Kudos to Sensible Medicine for being on the cutting edge of high-quality science discussion and also kudos for the authors from my brother country for both the letter and not having giving up to the tyrannic hammers of medical journal courts.
This post happily reminds me of why I don't subscribe classical journals anymore but subscribe Sensible Medicine.
That was a terrifically argued, clear, succinct letter. Its reasoning was tight and wonderfully delivered. Entresto may have a role to play in HF treatment, but it’s not clear to me that it should be first-line when high-dose ACE inhibitors and ARBs are probably at least non-inferior and a whole lot cheaper. Not publishing this letter is a disservice to medicine.
I don’t agree with the dosing criticism. SOLVD was with enalapril 10mg BID. That higher doses are used clinically does not mean such usage is evidence based. Pretty hard to fault their comparator with the dose used in the seminal trial. And if they did compare to a non-studied dose of enalapril, and sac/Val “wins”… people would complain about that. If it’s no-win either way, theirs is the more defensible choice.
Also, Val-HeFT used Val 160 mg BID….and entresto 200 mg BID only contains Val 103 mg BID…so it’s UNDER-dosed vs the landmark ARB study. To complain that this design advantages itself against enalapril would need to also acknowledge that it is disadvantaging itself against “standard” evidence based Val dosing.
I agree with the other criticisms. Open label design and a clinician-dependent subjective HF hospitalization endpoint is dumb. And if it comes down to a “win” based on a bio marker, that would render the result even more clinically useless. And if history with sac/Val is any guide, chances are this study will not show CV death improvement, and any result if positive will be driven by “wins” with those soft components of the composite endpoint. The study authors will get their just desserts and deserve all the ripping coming their way in that event.
The 103 mg of valsartan in entresto 200 mg corresponds to 160 mg of the original valsartan used in Val-heft and other trials. So your comments are wrong.
Also when comparing drug versus placebo you can use any dose of the drug that you want. Now when comparing 2 drugs it is crucial that if you use the maximum dose of one drug you should also use the maximum dose of the other drug. Remember the COMET trial!
Just looked it up in NICE UK. I stand corrected…on that part. Turns out the bioavailability of Valsartan salt is higher in entresto so the 103mg there is bioequivalent to 160mg of stand-alone valsartan. I did not know that. Thanks for pointing that out.
However, how do you figure that my “comments are wrong” independent of that point?
COMET was a silly trial from the get-go….since it compared a proven HF beta blocker formulation (carvedilol) vs one that was not (metoprolol tartrate). The proper comparator would have been another proper BB formulation with proven HF efficiency….either bisoprolol or metoprolol succinate (as used in MERIT-HF). That was the lesson from COMET, and not dosing.
The COMET trial not only used the wrong metoprolol (tartrate instead of succinate), but also the wrong dose: 50 mg twice daily instead of 100 mg twice daily. You’ve made a mistake again…
Well, this is disturbing. The objections the letter brings up seem obvious. Testing a full dose of an expensive med against a half dose of a cheap med is unlikely to favor the cheaper med.
Even though underdosing the comparison group is a well-known trick to make an intervention look better, they still manage to keep designing trials like this one. Ps I wonder why they published the protocol— isn’t that inviting criticism?
Thank you for posting this. I have had disagreements with some articles in Sensible Medicine, but this one is surely not one among them.
Kudos to Sensible Medicine for being on the cutting edge of high-quality science discussion and also kudos for the authors from my brother country for both the letter and not having giving up to the tyrannic hammers of medical journal courts.
This post happily reminds me of why I don't subscribe classical journals anymore but subscribe Sensible Medicine.
Reminds me of a quote from Voltaire:
"It is dangerous to be right in matters on which the established authorities are wrong."
That was a terrifically argued, clear, succinct letter. Its reasoning was tight and wonderfully delivered. Entresto may have a role to play in HF treatment, but it’s not clear to me that it should be first-line when high-dose ACE inhibitors and ARBs are probably at least non-inferior and a whole lot cheaper. Not publishing this letter is a disservice to medicine.
Why not just compare sacubitril/valsartan with valsartan alone at the equivalent dose?
So….
I don’t agree with the dosing criticism. SOLVD was with enalapril 10mg BID. That higher doses are used clinically does not mean such usage is evidence based. Pretty hard to fault their comparator with the dose used in the seminal trial. And if they did compare to a non-studied dose of enalapril, and sac/Val “wins”… people would complain about that. If it’s no-win either way, theirs is the more defensible choice.
Also, Val-HeFT used Val 160 mg BID….and entresto 200 mg BID only contains Val 103 mg BID…so it’s UNDER-dosed vs the landmark ARB study. To complain that this design advantages itself against enalapril would need to also acknowledge that it is disadvantaging itself against “standard” evidence based Val dosing.
I agree with the other criticisms. Open label design and a clinician-dependent subjective HF hospitalization endpoint is dumb. And if it comes down to a “win” based on a bio marker, that would render the result even more clinically useless. And if history with sac/Val is any guide, chances are this study will not show CV death improvement, and any result if positive will be driven by “wins” with those soft components of the composite endpoint. The study authors will get their just desserts and deserve all the ripping coming their way in that event.
Rx
The 103 mg of valsartan in entresto 200 mg corresponds to 160 mg of the original valsartan used in Val-heft and other trials. So your comments are wrong.
Also when comparing drug versus placebo you can use any dose of the drug that you want. Now when comparing 2 drugs it is crucial that if you use the maximum dose of one drug you should also use the maximum dose of the other drug. Remember the COMET trial!
Just looked it up in NICE UK. I stand corrected…on that part. Turns out the bioavailability of Valsartan salt is higher in entresto so the 103mg there is bioequivalent to 160mg of stand-alone valsartan. I did not know that. Thanks for pointing that out.
However, how do you figure that my “comments are wrong” independent of that point?
COMET was a silly trial from the get-go….since it compared a proven HF beta blocker formulation (carvedilol) vs one that was not (metoprolol tartrate). The proper comparator would have been another proper BB formulation with proven HF efficiency….either bisoprolol or metoprolol succinate (as used in MERIT-HF). That was the lesson from COMET, and not dosing.
The COMET trial not only used the wrong metoprolol (tartrate instead of succinate), but also the wrong dose: 50 mg twice daily instead of 100 mg twice daily. You’ve made a mistake again…
There has NEVER been an RCT using metoprolol tartrate in HFrEF. And the dose of metoprolol succinate in MERIT-HF was 200mg ONCE daily.
Do you even see or treat HFrEF patients in a clinical setting?
The lesson from COMET: use a HF drug that actually has RCT data. At the dose tested. You might want to do a lit review.
Very good! 👏🏻👏🏻
Well, this is disturbing. The objections the letter brings up seem obvious. Testing a full dose of an expensive med against a half dose of a cheap med is unlikely to favor the cheaper med.
Even though underdosing the comparison group is a well-known trick to make an intervention look better, they still manage to keep designing trials like this one. Ps I wonder why they published the protocol— isn’t that inviting criticism?
Of course the letter was rejected, JACC is probably paid by the pharma companies to promote their products. Anyone know where to look to find that?.
https://www.jacc.org/policies/editorial-operating-policies
https://openpaymentsdata.cms.gov/