NEJM: Bhatt editorial evaluates prasugrel in clinical practice

Only days after the FDA approval of prasugrel, the New England Journal of Medicine has published an editorial by Deepak Bhatt on “Prasugrel in Clinical Practice.

Bhatt writes that because prasugrel is a more potent inhibitor of the platelet receptor than previously available theinopyridines it can cause “a greater reduction in ischemic events– but it may also lead to more bleeding.” Bhatt notes that TRITON-TIMI 38 demonstrated both increased efficacy and bleeding, and warns that “the risk of bleeding might be increased still further with real-life use, and the FDA has required that prasugrel’s labeling include a black-box warning about that risk.”

The increase in bleeding occurs most often in three subgroups: the elderly, the underweight, and patients with a previous stroke or TIA. Bhatt writes that “the option of using a lower dose of prasugrel is appealing,” but points out that there is as yet no evidence of either efficacy or safety in the lower dose.

Bhatt also takes note of the high bleeding rate in patients who ended up undergoing CABG. Writes Bhatt, “cardiac surgeons who have been reluctant to operate on patients receiving clopidogrel will probably find prasugrel even more objectionable.” Bhatt warns against  against early prasugrel treatment prior to catheterization.

Robert Harrington offered the following comment on the editorial:

Thoughtful assessment by a very thoughtful investigator of the issues/FDA approval. Drug should be confined to the ACS setting when anatomy known (except in STEMI)  and bleeding risk acceptable.  It should not be routinely used “upstream” in the absence of more data.  The 5 mg dose approval while intuitively appealing has no outcome data associated with it and therefore additional caution really should be taken about its use instead of clopidogrel until more data are available.

David Kandzari provided another perspective:

The real issue is how often prasugrel will be used according to the exact indications studied. There is a clear off label use (eg, elective PCI, no ACS, but maybe high risk like left main PCI)– or prescribing a 5 mg dose in an normal weight, elderly patient– then there is a grey area like use in ACS and PCI but then switching over to clopidogrel at 30 days. There is a lot of speculation that the black box associated with the drug’s approval will destabilize a lot of predictions about off label use, but I don’t think it will have much influence. The warnings about prasugrel are fairly self evident (active bleeding, prior stroke/TIA, urgent surgery…), and doctors won’t test that. I doubt there will be much prescription of the 5 mg dose beyond indications, either, unless doctors start performing point of care testing more often. But my guess is that there will be an expansion of use in this grey area, and it reminds us just how little we know about prasugrel in clinical practice– no evidence with drugs like bivalirudin (vs heparin), nothing to say about prasugel in peripheral arterial disease, nothing about the non ACS high risk lesion complexities, etc. There’s a responsibility (and opportunity) for the manufacturer here to support these trials, because otherwise clinicians will perform their own studies that might not represent the best designs or sample size, or worse yet, base their decisions on incomplete evidence from TIMI 38 and extrapolate to other indications.

Sanjay Kaul provided the following comment:

Overall, it is a balanced perspective that highlights the uncertainties in the evidence and offers suitably conservative recommendations that are generally supported by the evidence. I have, however, two issues with recommendations regarding risk-mitigating interventions. I remain unconvinced regarding the claim of being able to identify patients at higher bleeding risk. While absolute risk is doubled in the high-risk subgroups, the relative risks amongst the subgroups are statistically indistinguishable. Neither is there any outcome data to support the claim that by reducing the maintenance to 5mg daily, the bleeding risk will be minimized in patients weighing <60 kg, an arbitrary cut-off with relatively few patients (6% of the overall cohort). It is interesting to note that more fatal hemorrhage was observed in >60kg subgroup overall and all fatal bleeding in prasugrel group occurred in >60kg.

With regards to patients with STEMI, the benefit with prasugrel was “front loaded” with little incremental benefit beyond 30 days. Furthermore it was observed only in anterior (presumably large) infarcts and not in the primary PCI cohort, which is the typical practice pattern in the US.

Finally, Victor Serebruany provided the following comment:

This is a very carefully written and edited Perspective representing an “official” view on prasugrel. However, there are 2 major issues which are deliberately avoided, but will represent the real chellenge for prasugrel.

  • First, it is  unjustified to recommend long-term duration of therapy when all the benefits are entirely front – loaded, and all the risks grow over time. If TRITON was such a success, why were all the patients  switched to clopidogrel at the end of the study, rather then provide urgently needed longer follow up as part of a prasugrel registry?
  • Second, the editorial does not mention the overwhelming significant increase in cancers after prasugrel, which may (if confirmed) get everybody in big trouble.

Finally, several observers raised the issue with CardioBrief of whether the New England Journal editors should have asked Bhatt to write the editorial. Bhatt, they note, is a senior TIMI investigator, though this is not mentioned in the disclosure at the end of the editorial. In addition, Bhatt wrote the editorial accompanying the original TRITON-TIMI 38 publication in the New England Journal of Medicine, a few months before moving to Boston from the Cleveland Clinic. One writer wondered why the editors couldn’t find at least one other expert qualified to write on prasugrel.

Click here for a complete chronology of the prasugrel controversy.

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  1. […] his editorial, Bhatt, who appears to have a near monopoly on editorials relating to clopidogrel and prasugrel, notes that “potentially, higher doses of clopidogrel could overcome impaired antiplatelet […]

  2. […] NEJM: Bhatt editorial evaluates prasugrel in clinical practice (CardioBrief story) […]

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