The effects of sodium–glucose cotransporter 2 inhibitors on the ‘forgotten’ right ventricle - Qu - 2025 - ESC Heart Failure
ESC Focused Update On HF Synthesizes New Trial Data For Practical Use
More than a dozen new RCTs dedicated to acute and chronic heart failure (HF) have come out over the course of just the past few years since the 2021 European Society of Cardiology (ESC) Guidelines on the topic—the time was ripe for a focused update, the writing committee said last week.
"We felt we had to do an update because heart failure is obviously a rapidly changing field," said guideline chair Theresa A. McDonagh, MD (King's College Hospital, London, England), who presented the latest recommendations in a Hot Line session at the ESC Congress 2023 in Amsterdam, the Netherlands.
The update, which featured advice for treatment and diagnosis, was simultaneously published in the European Heart Journal.
Among the influential trials up for consideration across the spectrum of acute HF, chronic HF, and comorbidities were ADVOR, COACH, DELIVER, EMPEROR-Preserved, EMPA-KIDNEY, IRONMAN, REVIVED-BCIS-2, and STRONG-HF.
"Obviously, the main new evidence we had to consider for chronic heart failure was the SGLT2 inhibitors dapagliflozin and empagliflozin," McDonagh said, "because both the EMPEROR-Preserved trial and the DELIVER trial met their primary endpoints with reduction in cardiovascular deaths or hospitalizations for heart failure by similar degree."
Based on that evidence, the guidelines now give both SGLT2 inhibitors a class IA indication for management of patients who have symptomatic HF with mildly reduced ejection fraction (HFmrEF) and those who have heart failure with preserved ejection (HFpEF).
In acute HF, the main change is the level of evidence for predischarge and early postdischarge follow-up of patients with a HF hospitalization. This upgrade is based on results of the STRONG-HF study, which showed a reduction in the rate of all-cause death or HF readmission with rapid uptitration to full doses of renin-angiotensin-aldosterone-system (RAAS) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists (MRAs) compared with usual care. The trial was stopped early due to a greater-than-expected benefit of the high-intensity management strategy.
"We added the recommendation, level of evidence B, class I, to have the initiation and the rapid uptitration of evidence-based treatment before discharge [then] doing frequent and careful follow-up visits in the first 6 weeks after the heart failure hospitalization," said McDonagh's co-chair, Marco Metra, MD (University of Brescia, Italy).
To TCTMD, Metra noted that it may be challenging to implement the frequency of follow-up visits in the real world as was done in STRONG-HF, with approximately four postdischarge visits in 6 weeks.
"Accordingly, we kept our recommendation more generic, stating that evidence-based treatment had to be initiated and titrated before discharge and during 'frequent and careful follow-up visits in the following 6 weeks,'" he said in an email.
Addressing Comorbidities, Pondering Iron
The committee also reviewed the EMPA-KIDNEY data, DAPA-CKD, and a meta-analysis on the effects of SGLT2 inhibitors on kidney outcomes. They give a class IA recommendation for dapagliflozin or empagliflozin in patients with type 2 diabetes and chronic kidney disease (CKD) to reduce the risk of HF hospitalization or CV death.
The CKD recommendation change applies to the use of finerenone, which is supported by data from FIDELIO-DKD, FIGARO-DKD, and a pooled analysis showing reductions for the MRA versus placebo on composite CV and HF hospitalization outcomes. On the basis of these data, finerenone also gets a class IA recommendation in patients with type 2 diabetes and CKD to reduce the risk of HF hospitalization.
The other comorbidities that the guidelines take aim at are anemia and iron deficiency in HF patients.
"We had the IRONMAN and four meta-analyses, all consistently showing a reduction in recurrent heart failure hospitalizations or cardiovascular death or total heart failure hospitalizations or cardiovascular death," Metra noted.
The committee gave a class IA recommendation to IV iron supplementation in symptomatic patients with HFrEF or HFmrEF to alleviate HF symptoms and improve quality of life. The other new recommendation is a class IIa, level of evidence A, "to treat iron deficiency with ferric carboxymaltose or ferric derisomaltose in patients with HFrEF or HFmrEF to reduce their risk of heart failure hospitalization," Metra added.
McDonagh noted that HEART-FID, which was just presented at ESC, may raise a question for some about the role of ferric carboxymaltose (FCM) in HFrEF. HEART-FID missed its primary endpoint, although a meta-analysis combining HEART-FID patients with those from CONFIRM-HF and AFFIRM-AHF, showed that FCM significantly reduced total cardiovascular hospitalizations and cardiovascular death compared with placebo (rate ratio 0.86; 95% CI 0.75-0.98).
