Next-generation anticoagulants

SomeDose

Lately, there's a whole raft of new anticoagulants being brought into clinical use and early findings suggest that at least some of them will offer significant benefits over traditional agents such as warfarin and heparins. Many people will be aware of the disadvantages of these existing drugs i.e. monitoring requirements, bleeding risks, drug/food interactions and the need for s/c admininistration after hospital discharge (for LMWHs).

Dabigatran is an oral direct thrombin (factor IIa) inhibitor and has shown non-inferiority along with lower rates of haemorrhage versus warfarin in stroke and VTE prevention in patients with AF. It's published here in the NEJM - I don't have full access but on the face of it the study seems to be of reasonable quality. I think the primary end-point follow up was only around 2 years though, so maybe a longer duration would be more valid in these patients. Aside from the published findings, the other obvious advantages over warfarin are no monitoring requirements and significantly less drug/food interactions. This also means clinicians and pharmacists would no longer need to complete lengthy counselling with patients, which is necessary for warfarin.

Another new oral drug, Rivaroxaban, is a direct factor Xa inhibitor and has recently been approved by NICE for thromboprophylaxis in patients undergoing elective hip and knee replacement surgery, based on lower mortality rates and reduced incidence of DVT/PE compared to enoxaparin. The other big advantage here is that enoxaparin and other LMWHs must be given for several weeks post-op, which is a major faff since it means patients either need to be trained to inject themselves or a community nurse has to make daily visits to administer the drug. It's just been added to our formulary so we should be seeing it in use fairly shortly.

So, it appears these new drugs will offer clear advantages over existing agents. Downsides? Well, there is still a bleeding risk associated with both drugs but, due to their mechanism of action, there are no specific antidotes in cases of haemorrhage (warfarin and heparin being fully reversible, and LMWHs partially reversible). Aside from stopping the drug, I'm not sure if there's any option here...they've both got relatively long half-lives so even after stopping they'll still be exerting an anticoagulant effect. I guess dialysis may be an option in urgent circumstances, since I think they're both mainly renally excreted.

MrCreosote

Any idea how the prices compare with warfarin and LMWH?

SomeDose

I don't have accurate costs to hand, but both agents are undoubtedly more expensive than their comparators. However, higher apparent costs are offset by all kinds of economic analyses which would indicate the newer agents save money in terms of no monitoring requirements, no anti-coag clinic appointments, less risk of adverse events, no need for community nurse visits etc etc.

Echani

I was at a few cardiology meetings where they were discussing dabigatran, I think the price was about 10 times that of warfarin. Even more at the moment because it's only being sold in smaller packet sizes intended for short courses post-orthopaedic procedures or something, but the pharm rep at the meeting said that the price will drop when approval comes through for more broad usage in order to be a more competitive option.

Vorsprung

Echani wrote: »

I was at a few cardiology meetings where they were discussing dabigatran, I think the price was about 10 times that of warfarin. Even more at the moment because it's only being sold in smaller packet sizes intended for short courses post-orthopaedic procedures or something, but the pharm rep at the meeting said that the price will drop when approval comes through for more broad usage in order to be a more competitive option.

Do you know if that comparison took the cost of INRs/Warfarin clinics into consideration?

Anyone know the half-life of those drugs?

Echani

Vorsprung wrote: »

Do you know if that comparison took the cost of INRs/Warfarin clinics into consideration?

Anyone know the half-life of those drugs?

No, I believe it was just a direct pill for pill cost.

Half-life is 12-17 hours

Vorsprung

Echani wrote: »

No, I believe it was just a direct pill for pill cost.

Half-life is 12-17 hours

So is it effectively it probably is cheaper then warfarin in term of cost of use?

I asked the half-life question because I was thinking of the 70 odd year old dear who has a fall, smakes her head while on one of these next generation drugs. So basically there's nothing available at the moment to reverse the effect of these drugs?

SomeDose

I should clarify that both dabigatran and rivaroxaban are currently only licensed for the prevention of VTE in patients post elective knee and hip replacements. There's quite a few trials in progress looking at their use (and various other new agents) for other indications such as AF, ACS, VTE treatment etc. So I'm not sure if there's any precise economic analyses comparing them to conventional warfarin treatment available at the moment.

