for LMWH, warfarin and rivaroxaban...
LMWH + warfarin for 3 months
LMWH: 70 dollars a dose. Five days at two doses a day: $700.
Warfarin for 95 days: about 10 dollars
INR testing: $44 dollars per test. There are a few INR checks in the first week and the total number of tests is going to vary but let’s say 8 total tests that’s one every other week once therapeutic and some extra in the beginning before therapeutic. Say $350 for all the INR testing in a three-month period.
Total cash payout $1060
That’s only the money, not the other pains challenges that come with the warfarin package: diet, requirement of frequent testing, variable metabolism. It’s no secret that warfarin is metabolized differently by different people (and even in the same person depending on the circumstances)
Rivaroxaban for 3 months
First 3 weeks, or 21 days at 15 mg bid is $450
69 days of 20 mg per day, at 11 bucks a pill: $759.
Total cash payout $1209
The the elephant in the room, and not such a quiet elephant, is bleeding. No matter how great the drug, if it causes a life threatening complication we can’t reverse, like severe bleeding, is it really worth it? In many cases no. That’s still the problem with dabigatran and why most ED docs, especially those who have cared for patients with dabigatran bleeds, are not fans.
What do we know about rivaroxaban reversal?
There are a few studies that give some idea on reversal, but there’s not a mountain of evidence where we can say, “Yup, we’ve got this covered.”
Rivaroxaban pharmacology basics
Half life 5-9 hours.
Can it be dialyzed? No, it’s 95% protein bound.
Is there a product that can reverse rivaroxaban’s anticoagulant effect? What about PCC? Yes. Kind of. Probably. Maybe.
The study that’s most quoted about reversing rivaroxaban was published in Circulation 2011. Twelve healthy males were given rivaroxaban for three days. Rivaroxaban prolonged the PT and another test called endogenous thrombin potential. OK, blood is thinner. So we’re following these two lab tests then given Cofact - a four factor PCC. This has factors II, VII, IX and X, protein C and S, and antithrombin. As an aside, four factor PCC was just FDA approved in the United states. Back to the study. So here are our healthy male subjects, a wad of cash in their pockets, and the’ve been taking rivaroxaban for three days. Blood is thin, clotting tests are abnormal and in goes the PCC. What happened?
PCC immediately normalized the prothrombin time. The control reversal agent was saline which, not surprisingly, did nor correct the PT. We know that when PCC works for warfarin, it works right away. In healthy subjects taking rivaroxaban, it did just that. The PT was normal right away. The endogenous thrombin potential was also normalized by PCC, but not by saline. Lab tests corrected. Good so far. But what about actual bleeding? No human studies on this, but there is some animal data.
Reversal of rivaroxaban associated bleeding
2012 Anesthesiology- Rabbits given rivaroxaban and then PCC had improved lab tests but their ears bled just as long. Possibly under-dosing of PCC in this trial, but, no difference between the two groups.
2009 Journal of Thrombosis and Hemostasis looked at mesenteric bleeding in rats given rivaroxaban followed by PCC. PCC at a dose of 50 units per kilogram almost completely normalized bleeding time, whereas 25 units per kilogram did not. Going back to the healthy human volunteer study, 50 units/kg of PCC was the effective dose used. At 25 units/kg, PCC had no effect.
So there is some animal data that says that PCC has little effect on bleeding, and other evidence that says PCC reverses bleeding. But a rat’s gut is not a human’s brain. Can we infer that the correction of bleeding in this surrogate model applies to the catastrophic brain bleed you are seeing in resuscitation bay one? Maybe, but it’s still unknown. The evidence is better for rivaroxaban than for dabigitran. In the previously mentioned study on healthy subjects given rivaroxaban, subjects were also given dabigatran at another time and PCC had no effect on the clotting tests. There is, however, some animal evidence that PCC may help with dabigitran associated bleeding.
What about our old friend FEIBA, factor eight inhibitor bypassing activity? Not everyone has PCC, but a lot of shops have FEIBA. There is some lab and animal data in baboons and rats given rivaroxaban that FEIBA reduces prothrombin time and bleeding time.
On the horizon: recombinant and plasma derived factor Xa antidote, monoclonal antibodies Still in testing, we’ll let you know more when and if they’re ready for prime time.
Rivaroxaban starts with a loading dose: 15 mg twice daily for three weeks followed by 20mg once daily. Starting with twice daily dosing gives better thrombus regression than staring once daily.
We have another 10a antagonist that we’ve been using for a long time: low molecular weight heparin. LMWH is dosed by weight yet rivaroxaban is not. Rivaroxaban is mostly protein bound, giving it a low volume of distribution. This means that most of the drug going to moving about in the vascular bed, not body tissue. In a pharmacokinetics study of forty eight patients with a mix of males and females, light (<50kg), average (70-80 kg), and heavy (120kg) subjects were given rivaroxaban. Anticoagulant effect was similar between genders. In the different body weights, there was a little more anticoagulant effect in the light group and a little less in the heavy group, but not enough of a difference for dose adjustment.
So what to do? We have two therapeutic pathways for DVT. I think you can be honest with your patients and, if they are candidates for both, give them the option.
Efficacy, about the same.
Complication rate, about the same. This is always an interesting part of the conversation. “You have a condition that can potentially kill you, a blood clot. The treatment for this is to make your blood thinner. Good thing there, because that’s going to help you in the long run. The down side to this treatment is that thin blood means you’ll bleed easier. Eight percent is a fair number to give, or you can say 1% serious bleeding. There you have a number needed to harm. How does that compare to number needed to treat? It’s going to be the same with rivaroxaban and warfarin, because the efficacy for recurrent VTE is the same.