Next Article in Journal
Mapping District-Level Asbestos Exposure Risk in Java, Indonesia: Integrating Infrastructure, Demographics, and Seismic Vulnerability
Previous Article in Journal
Self-Compassion and Eco-Anxiety: Examining Their Relationship in a Greek Sample
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJERPH
Volume 23
Issue 9
10.3390/ijerph23091130
ijerph-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Efficacy and Safety of Oral Creatine Supplementation in Patients with Heart Failure: A PRISMA 2020 Systematic Review and Narrative Evidence Synthesis

by
Francisco Epelde
1,2,3,4,* and
María Pilar Martínez López
3
1
Internal Medicine Department, Parc Taulí Hospital Universitari, 08208 Sabadell, Spain
2
Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), 08208 Sabadell, Spain
3
Department of Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
4
APTIMA Centre Clinic, Mutua de Terrassa, 08221 Terrassa, Spain
*
Author to whom correspondence should be addressed.
Int. J. Environ. Res. Public Health 2026, 23(9), 1130; https://doi.org/10.3390/ijerph23091130
Submission received: 15 July 2026 / Revised: 25 August 2026 / Accepted: 28 August 2026 / Published: 30 August 2026
(This article belongs to the Section Infectious Diseases, Chronic Diseases, and Disease Prevention)
Browse Figures
Versions Notes

Highlights

Public health relevance—How does this work relate to a public health issue?
  • Heart failure is frequently accompanied by exercise intolerance, skeletal-muscle dysfunction, and impaired quality of life; accessible adjunctive strategies that target peripheral muscle function are therefore of potential public health interest.
  • Oral creatine is inexpensive and widely available, making a rigorous appraisal of its benefits and safety important to prevent unsupported use in a clinically vulnerable population.
Public health significance—Why is this work of significance to public health?
  • Four randomized heart-failure-only trials form the primary causal evidence base; one additional heart-failure open-label study is retained as exploratory evidence, while mixed-population or mechanistic reports are discussed only as external context.
  • Current evidence does not show a consistent benefit for peak oxygen uptake, 6-min walk distance, quality of life, cardiac systolic function, hospitalization, or mortality; certainty is very low across the evaluated critical outcomes.
Public health implications—What are the key implications or messages for practitioners, policy makers and/or researchers in public health?
  • Oral creatine should currently be regarded as an investigational adjunct rather than standard evidence-based therapy for heart failure.
  • Future trials should be adequately powered, double-blind, and placebo-controlled; include patients receiving contemporary guideline-directed therapy; and prioritize patient-centered functional outcomes, together with systematic renal and adverse-event surveillance.

Abstract

Background: Oral creatine is biologically plausible as an adjunct in heart failure (HF), but its clinical efficacy and safety remain uncertain. Methods: We performed a PRISMA 2020 systematic review (PROSPERO CRD420261391605) of oral creatine supplementation in adults with HF. Randomized parallel-group and crossover trials formed the primary causal evidence base; non-randomized HF evidence was analyzed separately. Risk of bias was assessed with RoB 2 and certainty with GRADE. Results: Four randomized HF-only trials were identified as primary evidence, with one additional open-label HF study retained as exploratory evidence. Because studies differed in dose, duration, outcome definitions, measurement scales, crossover structure, and availability of variance data, meta-analysis was not considered defensible. Randomized evidence showed no consistent benefit for peak VO2, 6-min walk distance, quality of life, or cardiac systolic function. A preliminary signal was observed for selected peripheral muscle and muscle-energetic outcomes. Safety reporting was sparse and insufficient to establish long-term renal or clinical safety. Certainty was very low across critical outcomes. Conclusions: Current evidence does not support routine oral creatine supplementation in HF. Larger contemporary placebo-controlled trials with systematic safety surveillance are required.

Graphical Abstract

1. Introduction

Heart failure is a major clinical syndrome associated with recurrent hospitalization, impaired survival, reduced health-related quality of life, and progressive limitation in physical function [1,2,3,4]. Contemporary management includes guideline-directed pharmacological therapy, device therapy when indicated, multidisciplinary follow-up, and structured exercise-based rehabilitation [1,2,3,5,6,7,8]. Despite these advances, many patients continue to experience fatigue, dyspnea, muscle weakness, and reduced exercise tolerance [9,10].
Exercise intolerance in heart failure is not explained solely by cardiac systolic function or resting hemodynamics [10]. Peripheral mechanisms, including skeletal-muscle atrophy, impaired oxidative metabolism, mitochondrial dysfunction, abnormal fiber-type distribution, endothelial dysfunction, inflammation, and reduced muscle strength, contribute substantially to symptoms and functional limitation [9,10,11,12,13,14,15,16,17,18,19,20,21,22]. This peripheral component has been conceptualized as the muscle hypothesis of chronic heart failure and provides a rationale for interventions targeting skeletal-muscle metabolism [14,15].
Creatine is a naturally occurring compound synthesized from arginine, glycine, and methionine and also obtained from the diet [23]. It is stored predominantly in skeletal muscle and participates in rapid adenosine triphosphate buffering through the creatine kinase/phosphocreatine system [23,24,25,26,27]. Oral creatine monohydrate has been extensively studied in exercise physiology, aging, and rehabilitation, where it can improve muscle strength, lean tissue mass, and performance in selected settings [28,29,30,31,32,33,34,35,36]. In heart failure, abnormalities in cardiac and skeletal-muscle energetics provide a biologically plausible rationale for oral creatine supplementation [9,10,11,12,13,37,38,39,40,41,42]. Nutritional and nutraceutical interventions have also been investigated in heart failure, although effects are heterogeneous and often condition- or nutrient-specific [43,44,45,46,47].
Clinical evidence in heart failure remains sparse and mixed. Early placebo-controlled studies suggested that oral creatine may increase skeletal-muscle phosphocreatine availability and improve selected muscle performance or endurance measures [48,49]. Other studies have not consistently shown improvements in integrated functional-capacity outcomes such as peak oxygen uptake or 6-min walk distance [50,51]. Recent open-label data in heart failure with reduced ejection fraction suggest possible improvements in functional capacity and quality of life, but the absence of randomized placebo control limits causal inference [52].
Previous evidence syntheses of creatine-related interventions in cardiovascular disease, including the earlier Cochrane review by Horjus et al. [53], considered broader cardiovascular populations and heterogeneous creatine-related compounds and routes. The present review differs by focusing specifically on adults with heart failure, restricting the intervention to oral creatine, separating randomized causal evidence from exploratory non-randomized evidence, and updating the literature through May 2026. Intravenous phosphocreatine and creatine phosphate sodium were excluded because their route of administration, pharmacokinetics, clinical context, and therapeutic intent differ substantially from oral creatine supplementation.

