LBS 06: Medical therapy for heart failure
Myeloperoxidase inhibitor, Sacubitril-Valsartan, standard loop diuretic and sodium zirconium cyclosilicate and spironolactone.
Trial results highlight a new approach for cardioprotection during chemotherapy, a novel nasal spray for potentially managing edema and ENDEAVOR and REALIZE K trials. Monday’s Late-Breaking Science Session: Building on the Four Pillars: Novel Trials of Medical Therapy for Heart Failure, found that:
- Myeloperoxidase inhibitor did not provide relief for patients with heart failure with preserved ejection fraction.
- Sacubitril-Valsartan shows cardioprotective benefit in high-risk patients undergoing chemotherapy.
- A novel nasal spray form of a standard loop diuretic shows clinical benefit in healthy subjects.
- Sodium zirconium cyclosilicate and spironolactone show clinical benefit in patients with HFrEF and hyperkalemia.
Myeloperoxidase inhibitor did not improve heart failure symptoms
The primary endpoints were change in KCCQ-TSS and 6MWD from baseline to 16 weeks. An analysis of covariance model was used to estimate treatment effects of mitipersant versus placebo. A composite cardiovascular endpoint of heart failure hospitalization, myocardial infarction or death during 48 weeks of treatment was an exploratory endpoint.
Overall, mitiperstat was safe, with few serious adverse events, but it did not improve symptoms or exercise function over 16 weeks in patients with HFpEF. “But mitiperstat did result in reduced heart failure hospitalization,” said Sanjiv Shah, MD, principal investigator and director of research for the Bluhm Cardiovascular Institute at Northwestern Feinberg School of Medicine in Chicago. Shah noted that the potential beneficial longer-term effect of mitiperstat on reducing heart failure hospitalization and death requires further investigation. 
Sanjiv Shah, MD
Sacubitril-Valsartan offers cardioprotection in high-risk patients undergoing chemotherapy
Anthracycline, a class of potent chemotherapy drugs commonly used to treat breast cancer, leukemia, lymphoma and sarcoma, is associated with significant cardiotoxic effects, potentially leading to cardiac failure and interruption of chemotherapy. Could Sacubitril-Valsartan, a well-established heart failure medication, prevent heart damage in high-risk patients undergoing anthracycline chemotherapy? That’s the question asked in Effects of Sacubitril-Valsartan on Prevention of Cardiotoxicity in High-Risk Patients Undergoing Anthracycline Chemotherapy: A Double-Blind Randomized Placebo-Controlled Clinical Trial (SARAH Trial).
In the single-center, double-blind study, 114 patients at high risk of developing cardiac dysfunction marked by elevated troponin levels were randomly assigned to Sacubitril-Valsartan, 97/103 BID or placebo. Of study participants, 90% were women and 92% had breast cancer. Over six months of follow-up, patients underwent clinical assessments that included biomarker measurements and cardiac evaluations through echocardiography and cardiac magnetic resonance imaging.
Sacubitril-Valsartan significantly lowered the risk of cardiac damage caused by anthracycline chemotherapy in high-risk patients. The primary endpoint, the rate of cardiotoxicity, was 25% in the placebo group compared to 7.1% in patients receiving Sacubitril-Valsartan, representing a 77% risk reduction. Patients taking Sacubitril-Valsartan had better cardiac function and improved heart structure, compared to the placebo group. Additionally, fewer patients in the Sacubitril-Valsartan group completed the study with ventricular dysfunction compared to those in the placebo group. There were no serious adverse events or an increased need to interrupt treatment compared to the placebo group.
Marcely Bonatto, MD
“These results suggest that Sacubitril-Valsartan could be a safe and effective way to protect the heart in patients undergoing anthracycline treatment,” said Marcely Bonatto, MD, the study’s principal investigator and a cardiologist with the Heart Institute of Medical University of Sao Paulo in Brazil. “By selecting only patients with elevated troponin levels, we identified those at high risk for cardiotoxicity and therefore, a greater likelihood of progression of the cardiotoxicity process.”
“Overall, Sacubitril-Valsartan for preventing cardiotoxicity associated with anthracycline chemotherapy offers an important option for protecting cancer patients during treatment who are identified early to be at high risk for heart dysfunction,” Bonatto said. “This targeted and proactive strategy not only helps identify who stands to benefit from cardioprotective measures but allows patients to continue their cancer treatment with less worry about potential heart-related side effects,” Bonatto said.
A standard loop diuretic as a nasal spray shows promise for managing edema
A novel intranasal formulation of bumetanide, a standard loop diuretic to treat patients with heart failure and other conditions associated with edema, achieved plasma drug blood concentrations similar to oral administration of the drug and at faster absorption rate when tested in healthy subjects, according to Novel Bumetanide Nasal Spray Demonstrates Safety, Tolerability and Equivalent Efficacy Compared to Intravenous and Oral Bumetanide.
