The Study of the Week stays with the theme of applying trial evidence to patients, once again in the heart failure field. Perhaps GDMT might not always apply?
In the RALES trial, if the participants lost to follow-up were already accounted for in the intention-to-treat analysis, why do Users’ Guides to the Medical Literature recommend performing a worst-case scenario sensitivity analysis by assuming the worst possible outcomes for those lost participants?
If intention-to-treat already includes all randomized patients, what additional information does this worst-case analysis provide?
Carvedilol. That's so 20th century.The straw man they set up was a dose of metoprolol that was 4 times weaker than the Coreg. I call it the VOMET study, not the COMET study. It's a great teaching example of BigPharma pulling the wool over innocent physicians' eyes.
When the evidence conflicts with “guidelines”, screw the guidelines….since much of what’s in them these days aren’t truly evidence based anyway.
But in this case, this is a retrospective subgroup from prior trials. So ideally what we would need is a trial with persistent/permanent AF/CHF patients, to know for sure whether BB benefit in HFrEF is preserved in AF patients. Good luck getting companies to fund a study that might result in LESS use of their wares.
I’ve literally just done this in an 89 yr old with AF and HFrEF, having made him feel ill with some GDMT that his BP couldn’t tolerate. He feels - and looks - a heck of a lot better now the digoxin has kicked in!
As complex as the systems are that we are trying to impact in a positive way, and guided by the first do no harm oath, guidelines are needed for most, but not all patients. Sepsis and Pneumonia protocols, Helicobacter treatments even in asymptomatic patients, DM and CHF GDMT should evolve and not become the law of the land and tied to quality and remuneration. In years past, where there were no blood tests for drug levels, they used to treat patients to efficacy or toxicity. We have come a long way and should question recommendations that we think do not apply to the individual patient. We are their advocates. Phobias to benzodiazepines, opiates, lanoxin, are hurting some.
Who, exactly, are “those measuring how well I practiced evidence-based medicine”? The clipboard nurses? Joint Commission? Insurers? I’m asking honestly—I am not a physician and don’t know how this monitoring works.
Physicians don’t have the full freedom to treat their patients as they see best.
One commenter said it well: it’s these “One size fits all” guidelines. How did we get here? Everyone BUT the patient’s physician is making decisions on how best to treat their patient. I get it that there are quacks doing really crazy things—and I bet they’re still doing them because they aren’t a part of these monitored health settings. There’s a place for oversight, but how do we let doctors be doctors?
I truly don’t know what to think, personally or professionally.
I’ve had atrial fib since my second year of medical school, some (“many” is a relative adjective) decades ago, and for years the mainstays of my treatment were digoxin and quinidine….which at least made me feel part of the gang – seemingly half of my adult patients – AF or no – were taking one or the other drug (mostly digoxin).
Now I see a patient on digoxin about once every six months, and quinidine is a word roughly on a par with bathroom wall graffiti. On the other hand, despite having had no problems with rate controlI I have been taking metoprolol for years, and in my clinics I frequently encounter AF patients on a beta blocker per guidelines but with heart rates <60 and systolic pressures of <110 despite having 85-year-old brains that perhaps need a somewhat higher cardiac output/cerebral perfusion pressure for those brains to work at peak efficiency.
I have spent my career helping to develop evidence-based therapies for stroke and for migraine… and yet the current guidelines in my own medical neck of the woods do not always match up with the ever-changing existing evidence. I suspect the same maybe so for the beta blockers.
Unfortunately, guidelines can act much like the clinical trials that create those guidelines: like steamrollers that seek to flatten a diverse population with diverse needs into one where “one size fits all“.
Combining patient level data across studies allows investigators to construct huge datasets that allow analyses that would not be otherwise possible. These patient-level data meta-analyses (PLDMAs) can show us which types of patients are likely to benefit from a treatment and which types aren’t.
When the difference between sub-populations in a PLDMA is large , as demonstrated by a very low p-value (e.g. 0.002), the statistical power lost by performing a comparison that was not pre-specified by the original investigators becomes moot. We get a large powerful RCT for free!
As physicians, we are obligated to practice according to our understanding of the data to best benefit the patient in front of us. Go ahead, John: Give your HFrEF/AF patients digoxin, and not a beta-blocker, as you have interpreted the data. “Best” practice alerts be damned. They are written by short-sighted bureaucrats. Educate your colleagues so they join you.
At the end of the day, it is yourself you must answer to.
Just a couple of thoughts off the top of my head, one of the biggest issues in patients with HFrEF and AF is rate control so typically I end up treating with Metoprolol Tartarate +/- Digoxin but I'm really trying to restore SR first. If they have permanent AF rate control is always going to be an issue so I'm looking ultimately at an AV nodal ablation at CRT. I like Dig but a lot of these patients have CKD and/or polypharmacy so Dig toxicity is always a concern. In the end this is definitely a sicker cohort of patients.
I think you are very much correct in your analysis and approach for your patients.
Dear Dr. Mandrola,
Could you explain something to me?