2. Materials and Methods

This PRISMA 2020 systematic review was conducted in accordance with the PRISMA 2020 statement, the Cochrane Handbook for Systematic Reviews of Interventions, and PRISMA-S reporting guidance for literature searches [54,55,56,57]. The review protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews; registration number CRD420261391605). The review question, eligibility criteria, outcomes, and synthesis plan were defined before final screening and extraction. Study selection, data extraction, and risk-of-bias assessment were undertaken independently by both authors, Francisco Epelde and María Pilar Martínez López, who contributed complementary clinical and methodological expertise. Disagreements were resolved by consensus; when agreement was not reached initially, the prespecified eligibility criteria and full-text source were rechecked before a final decision was recorded.
Eligible studies included adults aged 18 years or older with heart failure, including heart failure with reduced, mildly reduced, or preserved ejection fraction, or investigator-defined chronic congestive heart failure. The eligible intervention was oral creatine supplementation, including creatine monohydrate and dietary oral creatine supplementation. Studies in which creatine was combined with exercise training were eligible only when the comparator group received the same exercise intervention without creatine.
The primary outcome was functional capacity, prioritized as 6-min walk distance, peak oxygen uptake, exercise duration, maximal workload, or other validated exercise-performance measures [58,59,60,61,62]. Secondary outcomes included skeletal-muscle strength and endurance, muscle metabolic indices, health-related quality of life, New York Heart Association functional class, left ventricular ejection fraction, natriuretic peptides, renal safety, adverse events, treatment discontinuation, hospitalization, and mortality. The PICOS eligibility criteria are summarized in Table 1.
Randomized parallel-group and crossover trials in heart-failure-only populations formed the primary causal evidence base. A non-randomized HF study could be retained as exploratory evidence only if the population had HF, the oral-creatine exposure was identifiable, and at least one prespecified efficacy or safety outcome was reported. Mixed cardiac-rehabilitation cohorts without an extractable HF subgroup and mechanistic studies reporting only non-prespecified biomarker outcomes were not counted as included studies; when clinically informative, they were cited only as external contextual literature. This rule was applied consistently to Cornelissen et al. [63] and Hemati et al. [64], which are therefore not included in the formal qualitative synthesis.
MEDLINE/PubMed, Embase, Cochrane CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and WHO ICTRP were searched from 1 January 1985 through 1 May 2026. The lower date limit was prespecified because the review targeted the modern era of oral creatine supplementation and was intended to reduce retrieval of older parenteral phosphocreatine literature representing a clinically distinct intervention; we acknowledge that a database-inception search would be methodologically preferable and identify this restriction as a limitation. No language restrictions were applied. Reference lists of included studies and relevant reviews were screened. Backward and forward citation tracking used the four primary HF oral-creatine trials (Gordon et al. [48], Andrews et al. [49], Kuethe et al. [50], and Carvalho et al. [51]) and the earlier Cochrane review by Horjus et al. [53] as seed reports. The database/source, complete search strategies, search dates, and source-specific yields are provided in Supplementary Table S1. Duplicate records were identified by bibliographic-field matching (author, title, publication year, and DOI when available) followed by manual verification. No automated screening tool or dedicated statistical software was used because no quantitative meta-analysis was performed. The search strategy did not undergo formal peer review.
Both authors independently screened titles and abstracts, retrieved potentially eligible full texts, extracted data using a piloted extraction form, and assessed risk of bias at the outcome level. Any differences were resolved through discussion and consensus. Cochrane RoB 2 [65] was used for parallel-group randomized trials, and its crossover-trial variant was applied to the crossover study by Kuethe et al. [50]. The crossover assessment explicitly considered period effects, carry-over effects, and whether the reported washout period was sufficient to minimize residual exposure. The washout was judged biologically plausible for reducing carry-over, although residual carry-over could not be completely excluded because period-specific paired estimates and formal carry-over testing were not fully reported. Crossover-specific period and carry-over considerations were recorded separately in the outcome-level risk-of-bias assessment. Certainty of evidence for critical and important outcomes was assessed using GRADE [66]. Randomized evidence started at high certainty and was downgraded, where applicable, for risk of bias, inconsistency, indirectness, imprecision, and publication bias. When confidence intervals or paired variance estimates were not reported or derivable, they were not imputed; imprecision judgments instead considered the number of participants and events, attrition, available effect ranges, and whether clinically important benefit or no benefit remained plausible. Non-randomized exploratory evidence was kept separate and was not used to increase certainty for causal treatment effects.
A formal meta-analysis was planned only when at least two randomized studies were sufficiently comparable in population, intervention, comparator, outcome definition, time point, and effect measure and when usable variance data were available. Pooling was not performed. For functional capacity, peak VO2 and 6-min walk distance were reported across different trial structures and time points, and the crossover study lacked sufficiently detailed paired variance estimates for robust combination with parallel-group trials. Muscle outcomes used non-equivalent constructs and scales (knee-extensor endurance, peak torque, handgrip endurance, and sphygmomanometer-based strength). Quality-of-life data were sparse and derived from different designs, while cardiac and safety outcomes were incompletely and inconsistently reported. Differences in creatine dose (5–20 g/day), duration (5 days to 6 months), crossover design, outcome measurement, and unavailable variance data therefore precluded defensible quantitative pooling.
For the narrative synthesis, outcomes were grouped into functional capacity, peripheral muscle/energetics, health-related quality of life, cardiac function, renal/safety outcomes, and clinical events. Randomized between-group comparisons at the end of the assigned treatment period were prioritized for causal interpretation. When several measures or time points were available, the clinically prespecified endpoint and the latest assessment within the randomized treatment period were used; crossover findings were interpreted using treatment-period comparisons when reported. Effect direction, magnitude, uncertainty, attrition, and consistency across randomized studies were considered together rather than using statistical significance as a vote-counting rule. For transparent reporting, a domain was labelled directionally consistent only when at least two randomized studies pointed in the same direction without a clearly contradictory randomized result in that domain; otherwise, it was described as neutral/inconsistent. Non-randomized findings were labelled exploratory or hypothesis-generating and were not combined analytically with randomized effects.
The database/source, complete search strategies, search dates, and source-specific yields are provided in Supplementary Table S1. The aggregate counts used in the PRISMA flow diagram were checked against the final search exports and screening log before resubmission. The PRISMA flow diagram reports the number of reports excluded after full-text assessment and the principal reasons for exclusion. Reports that could reasonably appear to meet the eligibility criteria are identified individually in the Results, together with the specific reason for exclusion, consistent with PRISMA 2020 item 16b.

