Maximally tolerated guideline-directed medical therapy and barriers to optimization in patients with heart failure with reduced ejection fraction: the COAPT trial
Authors: Cox Z , Zalawadiya S , Simonato M , Redfors B , Zhou Z , Kotinkaduwa L , Zile M , Udelson J , Lim D S , Grayburn P A , Mack M J , Abraham W T , Stone G W , Lindenfeld J 
Published: October 2022

Abstract

Background
The COAPT trial of MitraClip therapy employed a central screening eligibility committee (CSEC) of heart failure (HF) experts to ensure the use of maximally tolerated guideline-directed medical therapy (GDMT) and systematically document intolerances in all potential patients prior to approval for randomization.

Purpose
To describe the percentage of GDMT classes, doses tolerated, predictors of intolerance, and specific intolerances limiting GDMT among patients approved for randomization by the CSEC.

Methods
We analyzed baseline use, dose, and intolerances of i) angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB) or angiotensin receptor neprilysin inhibitor (ARNI); ii) beta-blockers (BB); and iii) mineralocorticoid receptor antagonists (MRA) in the CSEC-approved COAPT population with HF with reduced ejection fraction (HFrEF; LVEF ≤40%). We analyzed variables associated with GDMT tolerance.

Results
In COAPT, 464 patients had HFrEF and complete screening medication information. Any dose of all 3, 2 or 1 GDMT classes were tolerated in 39%, 39% and 20% of patients respectively; only 2% of patients (n=9) could not tolerate any GDMT (Figure 1). BB were prescribed in the most (93%) patients followed by ACEI/ARB/ARNI (69%) and MRA (55%). Intolerances limiting each GDMT class differed, but hypotension and kidney dysfunction were most common (Figure 2). No patients tolerated goal doses of all 3 GDMT classes. For BB, only 32% tolerated ≥50% of the goal dose; while for ACEI/ARB/ARNI, no patients achieved goal doses, and only 1% tolerated ≥50% of the goal dose. For MRA, 86% of patients tolerated 25mg/day or less. Patients intolerant of BB were less likely to tolerate an ACEI/ARB/ARNI (OR 0.39, 95% CI 0.20–0.76; p=0.004) but not a MRA (p=0.21) compared with patients tolerating a low dose BB. Patients intolerant of MRA were less likely to tolerate ACEI/ARB/ARNI therapy (OR 0.37, 95% CI 0.25–0.57; p&lt;0.0001) but not a BB (p=0.31) compared with patients tolerating MRA. Patients tolerating low dose ACEI/ARB/ARNI had a higher baseline mean eGFR (52±21 versus 40±21 ml/min/m2; p&lt;0.0001) compared with patients intolerant of ACEI/ARB/ARNI. Likewise, patients tolerating MRA had a higher baseline mean eGFR (52±21 versus 42±21 ml/min/m2; p&lt;0.0001) compared with patients intolerant of MRA.

Conclusion
In a contemporary trial in which HF specialists ensured GDMT optimization, many patients had medical intolerances prohibiting use of one or more GDMT classes, and few patients tolerated target doses. These findings indicate medical intolerances are the primary cause of low GDMT prescription rates in patients with moderate to severe HFrEF. Yet, use of GDMT in this very ill population was much better than “real world” registries of HFrEF suggesting that mandating careful CSEC review prior to study enrollment is important for clinical trials having the objective of randomizing a maximally treated patient cohort.

Funding Acknowledgement
Type of funding sources: None.