The lack of reversibility is probably the most significant issue with these drugs. I'm not sure if even using blood factors would be effective. One of the newer parenteral anticoagulants, Fondaparinux, can be reversed with factor VIIa if necessary. It's like rivaroxaban since it purely inhibits factor Xa only, but rivaroxaban is a direct (non AT-dependent) Xa inhibitor rather than an indirect inhibitor. So I'm guessing this pharmacodynamic difference probably rules out reversal with VIIa.

Despite the above reservations, I think we'll start seeing some of these drugs getting extended licenses for cardiology indications which could be the death knell for warfarin in many patient populations.

charlieroot

Was having a look at these new drugs and decided to try and work out costs. If I've made any glaring mistakes please let me know.

I think the results are quite surprising! There isn't a huge discrepancy in price with the exception of warfarin. Note I haven't taken into account the cost of warfarin monitoring/clinic which would probably bring the price of warfarin closer to the rest (monthly clinic cost = €50 (guessed = average price of GP visit), blood tests = €20 additional €70 per month hence the real price of warfarin would probably be closer to €19 per week) . I also haven't taken into account the cost of syringes/needles.

Pricing according to the IMF Ed 6, 2009. Dosages may be off, if you notice a mistake please let me know.

Cost of 1 week of treatment on each drug (calculations below)

Dabigatram (Pradaxa) €39
Rivaroxaban (Xarelto) €42
Warfarin (warfant) €2
Enoxaparin (Clexane) €41
Heparin (Monoparin Parenteral) €30.13


Calculations:

Dabigatran
Price: 75mg,110mg x 10 €28.12, x 60 €169.08
Dose post-op(knee/hip surg) 220mg od
Cost of week of treatment = 7x2x169.08/60 = €39

Rivaroxaban (Xarelto)
Price: 30x10mg €181.78
Dose post-op (knee/hip surg) 10mg od
Cost of week of treatment = 7x(181.78)/30 = €42


Warfarin (Warfant)
Price: 1mg x 100 €3.64, 3mg x 100 €6.19, 5mg x 100 €8.75
Maintence dose (average/guess on range 2-30mg/day) 16mg /day
Cost of week of treatment = 7x(3x8.75 + 1x3.64)/100 = €2

Enoxaparin (Clexane)
Price: 20mg x 10 €35.11, 40mgx10 €59.96 60mgx10 59.74 80mgx10 72.30
Medical patients 40mg/day
Cost of week of treatment = 7x59.96/10 = €41

Heparin (Monoparin Parenteral)
5000 IU/ mL,0.2mL x 10 €14.35
Prophylaxis maintenance dosage 5000 IU t.d.s.
Cost of week of treatment = 7x3 14.35/10 = €30.13

SomeDose

The costs you've given above look pretty realistic, although we can probably ignore heparin since it wouldn't be a relevant comparator. At the moment, we can only really compare costs for rivaroxaban/dabigatran with the LMWHs for VTE prophylaxis since this is the only licensed indication at present. Treatment is usually for 2 weeks post knee replacement and 4-5 weeks post hip replacement, so you would need to factor in any community nurse visits for LMWH administration after discharge. Since the trials have shown superiority and non-inferiority for rivaroxaban and dabigatran respectively, you can see the advantage to using the new agents.

Just to also add that you won't see many people on 16mg warfarin, so it isn't really a true average. Probably somewhere around 3-8mg would be more realistic.

Moorsy22

interesting info on costs.
I am on long term meds, Xarelto (rivaroxiban) at the moment and will probably be on it for several years, maybe life
My Haemotoligist is talking of changing me to warfarin saying it is because they don't know about long term affects of using xarelto, but I was advised by 2 other medics that it is probably a cost cutting exercise as xarelto was very expensive and the HSE hand out warfarin like smarties.
Anybody have any insight or comments on this ?

RobFowl

Please don't drag up 4 year old threads and also don't ask for medical advice !

Moorsy22 wrote: »

interesting info on costs.
I am on long term meds, Xarelto (rivaroxiban) at the moment and will probably be on it for several years, maybe life
My Haemotoligist is talking of changing me to warfarin saying it is because they don't know about long term affects of using xarelto, but I was advised by 2 other medics that it is probably a cost cutting exercise as xarelto was very expensive and the HSE hand out warfarin like smarties.
Anybody have any insight or comments on this ?