3. Results

The search identified 184 records from databases and 12 records from other sources. After removal of 63 duplicates, 133 records were screened; 91 were excluded, 42 reports were sought for retrieval, and 40 full-text reports were assessed. After consistent application of the formal eligibility rule, 35 full-text reports were excluded, and five studies were retained in the systematic review: four randomized HF-only oral-creatine trials formed the primary causal evidence base, and one open-label HFrEF study was retained as exploratory evidence. Cornelissen et al. [63] (mixed cardiac-rehabilitation cohort without an extractable HF-specific effect) and Hemati et al. [64] (HF trial reporting mechanistic biomarkers outside the prespecified efficacy/safety domains) are discussed only as external contextual literature and are not counted among included studies.
Figure 1 summarizes the revised workflow, including the principal full-text exclusion categories and counts (total n = 35), and explicitly separates the four randomized primary studies from the single exploratory open-label HF study. Reports cited only as external context are not counted as included studies.
Four randomized heart-failure-only oral-creatine studies constituted the primary evidence base: Gordon et al., Andrews et al., Kuethe et al., and Carvalho et al. [48,49,50,51]. López-Clemente et al. was retained separately as exploratory open-label HF evidence [52]. Cornelissen et al. and Hemati et al. were removed from the formal included-study count and are used only to contextualize exercise-training and mechanistic literature [63,64]. Fumagalli et al. remained excluded because coenzyme Q10 and creatine were co-administered, preventing isolation of the creatine effect [67]. The characteristics of the five studies retained in the formal systematic review are summarized in Table 2, and study-level outcomes, attrition, safety findings, and interpretation are summarized in Table 3.
Randomized evidence did not demonstrate a consistent improvement in global functional capacity. Kuethe et al. randomized 20 patients (13 completed both crossover periods). Among completers, peak VO2 was 16.0 ± 4.2 mL/kg/min after placebo and 14.8 ± 3.4 mL/kg/min after creatine, while 6-min walk distance was 604 ± 103 m after placebo and 597 ± 125 m after creatine; no treatment benefit was demonstrated for peak VO2, VO2 at the anaerobic threshold, 6MWT, the Borg score, or MLHFQ, despite improved muscle strength [50]. Carvalho et al. randomized 33 men with NYHA class II–IV HF (17 creatine, 16 placebo) to 5 g/day for 6 months. The adjusted between-group difference was 0.30 mL/kg/min for peak VO2 (95% CI −3.47 to 4.08; p = 0.8708) and 25.29 m for 6MWT (95% CI −19.33 to 69.92; p = 0.2563), with no significant between-group benefit in anaerobic threshold or oxygen pulse [51]. The open-label HFrEF pilot reported within-group functional improvement, but this was treated as hypothesis-generating and was not used to infer a causal treatment effect [52].
The most reproducible preliminary signal concerned peripheral muscle or muscle-energetic outcomes, although the studies were small and used non-equivalent measures. In Gordon et al. (n = 17), creatine 20 g/day for 10 days increased skeletal-muscle total creatine by 17 ± 4% and phosphocreatine by 12 ± 4%, with improvements in one-leg endurance (21%), two-leg performance (10%), and peak torque (5%) versus placebo (all reported p < 0.05) [48]. Andrews et al. (n = 20) found an increase in contractions to exhaustion at 75% maximum voluntary contraction from a median of 8 (IQR 6–14) to 14 (IQR 8–17), p = 0.025, together with lower ammonia per contraction [49]. Kuethe et al. reported improved muscle strength after creatine but no corresponding improvement in integrated exercise capacity [50]. These findings support only a preliminary peripheral-muscle signal rather than a proven patient-centered benefit.
Health-related quality-of-life evidence was sparse. Kuethe et al. found no randomized benefit in Minnesota Living with Heart Failure Questionnaire scores [50]. The open-label HFrEF pilot reported a statistically significant HRQoL improvement, but the absence of blinding and a randomized control group makes this finding hypothesis-generating rather than confirmatory [52].
Available evidence does not suggest a consistent direct effect of oral creatine on cardiac systolic function. Gordon et al. did not show improvement in the ejection fraction, and Kuethe et al. reported no significant improvement in the ejection fraction or left ventricular end-diastolic diameter [48,50].
Safety evidence is limited by small samples, short follow-up, attrition, and inconsistent event reporting. The randomized trials were not powered for renal failure, HF hospitalization, or mortality, and an outcome that was not reported was not interpreted as evidence that no event occurred. In Kuethe et al., 7 of 20 participants discontinued before completing both crossover periods (3 while receiving creatine and 4 while receiving placebo); reported reasons included one death, one acute HF decompensation, one newly diagnosed breast cancer, one intercurrent cold, and three withdrawals without a stated reason. One participant reported transient mild gastric pain during creatine intake; the report did not permit assignment of the death or decompensation to a specific treatment period [50]. In Carvalho et al., adjusted serum creatinine at 6 months was 1.31 mg/dL (95% CI of 1.21–1.42) with creatine and 1.20 mg/dL (95% CI of 1.09–1.31) with placebo (p = 0.1499), with no significant between-group difference in urea [51]. The open-label HFrEF pilot reported a transient increase in serum creatinine and a decline in the estimated glomerular filtration rate at 3 months, with normalization after creatine discontinuation and no observed change in HF decompensations or mortality during follow-up [52]. Because creatinine is a metabolite of creatine, supplementation-related increases in creatinine generation should be distinguished from proven renal injury [23,28,68]. More specific renal monitoring strategies, such as cystatin C-based filtration estimates, are broader clinical considerations supported by external literature rather than findings established by the included HF trials. Long-term renal and clinical safety therefore remains uncertain. The outcome-level evidence map and pooling decisions are summarized in Table 4, and the GRADE summary of findings for critical outcomes is presented in Table 5.
Forest plots are not presented because eligible randomized studies were too few and too clinically and methodologically heterogeneous to support a defensible pooled estimate. The review is therefore reported as a systematic review with narrative evidence synthesis rather than as a completed meta-analysis. A qualitative evidence map of the formal HF evidence base is provided in Figure 2.
This visual summary separates functional capacity, muscle outcomes, quality of life, cardiac function, and safety to avoid inappropriate pooling of heterogeneous endpoints.
RoB 2 judgments are shown in Table 6. The principal concerns were incomplete reporting of randomization/allocation procedures in older trials, incomplete outcome reporting, and substantial attrition plus crossover-specific reporting limitations in Kuethe et al. [50]. For Kuethe et al. [50], the additional period/carry-over domain was judged as some concerns because the reported washout was biologically plausible, but period-specific paired estimates and formal carry-over testing were incompletely reported. The accessible report did not support defensible outcome-specific differentiation of this crossover-domain judgment; the same judgment was therefore applied across the principal outcome domains listed in Table 6. The overall RoB 2 judgment remained high, driven mainly by substantial attrition (13/20 completed both periods). These judgments informed the GRADE downgrades but were not applied to contextual/non-randomized evidence as if it were randomized causal evidence. Study-level safety reporting is summarized separately in Table 7.