In the guidelines session, McDonagh asked task force member Ewa A. Jankowska, MD (Wroclaw Medical University, Poland), if she thought the guideline committee "got it right" with regard to iron supplementation.
"I do believe that the totality of evidence is in favor of using this treatment and . . . Moreover, there are several cardiovascular avenues which require our attention in the context of intravenous therapy, like pulmonary hypertension and HFpEF, [and] like acute MI, so definitely this is the next stage regarding using intravenous iron in cardiology," Jankowska said.
Ferinject® Granted Upgraded Recommendations In 2023 ESC Heart Failure Guidelines
The 2023 European Society of Cardiology (ESC) guidelines for acute and chronic heart failure (HF) include upgraded recommendations for intravenous (IV) iron supplementation, including Ferinject® (ferric carboxymaltose), for the management of iron deficiency in patients with HF.
Phase IV HEART-FID study results and ferric carboxymaltose meta-analysis also presented at 2023 ESC Congress
ST. GALLEN, Switzerland, Aug. 28, 2023 /PRNewswire/ -- CSL Vifor is pleased to announce that the European Society of Cardiology (ESC) have upgraded recommendations in the ESC 2023 guidelines for the treatment of iron deficiency acute and chronic HF with IV iron supplementation, including Ferinject®.
The guidelines include higher level of recommendations and address a broader patient group for the management of iron deficiency in HF patients with compromised heart function (HFrEF and HFmrEF).
"We are pleased that ESC's new heart failure guidelines have been updated to reflect the latest scientific evidence," said Fabio Dorigotti, Head of Global Medical Affairs at CSL Vifor. "Improving iron deficiency diagnosis followed by IV iron supplementation based on the updated guidelines means more patients may potentially benefit from IV iron treatment. We are particularly pleased with the updated recommendations for IV iron including Ferinject® in the new 2023 focused update of the 2021 treatment guidelines. This revision will enable cardiologists and physicians to better treat more of the symptomatic heart failure patients with iron deficiency."
In addition, findings from the phase IV HEART-FID trial (NCT03037931) of ferric carboxymaltose were presented at the ESC congress 2023 in Amsterdam, Netherlands, and simultaneously published in the peer-reviewed medical journal New England Journal of Medicine.1 HEART-FID is the largest and longest duration trial to date evaluating IV iron in HF patients with reduced ejection fraction and iron deficiency.
The trial approached but did not meet the pre-specified statistical significance of p<0.01 on the primary endpoint, which was a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance (6-MWD). The results showed that with ferric carboxymaltose, there were numerically fewer deaths and hospitalizations for HF through 12 months and a modest benefit in the 6-MWD at 6 months compared to placebo. Ferric carboxymaltose was generally well tolerated and without unexpected safety findings.
"While the results from the HEART-FID study did not meet statistical significance at the pre-specified level, the totality of evidence with ferric carboxymaltose from prior studies assessing symptomatic and functional status endpoints – combined with recent clinical outcomes studies – show overall safety and potential benefits," said Robert Mentz, MD, Chief of the Heart Failure Section at Duke University Medical Center, Durham, US, and Clinical Lead for the trial.
To understand these new results in light of the totality of the evidence for IV iron in HF patients with iron deficiency, investigators also executed a pooled analysis using individual participant data from the three long-term trials FAIR-HF, CONFIRM-HF and HEART-FID of ferric carboxymaltose with a total of 4'501 patients. It represents the largest analysis to date to examine the effects of ferric carboxymaltose on clinical outcomes and was presented at the ESC congress 2023 with a parallel acceptance of the manuscript in the peer-reviewed European Heart Journal.2
Treatment with ferric carboxymaltose in iron-deficient HF patients with reduced or mildly reduced left ventricular ejection fraction was associated with a reduction in the composite endpoint of total cardiovascular hospitalizations and cardiovascular death compared with placebo, and with significantly reduced risks of hospitalization due to heart failure or cardiovascular causes, with no effect on survival.
"One in two patients with chronic HF has iron deficiency, with a significant number of patients not being diagnosed or inadequately treated for iron deficiency," commented Steve Pascoe, MD, Senior Vice President, Clinical and Therapeutic Area Strategy, CSL. "We are confident that the outcomes of this trial and the pooled analysis of ferric carboxymaltose are an important contribution to the growing body of evidence showcasing the advantages of IV iron treatment for HF patients."
About CSL Vifor
CSL Vifor is a global partner of choice for pharmaceuticals and innovative, leading therapies in iron deficiency and nephrology. We specialize in strategic global partnering, in-licensing and developing, manufacturing and marketing pharmaceutical products for precision healthcare, aiming to help patients around the world lead better, healthier lives. Headquartered in St. Gallen, Switzerland, CSL Vifor also includes the joint company Vifor Fresenius Medical Care Renal Pharma (with Fresenius Medical Care).
