Assessment of Limitations to Optimization of Guideline-Directed Medical Therapy in Heart Failure From the GUIDE-IT Trial: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes.

Objective: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy.

Design, setting, and participants: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP-guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019.

Main outcomes and measures: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes.

Results: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were "clinically stable" and "already at maximally tolerated therapy." Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of β-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P < .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes.

Conclusions and relevance: Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic.

Trial registration: ClinicalTrials.gov Identifier: NCT01685840.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fiuzat reported receiving grant or research support from Roche Diagnostics. Dr Ezekowitz reported receiving grant or research support from the Canadian Institutes of Health Research, Amgen, Inc, Bayer AG, Bristol-Myers Squibb, Merck & Co, and Novartis International AG and serving as a consultant for Amgen, Inc, Bayer AG, Merck & Co, and Novartis International AG. Dr Whellan reporting receiving grant support from the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Aging, CVR Global, Novartis International AG, and Aegerion Pharmaceuticals, Inc; serving as a consultant for CSL Behring and BDC Advisors; and serving on clinical end points committees for CVRx, Inc, and FibroGen, Inc. Dr Adams reported receiving grants and personal fees from Roche Diagnostics during the conduct of the study; grants and personal fees from Novartis and Amgen, personal fees from Cytokinetics, Relypsa, and Windtree Therapeutics, and grants from BMS, Boehringer Ingelheim, and Otsuka outside the submitted work. Dr Piña reported serving on the advisory board for Relypsa, Inc. Dr Ahmad reported receiving consulting income from Cytokinetics, Inc, and Amgen, Inc. Dr Anstrom reported receiving grant support from the NHLBI, Merck & Co, and Bayer AG. Dr Mark reported receiving grants from the National Institutes of Health (NIH)/NHLBI, Mayo Clinic, Merck & Co, Oxygen Therapeutics LLC, and HeartFlow outside the submitted work and consulting income from CeleCor Therapeutics, Cytokinetics, Inc, and Novo Nordisk A/S outside the submitted work. Dr Felker reported receiving grant support from Merck & Co, Amgen, Inc, Roche Diagnostics, the NIH, and the American Heart Association and consulting fees from Novartis International AG, Amgen, Inc, Cytokinetics, Inc, Medtronic plc, Bristol-Myers Squibb, MyoKardia, Inc, Innolife, Abbott Laboratories, Alnylam Pharmaceuticals, Inc, EBR Systems, Inc, Cardionomic, SphingoTec GmbH, scPharmaceutical, Inc, and Stealth BioTherapeutics Corp. Dr Januzzi reported receiving grant support from Roche Diagnostics, Abbott Diagnostics, Singulex, Inc, Prevencio, Inc, Novartis International AG, and Cleveland HeartLab, Inc, and consulting income from Roche Diagnostics, Abbott Diagnostics, Prevencio, Inc, and Critical Diagnostics; and participating in clinical end point committees/data safety monitoring boards for Siemens Healthcare Diagnostics, Inc, Novartis International AG, Bayer AG, AbbVie, Inc, and Amgen, Inc. Dr O’Connor reported receiving grant or research support from Roche Diagnostics and Merck & Co and consulting fees from Merck & Co, Bayer AG, Bristol-Myers Squibb, Windtree Therapeutics, Inc, and Arena Pharmaceuticals, Inc. No other disclosures were reported.

Figures

Figure 1.. Study CONSORT Diagram

The last medication data before 6 months are carried forward.

Figure 2.. Reasons for Not Titrating Medications by Treatment Arm

Data include all qualified visits, that is, all visits in the usual care arm and all visits in the guided therapy arm with N-terminal pro–brain natriuretic peptide (NT-proBNP) levels of greater than or equal to 1000 pg/mL, determined by local laboratories. To convert NT-proBNP to nanograms per liter, multiply by 1. aIncludes laboratory draw, telephone visit, or end of study.