4. Discussion

This review shows that the clinical evidence for oral creatine supplementation in heart failure is limited, heterogeneous, and based mainly on small studies. The most coherent, although still preliminary, signal concerns skeletal-muscle energetics and muscle performance. In contrast, randomized evidence does not demonstrate a consistent improvement in integrated functional-capacity outcomes such as 6-min walk distance or peak oxygen uptake.
The biological rationale for oral creatine in heart failure is plausible. Creatine supports rapid ATP regeneration through the creatine kinase/phosphocreatine system [23,24,25,26,27]. Heart failure is associated with altered energy metabolism and skeletal-muscle abnormalities, including reduced oxidative capacity, mitochondrial dysfunction, muscle wasting, and early fatigability [9,10,11,12,13,14,15,16,37,38,39,40,41,42]. Oral creatine could improve the ability of skeletal muscle to buffer ATP demand during repeated contractions [24,25,26,27,28].
A central interpretive issue is the distinction between muscle-specific endpoints and integrated whole-body functional outcomes. Muscle-specific tests may be more sensitive to creatine because creatine directly affects rapid energy buffering during repeated or high-intensity contractions. In contrast, 6-min walk distance and peak oxygen uptake integrate cardiac output reserve, pulmonary function, vascular regulation, chronotropic response, skeletal-muscle oxidative capacity, renal function, anemia, frailty, comorbidities, motivation, and measurement variability.
Safety conclusions necessarily remain cautious. Creatine has been widely studied outside HF, but patients with HF are clinically vulnerable because of older age, renal dysfunction, congestion risk, diuretic exposure, neurohormonal therapy, and multimorbidity. Serum creatinine should not be interpreted in isolation during creatine supplementation because creatinine generation may increase without a true reduction in filtration. When renal safety is uncertain, alternative filtration markers may be considered as part of broader clinical assessment; however, this monitoring approach is not directly validated by the included HF trials.
A major limitation is external validity. Most randomized trials predate contemporary guideline-directed HF therapy, including angiotensin receptor–neprilysin inhibition and SGLT2 inhibitors [69,70,71,72,73], and they provide limited information on current patients with multimorbidity, chronic kidney disease, frailty, sarcopenia, or intensive diuretic exposure. Contemporary treatment changes baseline risk, renal physiology, exercise capacity, and competing causes of functional limitation; therefore, efficacy and safety estimates from these older small trials cannot be assumed to apply directly to present-day HFrEF, HFmrEF, or HFpEF populations.
Current evidence is insufficient to recommend routine oral creatine supplementation as a standard heart-failure therapy. Future trials should be randomized, double-blind, placebo-controlled, adequately powered, and conducted in contemporary heart-failure populations receiving guideline-directed therapy. They should pre-specify clinically meaningful functional and patient-reported outcomes, report age, frailty, renal function, comorbidity burden, and background heart-failure therapy in detail, and include systematic renal and adverse-event surveillance.

5. Limitations

This review has several limitations. First, the number of eligible randomized studies was small, limiting statistical power, precision, and assessment of publication bias. Second, trials varied in creatine dose, duration, design, comparator, and outcome selection. Third, older studies may have incompletely reported randomization, allocation concealment, adherence, missing data, and prespecified outcomes. Fourth, crossover trials may lack paired variance estimates and may be vulnerable to carry-over or period effects if washout is inadequate. Fifth, participant-level data on age, frailty, renal function, background guideline-directed medical therapy, and comorbidity burden were inconsistently reported, limiting subgroup interpretation and applicability to older, multimorbid heart-failure populations.
Several clinically relevant studies were not eligible for the primary causal synthesis because they involved mixed cardiac populations, active cointerventions, combination supplements without an isolatable creatine effect, or open-label single-arm designs. In particular, the study of coenzyme Q10 terclatrate plus creatine by Fumagalli et al. was treated as contextual literature rather than as an included oral-creatine study because a creatine-only effect could not be isolated [67]. Small sample sizes and short follow-up periods limited conclusions about renal safety, heart-failure hospitalization, and mortality.
Finally, this review focuses strictly on oral creatine supplementation. This improves clinical homogeneity, but the conclusions should not be generalized to intravenous phosphocreatine, creatine phosphate sodium, perioperative metabolic therapy, or other parenteral creatine-related interventions.

6. Conclusions

Oral creatine supplementation in heart failure has a plausible mechanistic rationale and shows only a preliminary signal for improvement in selected peripheral skeletal-muscle and muscle-energetics outcomes. The small randomized evidence base does not demonstrate a consistent, clinically meaningful benefit for global functional capacity, HRQoL, cardiac function, hospitalization, or mortality. Safety evidence is sparse and does not establish long-term renal or clinical safety.
Oral creatine should therefore remain an investigational adjunct rather than routine evidence-based HF therapy pending adequately powered contemporary randomized placebo-controlled trials.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijerph23091130/s1, Table S1: Database/source, complete search strategies, search dates, and source-specific yields; Table S2: Completed PRISMA 2020 Checklist [54].

Author Contributions

F.E.: Conceptualization, methodology, search strategy, evidence synthesis, writing—original draft, writing—review and editing, and supervision. M.P.M.L.: Methodology, study selection, data extraction, risk-of-bias assessment, validation, and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