The parent company, CSL (ASX: CSL; USOTC: CSLLY), headquartered in Melbourne, Australia, employs 32,000 people and delivers its lifesaving therapies to people in more than 100 countries. For more information about CSL Vifor visit, www.Cslvifor.Com.
About the ESC guidelines
The ESC HF guidelines aim to provide practical, evidence-based recommendations for the diagnosis and treatment of HF, thereby improving and harmonizing standards of diagnosis and treatment of cardiovascular diseases for physicians, and potentially optimizing patient care. The ESC HF guidelines are updated periodically, with the 2023 version updated at the ESC congress end of August 2023.
About HEART-FID
HEART-FID is the first randomized clinical trial powered to evaluate the effects of intravenous ferric carboxymaltose on a hierarchical endpoint of death, heart failure hospitalizations, and functional status for adult patients with iron deficiency. The multicenter, randomized, double-blind, placebo-controlled trial enrolled 3,065 patients at 281 international centers. Eligible patients were at least 18 years old in stable chronic heart failure with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, iron deficiency (ferritin <100 ng/mL or ferritin 100–300 ng/mL with a transferrin saturation <20%), and documented heart failure hospitalization or elevated N-terminal pro-brain natriuretic peptide. The primary endpoint of the study was a hierarchical composite of death and heart failure hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance.
About the meta-analysis
The meta-analysis Impact of ferric carboxymaltose on heart failure-related clinical outcomes in patients with heart failure and iron deficiency: an individual participant data meta-analysis represents the largest pooled analysis to examine the effects of ferric carboxymaltose on clinical outcomes (hospitalizations and mortality) and the first to include the results of the HEART-FID trial. Patient-level data from the three randomized, placebo-controlled ferric carboxymaltose trials CONFIRM-HF, AFFIRM-AHF and HEART-FID with a total of 4'501 adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and composite of total HF hospitalizations and cardiovascular death. Both endpoints were examined through 52 weeks of follow-up and based on events adjudicated independently by blinded events committees. Key secondary endpoints included individual components of the composite endpoints.
About Ferinject®
Ferinject® (ferric carboxymaltose) is an IV iron therapy with market authorization in 86 countries by August 2023. It has a track record of delivering significant value to patients and healthcare systems which is based on extensive clinical data and more than 25 million patient years of exposure. Ferinject® is the most extensively studied IV iron.3
References:
1 Mentz RJ, Garg J, Rockhold FW, Butler J, De Pasquale CG, Ezekowitz JA, et al. Ferric carboxymaltose in heart failure with iron deficiency. N Engl J Med 2023 [published on-line] DOI: 10.1056/NEJMoa2304968.2 Ponikowski P, Mentz RJ, Hernandez AF, Butler J, Khan MZ, van Veldhuisen DJ, et al. Efficacy of Ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis. Eur Heart J 2023 [published on-line] DOI: 10.1093/eurheartj/ehad586.3 Data on file. Injectafer Studies. Daiichi Sankyo Inc., Basking Ridge, NJ.
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ENACT-HF: Natriuresis-Guided Diuretic Protocol Beats Usual Care
PRAGUE, Czechia—Current European Society of Cardiology (ESC) heart failure guidelines stipulate that a urinary sodium-guided approach is best for dosing diuretics in acute congestion, but many centers have continued to stick with their own protocols. Now a new study makes it clear: the ESC's stricter protocol, using a higher starting dose and an earlier check-in on sodium levels, leads to significantly better natriuresis within the first day as well as better natriuresis and diuresis after 2 days.
Moreover, said Jeroen Dauw, MD (AZ Sint-Lucas, Ghent, Belgium), who presented the ENACT-HF study at the ESC Heart Failure Congress 2023 earlier this week, "The protocol was safe and feasible in a wide variety of healthcare settings" and led to significantly shorter lengths of stay.
The diuretic recommendations in the ESC guidance stem from an earlier ESC/Heart Failure Association position statement on diuretics for acute decongestion based on consensus opinion protocol and not previously validated in a prior trial, Dauw noted during his presentation. As such, ENACT-HF is the first trial to show that this protocol "can be implemented: it is feasible, safe, and effective," he told TCTMD.
"I think we need more trials and longer follow-up. This is just the first piece of the puzzle, and there are a lot of trials coming up that will have more questions and answers about mortality and other endpoints," he acknowledged. But his prediction is that decongestion studies will never be able to demonstrate an effect on mortality.
"I don't think we should judge such trials on hard endpoints," he added. "I think if you get decongested better, if you get discharged from hospital sooner, I think that's a good [thing]."
