GDMT Bugs Me

A bit of a rant against the standard of care

Guideline-directed medical therapy for heart failure, otherwise known as GDMT, is in vogue. After a patient is diagnosed with heart failure with reduced ejection fraction (to keep things simple, I am going to stick with HFrEF), the goals of management are to improve symptoms and decrease mortality. To achieve these goals, we manage the etiology of the HF, consider the need for interventions and devices, employ non-pharmacologic treatments, and use proven medications. Recently, the medical management has been bundled into GDMT. While I recognize the benefits of the components of this bundle, I don’t think we understand the balance of harms and benefits of our approach.

What is GDMT?

GDMT is made up of four classes of drugs which, individually, are effective treatments for HFrEF. These classes are angiotensin receptor-neprilysin inhibitors[1], beta blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. These are effective medications. Over my career they have radically changed the outcomes of patients with heart failure. Being old enough to have watched patients dying of heart failure in the pre-ACE-I era, I am a true believer. Each of the classes is associated with about a 20% reduction in endpoints of interests in meta-analyses.

Why does GDMT bug me?

The use of GDMT is an intervention that is based less on evidence and more on the philosophy that if a little is good, more must be better. If we can show, in randomized controlled trials, that each of these medications is effective, then combining them must me good. As a reference, I am going to quote directly from the UpToDate chapter supporting GDMT:

“This therapeutic regimen is based upon indirect evidence derived from clinical trials that typically compared a single therapy with placebo plus background therapy. There are no trials that directly compare various regimens, and background therapy was not optimal in successive trials of HF pharmacotherapy, which limits indirect comparisons. However, in large trials, each component of this regimen reduced morbidity and mortality compared with placebo.”

What business do I, a general internist – rather than a better trained and better compensated heart failure cardiologists – have to criticize this approach. Often, I do the follow up of patients who have started GDMT after being diagnosed with HFrEF. Even in the best of all situations, in which the patient was diagnosed correctly (rather than having a single abnormal echo done at the time that a patient’s blood pressure was poorly controlled, or they were hospitalized with sepsis, or had atrial fibrillation with a fast ventricular rate), the patient often presents to me feeling terribly. When GDMT was begun, he had few, if any, symptoms of his reduced ejection fracture. Now he presents with fatigue, weakness, hypotension, ATN, and/or hyperkalemia from the GDMT. Our first post-hospital visit is spent undoing GDMT.

 Anecdotes, anecdotes, anecdotes, anecdotes…

C’mon Adam, you’re supposed to be a committed EBM guy. How can you object to GDMT based on few anecdotes?

This would be an appropriate response if we had robust data supporting GDMT as currently used in HF. I’d admit that I was seeing a skewed sample, a sub-selected group of patients showing poor outcomes, while most patients were experiencing symptom relief, decreased hospitalizations, and improved survival. But remember, we do not have these data. We have data that support the use of each of these medications. We do not know that starting all of them, often at once, improves quality of life or mortality. And, over the last few years, I have seen the harm we cause to a subset of patients.

I have three arguments against the data we have for GDMT. First the studies are not generalizable. The enrolled patients are carefully screened – the cause of their HF is determined and managed. These people are quite different than those diagnosed with HFrEF in real life. Second, data that we do have for the combination of the drugs used in GDMT demonstrates that one drug added to a stable regimen is effective. Again, this is not how these drugs are often initiated at present. Last, observational studies that find better outcomes associated with faster and more complete titration of GDMT are, obviously, confounded.

What is attractive about GDMT?

If we do not know that our current approach is the most effective one, how did we get here? I think there are four reasons. The first, one that is best described in this article, stems from the argument that we are undertreating HF and that simultaneous rather sequential initiation of GDMT will get more patients on appropriate therapy faster and, in doing so, save lives. It may be true that we are undertreating patients who could tolerate more therapy, it is just not clear that simultaneous initiation of GDMT is the answer. The argument (from the article linked above) that: “While initiating medications in a prolonged (my emphasis) sequence is tolerated based on clinical trials and observational data, and some would advocate for trials evaluating initiation strategies, there is no evidence this approach is any safer or more beneficial than a simultaneous/rapid sequence initiation strategy” is specious. When there is an accepted therapy, the burden of proof is on those who want to change the standard.

The second reason we are adopting GDMT, is the common error of extrapolation. If one drug is effective, four must be better. We make this error repeatedly in medicine. We adopt therapies proven effective in our sickest patients and use them in people who are relatively healthy. If a screening test works in a high-risk population, it must work in a low-risk one. We spend a whole lot of time on this mistake in Ending Medical Reversal. Third, the HF equals GDMT approach is easier (and more efficient) than tailoring medications based on symptoms, signs, and measurements. And last, is there any doubt that those making and selling the drugs (and influencing the guidelines) would rather have four medications prescribed simultaneously than only one (or at least one at a time, in succession)?

Conclusion

The components of GDMT have improved and extended the lives of countless patients with HFrEF. A combination of these medications is almost certainly superior to any one single agent. However, we do not know the balance of harms and benefits of combining the drugs. We do not know the best way to initiate this therapy. I expect that tailored care is superior to a one size fits all approach whose benefits include relieving doctors of the need to think and promising pharmaceutical companies sales of four times as many drugs.

OK, my cardiology friends and colleagues, have at it. If you’d like to tell me I’m wrong, I’d welcome a post.

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[1] There could be a whole other post about why I am still not convinced that this combination is better than and ACE-I or ARB alone, but we will save that for another or you can look here.