This systematic review is based on data reported in the published studies cited in the manuscript. The study-level data supporting the reported synthesis are summarized in the article and its tables. The review protocol is registered in PROSPERO (CRD420261391605), and the database/source, complete search strategies, search dates, and source-specific yields are provided in Supplementary Table S1. No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2021, 42, 3599–3726. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  2. McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2023, 44, 3627–3639. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  3. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J. Am. Coll. Cardiol. 2022, 79, e263–e421. [Google Scholar] [CrossRef] [Scilit]
  4. Bozkurt, B.; Coats, A.J.; Tsutsui, H.; Abdelhamid, M.; Adamopoulos, S.; Albert, N.; Anker, S.D.; Atherton, J.; Böhm, M.; Butler, J.; et al. Universal definition and classification of heart failure. J. Card. Fail. 2021, 27, 387–413. [Google Scholar] [CrossRef] [Scilit]
  5. O’cOnnor, C.M.; Whellan, D.J.; Lee, K.L.; Keteyian, S.J.; Cooper, L.S.; Ellis, S.J.; Leifer, E.S.; Kraus, W.E.; Kitzman, D.W.; Blumenthal, J.A.; et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009, 301, 1439–1450. [Google Scholar] [CrossRef] [Scilit]
  6. Flynn, K.E.; Piña, I.L.; Whellan, D.J.; Lin, L.; Blumenthal, J.A.; Ellis, S.J.; Fine, L.J.; Howlett, J.G.; Keteyian, S.J.; Kitzman, D.W.; et al. Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA 2009, 301, 1451–1459. [Google Scholar] [CrossRef] [Scilit]
  7. Taylor, R.S.; Long, L.; Mordi, I.R.; Madsen, M.T.; Davies, E.J.; Dalal, H.; Rees, K.; Singh, S.J.; Gluud, C.; Zwisler, A.-D. Exercise-based rehabilitation for heart failure: Cochrane systematic review, meta-analysis, and trial sequential analysis. JACC Heart Fail. 2019, 7, 691–705. [Google Scholar] [CrossRef] [Scilit]
  8. Sagar, V.A.; Davies, E.J.; Briscoe, S.; Coats, A.J.S.; Dalal, H.M.; Lough, F.; Rees, K.; Singh, S.; Taylor, R.S. Exercise-based rehabilitation for heart failure: Systematic review and meta-analysis. Open Heart 2015, 2, e000163. [Google Scholar] [CrossRef] [Scilit]
  9. Kinugawa, S.; Takada, S.; Matsushima, S.; Okita, K.; Tsutsui, H. Skeletal muscle abnormalities in heart failure. Int. Heart J. 2015, 56, 475–484. [Google Scholar] [CrossRef] [Scilit]
  10. Del Buono, M.G.; Arena, R.; Borlaug, B.A.; Carbone, S.; Canada, J.M.; Kirkman, D.L.; Garten, R.; Rodriguez-Miguelez, P.; Guazzi, M.; Lavie, C.J.; et al. Exercise intolerance in patients with heart failure: JACC state-of-the-art review. J. Am. Coll. Cardiol. 2019, 73, 2209–2225. [Google Scholar] [CrossRef] [Scilit]
  11. Springer, J.; Springer, J.I.; Anker, S.D. Muscle wasting and sarcopenia in heart failure and beyond: Update 2017. ESC Heart Fail. 2017, 4, 492–498. [Google Scholar] [CrossRef] [Scilit]
  12. Bielecka-Dabrowa, A.; Ebner, N.; dos Santos, M.R.; Ishida, J.; Hasenfuss, G.; von Haehling, S. Cachexia, muscle wasting, and frailty in cardiovascular disease. Eur. J. Heart Fail. 2020, 22, 2314–2326. [Google Scholar] [CrossRef] [Scilit]
  13. Takada, S.; Hirabayashi, K.; Kinugawa, S. Treatments for skeletal muscle abnormalities in heart failure. Am. J. Physiol. Heart Circ. Physiol. 2022, 322, H563–H575. [Google Scholar] [CrossRef] [Scilit]
  14. Coats, A.J.; Clark, A.L.; Piepoli, M.; Volterrani, M.; Poole-Wilson, P.A. Symptoms and quality of life in heart failure: The muscle hypothesis. Br. Heart J. 1994, 72, S36–S39. [Google Scholar] [CrossRef] [Scilit]
  15. Coats, A.J. The muscle hypothesis of chronic heart failure. J. Mol. Cell. Cardiol. 1996, 28, 2255–2262. [Google Scholar] [CrossRef] [Scilit]
  16. Mancini, D.M.; Walter, G.; Reichek, N.; Lenkinski, R.; McCully, K.K.; Mullen, J.L.; Wilson, J.R. Contribution of skeletal muscle atrophy to exercise intolerance and altered muscle metabolism in heart failure. Circulation 1992, 85, 1364–1373. [Google Scholar] [CrossRef] [Scilit]
  17. Curcio, F.; Testa, G.; Liguori, I.; Papillo, M.; Flocco, V.; Panicara, V.; Galizia, G.; Della-Morte, D.; Gargiulo, G.; Cacciatore, F.; et al. Sarcopenia and heart failure. Nutrients 2020, 12, 211. [Google Scholar] [CrossRef] [Scilit]
  18. Prokopidis, K.; Isanejad, M.; Akpan, A.; Stefil, M.; Tajik, B.; Giannos, P.; Venturelli, M.; Sankaranarayanan, R. Exercise and nutritional interventions on sarcopenia and frailty in heart failure: A narrative review of systematic reviews and meta-analyses. ESC Heart Fail. 2022, 9, 2787–2803. [Google Scholar] [CrossRef] [Scilit]
  19. Anker, S.D.; Ponikowski, P.; Varney, S.; Chua, T.P.; Clark, A.L.; Webb-Peploe, K.M.; Harrington, D.; Kox, W.J.; Poole-Wilson, P.A.; Coats, A.J. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997, 349, 1050–1053. [Google Scholar] [CrossRef] [Scilit]
  20. von Haehling, S.; Ebner, N.; dos Santos, M.R.; Springer, J.; Anker, S.D. Muscle wasting and cachexia in heart failure: Mechanisms and therapies. Nat. Rev. Cardiol. 2017, 14, 323–341. [Google Scholar] [CrossRef] [Scilit]
  21. von Haehling, S. Muscle wasting and sarcopenia in heart failure: A brief overview of the current literature. ESC Heart Fail. 2018, 5, 1074–1082. [Google Scholar] [CrossRef] [Scilit]
  22. Valentova, M.; von Haehling, S.; Anker, S.D. Cardiac cachexia revisited: The role of wasting in heart failure. Heart Fail. Clin. 2020, 16, 61–69. [Google Scholar] [CrossRef] [Scilit]
  23. Wyss, M.; Kaddurah-Daouk, R. Creatine and creatinine metabolism. Physiol. Rev. 2000, 80, 1107–1213. [Google Scholar] [CrossRef] [Scilit]
  24. Harris, R.C.; Söderlund, K.; Hultman, E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci. 1992, 83, 367–374. [Google Scholar] [CrossRef] [Scilit]