Enacting ENACT-HF
ENACT-HF was a prospective, multicenter, open-label, nonrandomized, pragmatic trial that enrolled 401 patients at 29 centers across Europe, North Africa, Latin America, the Middle East, and South Asia. For the first phase of the trial, centers enrolled patients then treated them according to usual care at their center. For the second phase, all centers switched to follow the standardized protocol, which had been formalized still further for the sake of the study.
In the usual-care phase, which saw 254 patients enrolled, IV diuretic dosing and frequency were at the physician's discretion for the first 2 days, with a spot urine sample 2 hours after initiation and urine collection stopped on day 3.
During the standardized phase, which enrolled 147 patients, physicians were instructed to double the current "home dose" of oral diuretics at the outset of care, individualized to each patient, up to a maximum of 200 mg. "The first thing is beginning with a good dose. This is very important: a strong enough dose," said Dauw. "A lot of physicians are very reluctant to giving higher diuretic doses because they think they will have some kind of toxicity—ototoxicity or renal toxicity—which was not the case in the doses that we used."
Then after 6 hours in the standardized protocol, a urine analysis was mandated. If urine sodium was less than 50 mmol/L or urine output was < 100 mL/hour, then the IV loop diuretic dose was to be doubled and if levels were above these cut points, the original dose was to be repeated twice daily.
This, too, was key, Dauw explained, noting that a lot of centers start a continuous infusion and don't check for natriuresis and diuresis until the next day. In ENACT-HF, investigators gave the high bolus dose then checked to see if a second bolus was needed. "That's the most important thing in the guidelines is that you should have an early follow-up," he said.
If you get decongested better, if you get discharged from hospital sooner, I think that's a good [thing]. Jeroen Dauw
During the second "protocol" phase of ENACT-HF, rates of natriuresis after day 1 were higher than seen in the first phase (282 mmol vs 174 mmol; mean ratio [MR] 1.64; 95% CI 1.37-1.95).
By day 2, rates of natriuresis (MR 1.52; 95% CI 1.31-1.76) and diuresis (MR 1.33; 95% CI 1.21-1.47) were both significantly higher among the protocol-treated patients than in the usual-care group, with no differences seen across a range of subgroups. Hospital length-of-stay was more than a day shorter in the protocol patients than the usual-care patients: 5.8 days versus 7.0 days (MR 0.87; 95% CI 0.77-0.99).
Of note, two other secondary endpoints—weight loss and congestion score—were not significantly different between groups at 2 days, which Dauw believed is likely a reflection of the pragmatic nature of the trial. ENACT-HF was not powered to look at these endpoints and weight measurements were not standardized in the study protocol. Congestion score, too, would typically take a few more days for a difference show up, he hypothesized.
In terms of safety, there were no differences in markers of renal dysfunction, hypokalemia, or hypotension between the two treatment phases. Despite physician fears over the doubled bolus dose, mean furosemide equivalent dose in the trial was 60 mg.
Some Self-reflection
To TCTMD, Dauw said he hoped physicians will be inspired by this small study to take a closer look at their own habits.
"Everybody is very self-confident in what they are doing," he said. In part because these drugs have been in use so long, people tend to be using them the way they were trained to do, years ago, without actually measuring their practice or questioning their success. "If you already think you're doing a good job, you don't question yourself," Dauw added.
There's also the perception that the protocol itself is difficult, since it involves more checks and dosing than a continuous 24-hour infusion. On this point, Dauw pointed to the diverse range of countries and centers that participated and were able to implement the protocol and get results.
"Diuretics are one of the most-used drugs in cardiology in general, and yet a lot of people don't understand enough about how they work and don't understand enough of the pharmacokinetics and pharmacodynamics to understand how they can optimize their therapies," he said.
Nathan Mewton, MD, PhD (Hôpital Cardiovasculaire Louis Pradel, Lyon, France), commenting on ENACT-HF for TCTMD, agreed that too few physicians understand how to best dose, then evaluate, diuretics. The study had flaws, he noted, including its nonrandomized phase 1/phase 2 design and the lack of an impact seen on weight loss and decongestion scores. These last, he noted, might merely reflect the fact that the study was done on a shoestring budget, without a centralized research coordinator.
"ENACT is really interesting because it's a pragmatic study," said Mewton. "It's a study that was performed basically on the goodwill of investigators trying to make progress in the way they're managing decongestion therapy."
"For 20 years, we've been using diuretics like newbies, and not really managing decongestion as a practical target," he observed. That's changing with a range of trials like ADVOR, CARRESS-HF, and DOSE that are taking a range of different approaches to try to improve the care of acute decompensation patients.
"We're moving into a phase of being intelligent with furosemide and diversifying the ways of using diuretics," Mewton said.
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