In the RALES trial, if the participants lost to follow-up were already accounted for in the intention-to-treat analysis, why do Users’ Guides to the Medical Literature recommend performing a worst-case scenario sensitivity analysis by assuming the worst possible outcomes for those lost participants?
If intention-to-treat already includes all randomized patients, what additional information does this worst-case analysis provide?
Thank you very much.
Carvedilol. That's so 20th century.The straw man they set up was a dose of metoprolol that was 4 times weaker than the Coreg. I call it the VOMET study, not the COMET study. It's a great teaching example of BigPharma pulling the wool over innocent physicians' eyes.
When the evidence conflicts with “guidelines”, screw the guidelines….since much of what’s in them these days aren’t truly evidence based anyway.
But in this case, this is a retrospective subgroup from prior trials. So ideally what we would need is a trial with persistent/permanent AF/CHF patients, to know for sure whether BB benefit in HFrEF is preserved in AF patients. Good luck getting companies to fund a study that might result in LESS use of their wares.
Which movie discussed the difference between a “guideline” and a rule?
Very interesting! We should be consequent and apply the evidence. Guidelines are not commandments.
The goal of our existence is to aim for the NNT = 1. Very high standard but the gold standard nonetheless.
I’ve literally just done this in an 89 yr old with AF and HFrEF, having made him feel ill with some GDMT that his BP couldn’t tolerate. He feels - and looks - a heck of a lot better now the digoxin has kicked in!
Brilliant and thought provoking. And, ideally should generate a trial.
As complex as the systems are that we are trying to impact in a positive way, and guided by the first do no harm oath, guidelines are needed for most, but not all patients. Sepsis and Pneumonia protocols, Helicobacter treatments even in asymptomatic patients, DM and CHF GDMT should evolve and not become the law of the land and tied to quality and remuneration. In years past, where there were no blood tests for drug levels, they used to treat patients to efficacy or toxicity. We have come a long way and should question recommendations that we think do not apply to the individual patient. We are their advocates. Phobias to benzodiazepines, opiates, lanoxin, are hurting some.
Who, exactly, are “those measuring how well I practiced evidence-based medicine”? The clipboard nurses? Joint Commission? Insurers? I’m asking honestly—I am not a physician and don’t know how this monitoring works.
Physicians don’t have the full freedom to treat their patients as they see best.
One commenter said it well: it’s these “One size fits all” guidelines. How did we get here? Everyone BUT the patient’s physician is making decisions on how best to treat their patient. I get it that there are quacks doing really crazy things—and I bet they’re still doing them because they aren’t a part of these monitored health settings. There’s a place for oversight, but how do we let doctors be doctors?
I truly don’t know what to think, personally or professionally.
I’ve had atrial fib since my second year of medical school, some (“many” is a relative adjective) decades ago, and for years the mainstays of my treatment were digoxin and quinidine….which at least made me feel part of the gang – seemingly half of my adult patients – AF or no – were taking one or the other drug (mostly digoxin).
Now I see a patient on digoxin about once every six months, and quinidine is a word roughly on a par with bathroom wall graffiti. On the other hand, despite having had no problems with rate controlI I have been taking metoprolol for years, and in my clinics I frequently encounter AF patients on a beta blocker per guidelines but with heart rates <60 and systolic pressures of <110 despite having 85-year-old brains that perhaps need a somewhat higher cardiac output/cerebral perfusion pressure for those brains to work at peak efficiency.
I have spent my career helping to develop evidence-based therapies for stroke and for migraine… and yet the current guidelines in my own medical neck of the woods do not always match up with the ever-changing existing evidence. I suspect the same maybe so for the beta blockers.
Unfortunately, guidelines can act much like the clinical trials that create those guidelines: like steamrollers that seek to flatten a diverse population with diverse needs into one where “one size fits all“.
Combining patient level data across studies allows investigators to construct huge datasets that allow analyses that would not be otherwise possible. These patient-level data meta-analyses (PLDMAs) can show us which types of patients are likely to benefit from a treatment and which types aren’t.
When the difference between sub-populations in a PLDMA is large , as demonstrated by a very low p-value (e.g. 0.002), the statistical power lost by performing a comparison that was not pre-specified by the original investigators becomes moot. We get a large powerful RCT for free!
As physicians, we are obligated to practice according to our understanding of the data to best benefit the patient in front of us. Go ahead, John: Give your HFrEF/AF patients digoxin, and not a beta-blocker, as you have interpreted the data. “Best” practice alerts be damned. They are written by short-sighted bureaucrats. Educate your colleagues so they join you.
At the end of the day, it is yourself you must answer to.
Just a couple of thoughts off the top of my head, one of the biggest issues in patients with HFrEF and AF is rate control so typically I end up treating with Metoprolol Tartarate +/- Digoxin but I'm really trying to restore SR first. If they have permanent AF rate control is always going to be an issue so I'm looking ultimately at an AV nodal ablation at CRT. I like Dig but a lot of these patients have CKD and/or polypharmacy so Dig toxicity is always a concern. In the end this is definitely a sicker cohort of patients.