  25. Greenhaff, P.L.; Bodin, K.; Söderlund, K.; Hultman, E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am. J. Physiol. 1994, 266, E725–E730. [Google Scholar] [CrossRef] [Scilit]
  26. Sahlin, K.; Harris, R.C. The creatine kinase reaction: A simple reaction with functional complexity. Amino Acids 2011, 40, 1363–1367. [Google Scholar] [CrossRef] [Scilit]
  27. Wallimann, T.; Tokarska-Schlattner, M.; Schlattner, U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 2011, 40, 1271–1296. [Google Scholar] [CrossRef] [Scilit]
  28. Kreider, R.B.; Kalman, D.S.; Antonio, J.; Ziegenfuss, T.N.; Wildman, R.; Collins, R.; Candow, D.G.; Kleiner, S.M.; Almada, A.L.; Lopez, H.L. International Society of Sports Nutrition position stand: Safety and efficacy of creatine supplementation in exercise, sport, and medicine. J. Int. Soc. Sports Nutr. 2017, 14, 18. [Google Scholar] [CrossRef] [Scilit]
  29. Devries, M.C.; Phillips, S.M. Creatine supplementation during resistance training in older adults-a meta-analysis. Med. Sci. Sports Exerc. 2014, 46, 1194–1203. [Google Scholar] [CrossRef] [Scilit]
  30. Lanhers, C.; Pereira, B.; Naughton, G.; Trousselard, M.; Lesage, F.X.; Dutheil, F. Creatine supplementation and lower limb strength performance: A systematic review and meta-analyses. Sports Med. 2015, 45, 1285–1294. [Google Scholar] [CrossRef] [Scilit]
  31. Lanhers, C.; Pereira, B.; Naughton, G.; Trousselard, M.; Lesage, F.X.; Dutheil, F. Creatine supplementation and upper limb strength performance: A systematic review and meta-analysis. Sports Med. 2017, 47, 163–173. [Google Scholar] [CrossRef] [Scilit]
  32. Chilibeck, P.D.; Kaviani, M.; Candow, D.G.; Zello, G.A. Effect of creatine supplementation during resistance training on lean tissue mass and muscular strength in older adults: A meta-analysis. Open Access J. Sports Med. 2017, 8, 213–226. [Google Scholar] [CrossRef] [Scilit]
  33. Harmon, K.K.; Stout, J.R.; Fukuda, D.H.; Pabian, P.S.; Rawson, E.S.; Stock, M.S. The application of creatine supplementation in medical rehabilitation. Nutrients 2021, 13, 1825. [Google Scholar] [CrossRef] [Scilit]
  34. Candow, D.G.; Forbes, S.C.; Kirk, B.; Duque, G. Current evidence and possible future applications of creatine supplementation for older adults. Nutrients 2021, 13, 745. [Google Scholar] [CrossRef] [Scilit]
  35. Kreider, R.B.; Stout, J.R. Creatine in health and disease. Nutrients 2021, 13, 447. [Google Scholar] [CrossRef] [Scilit]
  36. Wilkinson, T.J.; Lemmey, A.B.; Jones, J.G.; Sheikh, F.; Ahmad, Y.A.; Chitale, S.; Maddison, P.J.; O’BRien, T.D. Can creatine supplementation improve body composition and objective physical function in rheumatoid arthritis patients? A randomized controlled trial. Arthritis Care Res. 2016, 68, 729–737. [Google Scholar] [CrossRef] [Scilit]
  37. Balestrino, M. Role of creatine in the heart: Health and disease. Nutrients 2021, 13, 1215. [Google Scholar] [CrossRef] [Scilit]
  38. Del Franco, A.; Ambrosio, G.; Baroncelli, L.; Pizzorusso, T.; Barison, A.; Olivotto, I.; Recchia, F.A.; Lombardi, C.M.; Metra, M.; Chen, Y.F.F.; et al. Creatine deficiency and heart failure. Heart Fail. Rev. 2022, 27, 1605–1616. [Google Scholar] [CrossRef] [Scilit]
  39. Neubauer, S. The failing heart—An engine out of fuel. N. Engl. J. Med. 2007, 356, 1140–1151. [Google Scholar] [CrossRef] [Scilit]
  40. Nascimben, L.; Ingwall, J.S.; Pauletto, P.; Friedrich, J.; Gwathmey, J.K.; Saks, V.; Pessina, A.C.; Allen, P. Creatine kinase system in failing and nonfailing human myocardium. Circulation 1996, 94, 1894–1901. [Google Scholar] [CrossRef] [Scilit]
  41. Neubauer, S.; Horn, M.; Cramer, M.; Harre, K.; Newell, J.B.; Peters, W.; Pabst, T.; Ertl, G.; Hahn, D.; Ingwall, J.S.; et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997, 96, 2190–2196. [Google Scholar] [CrossRef] [Scilit]
  42. Ingwall, J.S. Energy metabolism in heart failure and remodelling. Cardiovasc. Res. 2009, 81, 412–419. [Google Scholar] [CrossRef] [Scilit]
  43. Abshire, M.; Xu, J.; Baptiste, D.; Almansa, J.R.; Xu, J.; Cummings, A.; Andrews, M.J.; Himmelfarb, C.D. Nutritional interventions in heart failure: A systematic review of the literature. J. Card. Fail. 2015, 21, 989–999. [Google Scholar] [CrossRef] [Scilit]
  44. Sciatti, E.; Lombardi, C.; Ravera, A.; Vizzardi, E.; Bonadei, I.; Carubelli, V.; Gorga, E.; Metra, M. Nutritional deficiency in patients with heart failure. Nutrients 2016, 8, 442. [Google Scholar] [CrossRef] [Scilit]
  45. McKeag, N.A.; McKinley, M.C.; Harbinson, M.T.; Noad, R.L.; Dixon, L.H.; McGinty, A.; Neville, C.E.; Woodside, J.V.; McKeown, P.P. The effect of multiple micronutrient supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: A randomized, placebo controlled trial. JACC Heart Fail. 2014, 2, 308–317. [Google Scholar] [CrossRef] [Scilit]
  46. Jain, A.; Mehta, R.; Al-Ani, M.; Hill, J.A.; Winchester, D.E. Determining the role of thiamine deficiency in systolic heart failure: A meta-analysis and systematic review. J. Card. Fail. 2015, 21, 1000–1007. [Google Scholar] [CrossRef] [Scilit]
  47. Mortensen, S.A.; Rosenfeldt, F.; Kumar, A.; Dolliner, P.; Filipiak, K.J.; Pella, D.; Alehagen, U.; Steurer, G.; Littarru, G.P.; Q-SYMBIO Study Investigators. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: Results from Q-SYMBIO: A randomized double-blind trial. JACC Heart Fail. 2014, 2, 641–649. [Google Scholar] [CrossRef] [Scilit]
  48. Gordon, A.; Hultman, E.; Kaijser, L.; Kristjansson, S.; Rolf, C.J.; Nyquist, O.; Sylven, C. Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance. Cardiovasc. Res. 1995, 30, 413–418. [Google Scholar] [CrossRef] [Scilit]