“The nasal spray form of bumetanide may be a new self-administered option for patients who require decongestion from edema associated with congestive heart failure and liver disease, particularly when they are unable to take their oral medications or their oral medications are no longer working,” said Daniel R. Bensimhon, MD, the study’s lead researcher and medical director of the advanced heart failure/mechanical circulatory support program at Cone Health in Greensboro, North Carolina.
Daniel R. Bensimhon, MD
The trial enrolled 68 healthy diverse patients ages 18 to 55 from December 2023 to April 2024 who were administered bumetanide via the nasal, oral and IV routes, with blood concentrations, absorption time and urine output carefully monitored in-house for 10 days for each dosing strategy. Plasma drug concentrations of intranasal bumetanide were similar to concentrations achieved with the oral route of administration of the drug. Intrasubject variability in absorption was >40% for the oral drug compared to 27% for both the intranasal and IV routes, suggesting that both IV and intranasal were more stable routes of dosing, even in healthy subjects, Bensimhon said. When compared to oral administration, intranasal bumetanide achieved maximum plasma concentration 33% faster, with a minimum time to maximum drug concentration of 14 minutes compared to 30 minutes for oral dosage of the drug. Urine output was approximately six liters across the three administrations of the drug. Bensimhon noted that bumetanide nasal spray was safe and well tolerated. “In patients with heart failure, oral medications are often least effective when the body needs them most due to diuretic resistance,” he said. “Having a diuretic that does not rely on gut absorption or intravenous administration may be a very important tool to help patients with heart failure and other conditions, especially underserved patient populations and those in rural areas where access to acute care facilities and IV medications is difficult or impossible.”
Subsequent studies will evaluate the variability of absorption and clinical effectiveness of the different formulations of bumetanide in heart failure patients with volume overload.
The study is scheduled to be published in Circulation.
Sodium zirconium cyclosilicate enables optimal use of spironolactone in patients with HFrEF and hyperkalemia
Mineralocorticoid receptor antagonists (MRA), such as spironolactone, reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Still, MRAs are underused due, in part, to hyperkalemia. Sodium zirconium cyclosilicate (SZC), an orally administered potassium binder, effectively enables the optimal use of spironolactone in high-risk patients with HFrEF, according to Sodium Zirconium Cyclosilicate and MRA Optimization in Heart Failure with Reduced Ejection Fraction and Hyperkalemia (REALIZE-K Trial).
The prospective, double-blind, randomized-withdrawal trial assigned 203 patients with symptomatic HFrEF, optimal guideline-directed therapy except the use of a MRA and prevalent or incident MRA-induced hyperkalemia to SZC or placebo (SZC 102, placebo 101). During the open-label run-in phase, patients had spironolactone titration, with a target dose of 50 mg/daily. Patients with prevalent or incident hyperkalemia started SZC. Those with normokalemia (potassium 3.5–5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for six months. The primary endpoint was optimal treatment response: normokalemia on spironolactone ≥25 mg/daily and without rescue therapy for hyperkalemia during months one to six. 
Mikhail Kosiborod, MD, FACC, FAHA
Overall, 71.2% of SZC-treated patients versus 35.7% of placebo-treated participants had optimal treatment response (OR 4.45 [95% CI 2.89–6.86]; p<0.001). SZC versus placebo also improved the first four key secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR 4.58 [2.78–7.55]; p<0.001), receiving spironolactone ≥25 mg/daily (81% vs 50%; OR 4.33 [2.50–7.52]; p<0.001), time to hyperkalemia (HR 0.51 [0.37–0.71]; p<0.001), and time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37 [0.17–0.73]; p=0.006). There was no between-group difference in the fifth secondary endpoint – Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 6 months (-1.01 points [-6.64–4.63]; p=0.72).
Adverse and serious adverse events were balanced between SZC and placebo, respectively. More participants had an adjudicated heart failure event with SZC 10 (10%) than placebo 2 (2%). In post-hoc analysis, this difference appeared to be mostly centered among participants with baseline N-terminal pro b-type natriuretic peptide >4000 pg/ml (7 vs. 1 with SZC vs. placebo).
“The REALIZE-K trial demonstrates, for the first time, that SZC effectively enables more optimal use of MRA in patients with HFrEF who would otherwise not be candidates for the therapy due to hyperkalemia,” said Mikhail Kosiborod, MD, FACC, FAHA, a cardiologist at Saint Luke's Mid America Heart Institute in Kansas City, the study’s principal investigator. “Although underpowered for clinical outcomes, more participants had heart failure events with SZC than placebo despite the more optimal use of spironolactone. From a clinical standpoint, our findings suggest that a balance between the efficacy of a higher use of MRA and the potential for fluid retention of SZC therapy should be considered as a part of clinical decision making.”
The study was published simultaneously in the Journal of the American College of Cardiology.
