Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial

Lin, Yani; Zhong, Xiangbin; Liu, Menghui; Zhang, Shaozhao; Xiong, Zhenyu; Huang, Yiquan; Fan, Yun; Xu, Xin; Guo, Yang; Li, Yuqi; Sun, Xiaochuan; Zhou, Huanjiao Jenny; Yang, Dongzi; Ye, Xiaomin; Liao, Xinxue; Zhuang, Xiaodong

doi:10.1007/s10557-021-07178-y

Cited by 3 publications

(5 citation statements)

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“…26 Recently, Lin et al developed a risk score scheme with five risk predictors for the prediction of cardiovascular death and found that only the patients at very high risk of CV death benefited a lot from spironolactone treatment. 10 Nevertheless, few studies have used the machine learning algorithm to evaluate subgroup treatment effects for spironolactone therapy in patients with HFpEF. Furthermore, few studies have found HFpEF populations in which treatment with spironolactone was instead detrimental.…”

Section: Discussionmentioning

confidence: 99%

“…9 Based on the distinct baseline risks, patients at very high risk benefit substantially from spironolactone medication. 10 So it is critical and urgent to identify those patients with HFpEF who might be beneficial or harmful from spironolactone medication.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the clinical phenotypes, a post hoc analysis of the TOPCAT trial found that patients with HFpEF responded differently to spironolactone administration 9 . Based on the distinct baseline risks, patients at very high risk benefit substantially from spironolactone medication 10 . So it is critical and urgent to identify those patients with HFpEF who might be beneficial or harmful from spironolactone medication.…”

Section: Introductionmentioning

confidence: 99%

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Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

et al. 2022

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Aims We aimed to explore the heterogeneous treatment effects (HTEs) for spironolactone treatment in patients with Heart failure with preserved ejection fraction (HFpEF) and examine the efficacy and safety of spironolactone medication, ensuring a better individualized therapy. Methods and results We used the causal forest algorithm to discover the heterogeneous treatment effects (HTEs) from patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Cox regressions were performed to assess the hazard ratios (HRs) of spironolactone medication for cardiovascular death and drug discontinuation in each group. The causal forest model revealed three representative covariates and participants were partitioned into four subgroups which were Group 1 (baseline BMI ≤ 31.71 kg/m 2 and baseline ALP ≤ 80 U/L, n = 759); Group 2 (BMI ≤ 31.71 kg/m 2 and ALP > 80 U/L, n = 1088); Group 3 (BMI > 31.71 kg/m 2 , and WBC ≤ 6.6 cells/μL, n = 633); Group 4 (BMI > 31.71 kg/m 2 and WBC > 6.6 cells/μL, n = 832), respectively. In the four subgroups, spironolactone therapy reduced the risk of cardiovascular death in high‐risk group (Group 4) with both high BMI and WBC count (HR: 0.76; 95% CI 0.58 to 0.99; P = 0.045) but increased the risk in low‐risk group (Group 1) with both low BMI and ALP (HR: 1.45; 95% CI 1.02 to 2.07; P = 0.041; P for interaction = 0.020) but showed similar risk of drug discontinuation ( P for interaction = 0.498). Conclusion Our study manifested the HTEs of spironolactone in patients with HFpEF. Spironolactone treatment in HFpEF patients is feasible and effective in patients with high BMI and WBC while harmful in patients with low BMI and ALP. Machine learning model could be meaningful for improved categorization of patients with HFpEF, ensuring a better individualized therapy in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

et al. 2022

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“…Because of their limited applicability to human HFpEF, it is perhaps not surprising that therapeutic agents which were effective in these preclinical models often failed in clinical trials. A few unsuccessful attempts include angiotensin-converting enzyme inhibitors, angiotensin receptor one blockers and mineralocorticoid receptor antagonists (Khan et al, 2017;Lin et al, 2022) as well as nitric oxide donors and cyclic guanosine monophosphate stimulating therapies (Redfield et al, 2013;Komajda et al, 2017;Borlaug et al, 2018), and angiotensin receptor-neprilysin inhibitiors (Solomon et al, 2020;Wachter et al, 2020). Thus, pre-clinical models with single stressor may not represent a reliable platform for bench-to-bedside transition.…”

Section: Single Stressor Modelsmentioning

confidence: 99%

Modeling heart failure with preserved ejection fraction in rodents: Where do we stand?

Chou

Chin

2022

Front. Drug. Discov.

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Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.

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“…Spironolactone (SPL) is a poorly water-soluble (BCS II) aldosterone antagonist that possesses diuretic and antihypertensive effects. , To the best of our knowledge, there are no related reports on AA/SPL coamorphous systems. Therefore, this research aims to clarify the necessary conditions for the formation of AA/SPL coamorphous systems and explore the amorphization kinetics of AA/SPL coamorphous systems during the preparation process.…”

Section: Introductionmentioning

confidence: 99%

Co-Former Selection for Coamorphous Amino Acid/Spironolactone Formulations and Exploration of the Amorphization Kinetics of Systems

Jin

Han

et al. 2023

Crystal Growth & Design

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Spironolactone (SPL) has low bioavailability due to its poor solubility. Preparing amino acid (AA)/SPL coamorphous systems is one of the effective ways to overcome this disadvantage. In this study, mixtures of SPL and 10 different AAs were prepared by the ball milling method. Solid-state characterization revealed that only L-phenylalanine (PHE) and L-tryptophan (TRP) could successfully form a homogeneous coamorphous system with SPL. In addition, we investigated the formation of AA/spironolactone (SPL) coamorphous systems and successfully defined two reliable parameter indicators of formation: the difference in octanol−water partition coefficient (Δ log P) < 4.5 and a negative mixing enthalpy (ΔH mix ) value. The results of the amorphization kinetics showed that the AAs with low lattice energy amorphized first, whereas the SPL (201) crystal plane, possessing the highest crystal face energy of 1.89 × 10 −5 kcal/m 2 , disappeared at last in the process of ball milling. Stability experimental data showed that the TRP/SPL coamorphous system possesses better physical stability than the PHE/SPL coamorphous system, which was due to the higher hydrogen bond binding energy (−11.67 kcal/mol) of the TRP/SPL coamorphous system. Finally, powder dissolution experiments of the coamorphous systems indicated that the TRP/SPL coamorphous system exhibited a threefold improvement in dissolution rate compared to pure crystalline drug SPL.

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Risk Stratification and Efficacy of Spironolactone in Patients with Heart Failure with Preserved Ejection Fraction: Secondary Analysis of the TOPCAT Randomized Clinical Trial

Cited by 3 publications

References 25 publications

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

Targeting efficacy of spironolactone in patients with heart failure with preserved ejection fraction: the TOPCAT study

Modeling heart failure with preserved ejection fraction in rodents: Where do we stand?

Co-Former Selection for Coamorphous Amino Acid/Spironolactone Formulations and Exploration of the Amorphization Kinetics of Systems

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