Replies to post #151732 on Biotech Values

[genisi]

Quite clear to me that the NYT article is about making a headline and therefore is emphasizing the side of the story that serves its target by telling the sad cases of patients who "bled to death" without giving all the details (were there other bleeding risk factors such as decreased renal function, low body weight, other concomitant medications that interact with Pradaxa like amiodarone, quinidine or verapamil etc), nor highlighting Pradaxa's advantages.
Eliquis will probably have superior safety and efficacy over coumadin claim in its label so its advantages are better understood.
Of course an antidote will make docs/patients feel a lot more comfortable with factor Xa inhibitors drug class, although in reality it would be used very rarely.

[iwfal]

Biopearl/Dew - Pradaxa. Facts on the ground (i.e. from the registrational trial).

First an apology. I had (mis)remembered the overall data from the registrational trial - and the magnitude of the benefit both in stroke prevention and bleeding risk for the overall population (it was stat sig better efficacy in the overall population even though it was a non-inf trial). However I did correctly remember the location of the risk reward inflection points (where warfarin becomes the better choice) - which is somewhere around age 75, or with an INR control rate of 70% or more or (TBD) with patients already on warfarin (more reading/data would be required on this last to pin it down).

More particularly:

Patients like it since less blood work is required and dose adjustment (in the absence of renal dysfunction) is not required.

Agree (now and before).

The bleeding risk you cite in the elderly may in part be explained by failure to adequately adjust dose for reduced renal function in this population (now being increasingly recognized as very important.)

The 'in part' part of your quote may be correct - but only in 'small' part. The FDA analysis of the registrational data actually looked at the bleeding risk vs coumadin for a subset of patients with good renal function and found that bleeding risk keeps going up with age regardless. Crossover for bleeding risk occurs around 70. See section 7.5.3 Figure 24 of link at bottom. Also note that the data indicate that dose reduction does not solve the overall risk/reward vs age.

Older patients are precisely those who have the greatest difficulty in adjusting their doses of coumadin properly.

Agreed - but the regristrational data I cited above encompasses that issue and still found pradaxa to be increasing bleeding risk (relative to warfarin) at increasing age.

INR data

You did not address INR control, but given the tenor of your post I would suspect you would prescribe pradaxa regardless of a patients ability to control their INR. But FWIW the registrational data indicates that for patients overall the risk/reward probably passes to warfarin for patients that can keep their INR in the therapeutic range greater than 67-75% of the time. See section 7.3.2.1 Table 54 (a bleeding risk vs INR in therapeutic range greater than 2/3 of time) - and then there is another table (which I cannot refind at the instant of putting this post together) showing quartiles of investigational sites by their ability to control INR. Bleeding (and presumably stroke prevention) show advantage passing to warfarin as ability to control INR moves up. Where exactly the advantage passes probably varies with age, and in any case cannot be determined precisely from the 'small' amount of data in the registrational dataset. But nonetheless the data that does exist indicate this effect is robust (as you'd expect) and probably occurs around when patients can keep their INR in the therapeutic range around 70% of the time or greater. (for the overall population - and probably meaningfully lower for older patients although the FDA analysis doesn't speak directly to this).

And finally, a point on the trial - the data hints that most (all?) of the advantage seen by Pradaxa was in new patients. I.e. the first six(? 12? 18?) months on warfarin carries much greater bleeding risk and much less stroke prevention ability that pradaxa - but then after that run in period there are hints that pradaxa's risk/efficacy is less beneficial than warfarins. Assuming this kind of effect is real it would mean the trial data is misleading - because by its nature the trial is of limited duration. But I'd have to relook at the data to be more specific.

Sooo, in summary - some case points:

1) if you are even a moderately diligent patient over 75 I would suggest that putting them on pradaxa probably increases their overall risk of serious events (ever increasing bleeds) unless they are on a 2 sigma (for that age) number of medications (my WAG on the concurrent medications).

2) if you are a very diligent patient over 65 I would suggest that warfarin is probably the better drug from a serious events standpoint. Similar caveat to above wrt concurrent medications.

3) The really interesting question is about patients under, say, 60, who are likely to be on drug a long time. Pradaxa is undoubtedly the better drug for them for the next 5 or 10 years overall - but if Pradaxa's main benefit is the avoidance of warfarin startup issues but it has more issues than warfarin after startup... then the trades become trickier and without much data to inform them.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM247244.pdf