  49. Andrews, R.; Greenhaff, P.; Curtis, S.; Perry, A.; Cowley, A.J. The effect of dietary creatine supplementation on skeletal muscle metabolism in congestive heart failure. Eur. Heart J. 1998, 19, 617–622. [Google Scholar] [CrossRef] [Scilit][Green Version]
  50. Kuethe, F.; Krack, A.; Richartz, B.M.; Figulla, H.R. Creatine supplementation improves muscle strength in patients with congestive heart failure. Pharmazie 2006, 61, 218–222. [Google Scholar] [PubMed]
  51. Carvalho, A.P.P.F.; Rassi, S.; Fontana, K.E.; Correa, K.S.; Feitosa, R.H.F. Influence of creatine supplementation on the functional capacity of patients with heart failure. Arq. Bras. Cardiol. 2012, 99, 623–629. [Google Scholar] [CrossRef] [Scilit]
  52. López-Clemente, J.C.; Fuertes-Kenneally, L.; Huerta, J.A.; Arcos, F.S.; González-López, J.; Lozano, R.M.; Moreno, J.A.C. Efficacy and safety of creatine supplementation in patients with heart failure and reduced ejection fraction: A pilot study. REC Cardio Clin. 2025, 60, 76–86. [Google Scholar] [CrossRef] [Scilit]
  53. Horjus, D.L.; Oudman, I.; van Montfrans, G.A.; Brewster, L.M. Creatine and creatine analogues in hypertension and cardiovascular disease. Cochrane Database Syst. Rev. 2011, 2011, CD005184. [Google Scholar] [CrossRef] [Scilit]
  54. Page, M.J.; McKenzie, J.E.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021, 372, n71. [Google Scholar] [CrossRef] [Scilit]
  55. Page, M.J.; Moher, D.; Bossuyt, P.M.; Boutron, I.; Hoffmann, T.C.; Mulrow, C.D.; Shamseer, L.; Tetzlaff, J.M.; Akl, E.A.; Brennan, S.E.; et al. PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews. BMJ 2021, 372, n160. [Google Scholar] [CrossRef]
  56. Higgins, J.P.T.; Thomas, J.; Chandler, J.; Cumpston, M.; Li, T.; Page, M.J.; Welch, V.A. (Eds.) Cochrane Handbook for Systematic Reviews of Interventions; Version 6.5; Cochrane: London, UK, 2024; Available online: https://training.cochrane.org/handbook (accessed on 27 August 2026).
  57. Rethlefsen, M.L.; Kirtley, S.; Waffenschmidt, S.; Ayala, A.P.; Moher, D.; Page, M.J.; Koffel, J.B.; PRISMA-S Group. PRISMA-S: An extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews. Syst. Rev. 2021, 10, 39. [Google Scholar] [CrossRef] [Scilit]
  58. Guyatt, G.H.; Sullivan, M.J.; Thompson, P.J.; Fallen, E.L.; Pugsley, S.O.; Taylor, D.W.; Berman, L.B. The 6-minute walk: A new measure of exercise capacity in patients with chronic heart failure. Can. Med. Assoc. J. 1985, 132, 919–923. [Google Scholar] [PubMed]
  59. Bittner, V.; Weiner, D.H.; Yusuf, S.; Rogers, W.J.; McIntyre, K.M.; Bangdiwala, S.I.; Kronenberg, M.W.; Kostis, J.B.; Kohn, R.M.; Guillotte, M.; et al. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 1993, 270, 1702–1707. [Google Scholar] [CrossRef] [Scilit]
  60. Täger, T.; Hanholz, W.; Cebola, R.; Fröhlich, H.; Franke, J.; Doesch, A.; Katus, H.A.; Wians, F.H., Jr.; Frankenstein, L. Minimal important difference for 6-minute walk test distances among patients with chronic heart failure. Int. J. Cardiol. 2014, 176, 94–98. [Google Scholar] [CrossRef] [Scilit]
  61. Green, C.P.; Porter, C.B.; Bresnahan, D.R.; Spertus, J.A. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: A new health status measure for heart failure. J. Am. Coll. Cardiol. 2000, 35, 1245–1255. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  62. Spertus, J.A.; Jones, P.G.; Sandhu, A.T.; Arnold, S.V. Interpreting the Kansas City Cardiomyopathy Questionnaire in clinical trials and clinical care: JACC state-of-the-art review. J. Am. Coll. Cardiol. 2020, 76, 2379–2390. [Google Scholar] [CrossRef] [Scilit]
  63. Cornelissen, V.; Defoor, J.; Stevens, A.; Schepers, D.; Hespel, P.; Decramer, M.; Mortelmans, L.; Dobbels, F.; Vanhaecke, J.; Fagard, R.; et al. Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: A randomized controlled trial. Clin. Rehabil. 2010, 24, 988–999. [Google Scholar] [CrossRef] [Scilit]
  64. Hemati, F.; Rahmani, A.; Asadollahi, K.; Soleimannejad, K.; Khalighi, Z. Effects of complementary creatine monohydrate and physical training on inflammatory and endothelial dysfunction markers among heart failure patients. Asian J. Sports Med. 2016, 7, e28578. [Google Scholar] [CrossRef] [Scilit]
  65. Sterne, J.A.C.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.Y.; Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019, 366, l4898. [Google Scholar] [CrossRef] [Scilit]
  66. Guyatt, G.H.; Oxman, A.D.; Vist, G.E.; Kunz, R.; Falck-Ytter, Y.; Alonso-Coello, P.; Schünemann, H.J. GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008, 336, 924–926. [Google Scholar] [CrossRef] [Scilit]
  67. Fumagalli, S.; Fattirolli, F.; Guarducci, L.; Cellai, T.; Baldasseroni, S.; Tarantini, F.; Di Bari, M.; Masotti, G.; Marchionni, N. Coenzyme Q10 terclatrate and creatine in chronic heart failure: A randomized, placebo-controlled, double-blind study. Clin. Cardiol. 2011, 34, 211–217. [Google Scholar] [CrossRef] [Scilit]
  68. Longobardi, I.; Gualano, B.; Seguro, A.C.; Roschel, H. Is it time for a requiem for creatine supplementation-induced kidney failure? A narrative review. Nutrients 2023, 15, 1466. [Google Scholar] [CrossRef] [Scilit]
  69. McMurray, J.J.V.; Packer, M.; Desai, A.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.L.; Shi, V.C.; Solomon, S.D.; Swedberg, K.; et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med. 2014, 371, 993–1004. [Google Scholar] [CrossRef] [Scilit]
  70. McMurray, J.J.V.; Solomon, S.D.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Anand, I.S.; Bělohlávek, J.; et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 2019, 381, 1995–2008. [Google Scholar] [CrossRef] [Scilit]
