CLEVELAND -- Adverse events were common with rapid initiation and titration of heart failure medication around a heart failure hospitalization, but they didn't impact key clinical outcome benefits, analysis of the STRONG-HF trial showed.
Fully 57.7% of patients randomized to reach at least a 50% dose of guideline-directed medical therapy (GDMT) before discharge, and full dosing by 2 weeks afterward, met at least one "safety indicator" during uptitration of guideline-directed medical therapy at some point in the first 6 weeks after discharge.
Most of these events were a rise in natriuretic peptide tests measure levels of BNP (NT-proBNP) by more than 10% compared with pre-discharge levels or a potassium increase of more than 5.0 mmol/L, accounting for 41.1% and 27.5% of events, respectively, reported Daniela Tomasoni, MD, of the University of Brescia in Italy, at the Heart Failure Society of America (HFSA) meeting.
Quality-of-life scores improved in patients with and without these safety indicator events, although those with events saw less gain, adjusted mean difference -3.32 points on visual analogue scale (VAS) scores from randomization to day 90 (95% CI -5.97 to -0.66).
Outcomes on the trial's primary endpoint of 180-day all-cause death or heart failure readmission came out similar between those with and without any safety event (15.0 vs 14.2%; HR 0.84, 95% CI 0.48-1.46).
"So the appearance in any safety indicator -- when addressed by appropriate guideline-recommended therapy dose adjustment -- was not associated with a greater risk of the combined primary point of all-cause death or heart failure hospitalization despite more severe heart failure at baseline," Tomasoni concluded.
Those frequent safety visits built into the protocol are key to making this work in the clinic, suggested HFSA session study discussant Zachary Cox, PharmD, of Vanderbilt University in Nashville, Tennessee.
"We're unable to reliably distinguish these patients based off their baseline characteristics," he said, pointing to the largely similar characteristics between groups who had safety issues and who did not.
"So when we incorporate more rapid sequence and simultaneous titration, it's really important that we include these safety monitoring visits that include very basic things -- vital signs, BNP, proBNP," he added.
Main results from the STRONG-HF trial showed a relative 34% decrease in 180-day heart failure readmission or death from any cause with the high-intensity medication management intervention compared with usual care (15.2% vs 23.3%; RR 0.66, 95% CI 0.50-0.86, P=0.0021). More overall adverse events were recorded in the group with more frequent healthcare visits, but serious and fatal events were similar between strategies.
Lynne Stevenson, MD, also of Vanderbilt, chalked the good results of the trial up to the careful approach. "In the treatment arm, they were checked so many times for safety, whereas in the control arm there was no consistent follow-up," she told MedPage Today. "The point of careful follow-up is that you pick these signs up early so that you can avert true safety issues. And I think the modest increases in NT-proBNP, I do not think were safety issues at all. I think they were likely the need to adjust diuretics, which is a very frequent problem early after discharge."
The trial included 1,078 adults admitted to 87 hospitals in 14 countries for acute heart failure that was not treated with full doses of guideline-directed drug treatment and who had an NT-proBNP level over 1,500 pg/mL.
It randomized patients to open-label usual care or a high-intensity arm, in which patients were prescribed half of the optimal dose of either an ACE inhibitor, angiotensin receptor blocker, or angiotensin receptor/neprilysin inhibitor (ARNI) along with a half dose of a beta-blocker and a half dose of a mineralocorticoid receptor antagonist. One week after discharge, they got a safety visit with a clinical exam and biomarker check on NT-proBNP, potassium, creatinine, and hemoglobin. Then the next week, the three drugs were uptitrated to full doses if there were no safety problems. Safety visits were also done at weeks 3 and 6. The trial used largely cardiologists and heart failure specialists to carry out the intervention.
Aside from hyperkalemia and natriuretic peptide increases, 5% of patients had an eGFR drop to less than 30 mL/min/1.73 m2, 9% had their heart rate drop below 55 bpm, and 9% had systolic blood pressure fall below 95 mm Hg.
The impact of these events on GDMT uptitration was significant: 70% of those with a proBNP increase didn't have uptitration of their beta-blocker whereas about 70% of those without an event did, and 80% of those with hyperkalemia didn't get uptitration of their renin-angiotensin-aldosterone system inhibitor compared with uptitration for 75% of those without an event.
"Patients with safety events during this should not be labeled as GDMT intolerant necessarily, but should instead identify patients in whom slower GDMT titration may be needed, as opposed to not moving any further," Cox argued.
Tomasoni agreed. In case of natriuretic peptide elevations, for example, she said: "We need to check for clinical signs of congestion. If clinical signs of congestion are present, I would suggest uptitrating loop diuretics. And as regard beta-blockers, it's true that an increase in NT-proBNP levels could be considered as an episode of worsening heart failure. But in our protocol ... we maintain beta-blockers. So it's important not to stop, not to down-titrate, but to slowly uptitrate."
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Disclosures
STRONG-HF was funded by Roche Diagnostics.
Tomasoni disclosed speaker fees from Boehringer Ingelheim, Alnylam Pharmaceuticals, and Pfizer.
Primary Source
Heart Failure Society of America
Tomasoni D "Safety indicators in patients receiving high-intensity care after acute heart failure admission: The STRONG-HF trial" HFSA 2023.