  71. Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 2020, 383, 1413–1424. [Google Scholar] [CrossRef] [Scilit]
  72. Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Bocchi, E.; Böhm, M.; Brunner–La Rocca, H.-P.; Choi, D.-J.; Chopra, V.; Chuquiure-Valenzuela, E.; et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 2021, 385, 1451–1461. [Google Scholar] [CrossRef] [Scilit] [PubMed]
  73. Solomon, S.D.; McMurray, J.J.; Claggett, B.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.; Martinez, F.; et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. 2022, 387, 1089–1098. [Google Scholar] [CrossRef] [Scilit] [PubMed]
Ijerph 23 01130 g001
Figure 1. PRISMA 2020 flow diagram.
Figure 1. PRISMA 2020 flow diagram.
Ijerph 23 01130 g001
Ijerph 23 01130 g002
Figure 2. Qualitative evidence map restricted to the formal HF evidence base, based on Gordon et al. [48], Andrews et al. [49], Kuethe et al. [50], Carvalho et al. [51], and López-Clemente et al. [52]. Randomized causal evidence and exploratory non-randomized evidence are visually separated; “NR” indicates not reported.
Figure 2. Qualitative evidence map restricted to the formal HF evidence base, based on Gordon et al. [48], Andrews et al. [49], Kuethe et al. [50], Carvalho et al. [51], and López-Clemente et al. [52]. Randomized causal evidence and exploratory non-randomized evidence are visually separated; “NR” indicates not reported.
Ijerph 23 01130 g002
Table 1. PICOS eligibility criteria.
Table 1. PICOS eligibility criteria.
DomainInclusionExclusion
PopulationAdults with chronic heart failure, including HFrEF, HFmrEF, HFpEF, or investigator-defined congestive heart failureNon-heart-failure populations without extractable HF data; animal or in vitro studies
InterventionOral creatine supplementation, preferably creatine monohydrateIntravenous phosphocreatine, creatine phosphate sodium, and parenteral creatine-related compounds
ComparatorPlacebo, usual care, same exercise intervention without creatine, or non-creatine controlNo comparator for primary causal synthesis; non-isolatable active cointervention excluded from included evidence base
OutcomesFunctional capacity, muscle strength/endurance, quality of life, cardiac function, renal safety, adverse events, hospitalization, and mortalityStudies without extractable efficacy or safety outcomes
Study designRandomized parallel-group or crossover trials for primary synthesis; selected non-randomized studies for narrative contextCase reports, reviews, editorials, and non-clinical studies
Table 2. Characteristics of studies included in the formal systematic review.
Table 2. Characteristics of studies included in the formal systematic review.
StudyDesign/nPopulation and Key Clinical DescriptorsRegimenComparatorRole
Gordon 1995 [48]Double-blind placebo-controlled; n = 17Chronic HF; age, 43–70 years; LVEF < 40%; sex, NYHA class, background HF therapy, and funding not reported in the accessible abstract/extraction20 g/day; 10 daysPlaceboPrimary RCT
Andrews 1998 [49]Randomized placebo-controlled; n = 20Chronic HF; age, sex distribution, NYHA class, LVEF, background HF therapy, and funding not reported in the accessible abstract/extraction20 g/day; 5 daysPlaceboPrimary RCT
Kuethe 2006 [50]Double-blind crossover RCT; n = 20; 13 completersCHF > 6 months; mean age, 59.5 years; 5 women/15 men; NYHA II (n = 12) or III (n = 8); LVEF 27.5 ± 10.2%; stable HF medication ≥ 3 months20 g/day; 6 weeks/periodPlaceboPrimary RCT
Carvalho 2012 [51]Randomized double-blind; n = 33 (17/16)Men; NYHA II–IV; age 51.7 ± 10.5 years (creatine) vs. 59.9 ± 10.0 (placebo); LVEF 32.3 ± 13.6% vs. 35.1 ± 14.8%; common therapy included ACE inhibitors, diuretics, digitalis, and beta-blockers; no external funding5 g/day; 6 monthsMaltodextrinPrimary RCT
López-Clemente 2025 [52]Prospective single-center open-label pilot; n = 43HFrEF; mean age, 60.73 ± 11.73 years; 30.43% women; exact baseline LVEF, NYHA distribution, background HF therapy, and funding not reported in the accessible abstract/extraction5 g/day; 3 months; clinical follow-up to 1 yearNo
randomized control		Exploratory HF evidence
Table 3. Study-level outcomes, attrition, and interpretation in the formal systematic review.
Table 3. Study-level outcomes, attrition, and interpretation in the formal systematic review.
StudyKey Outcome DataSafety, Attrition, and Interpretation
Gordon 1995 [48]Total muscle creatine +17 ± 4%; phosphocreatine +12 ± 4%; one-leg endurance +21%; two-leg performance +10%; peak torque +5%; ejection fraction unchanged.Adverse-event and clinical-event reporting was limited. Preliminary peripheral muscle/energetic signal; randomized; 10-day intervention.
Andrews 1998 [49]Contractions to exhaustion at 75% MVC increased from median 8 (IQR 6–14) to 14 (IQR 8–17), p = 0.025; ammonia per contraction decreased.Adverse-event reporting was limited. Muscle-endurance/metabolic signal; randomized; 5-day intervention.
Kuethe 2006 [50]Peak VO2 16.0 ± 4.2 with placebo vs. 14.8 ± 3.4 with creatine; 6MWT 604 ± 103 vs. 597 ± 125 m; elbow-flexor strength 88.3 ± 11.9 vs. 112.5 ± 14.8 mmHg (p < 0.05).13/20 completed both periods; 7/20 discontinued (3 during creatine and 4 during placebo). One death and one acute HF decompensation occurred among withdrawals, but treatment-period attribution was not reported. One participant reported transient mild gastric pain during creatine intake. Muscle-strength signal without global functional benefit; crossover RCT; paired-variance/carry-over reporting incomplete.
Carvalho 2012 [51]Peak VO2 between-group difference 0.30 mL/kg/min (95% CI −3.47 to 4.08); 6MWT difference 25.29 m (95% CI −19.33 to 69.92); no benefit in AT or O2 pulse.Creatinine 1.31 mg/dL (95% CI 1.21–1.42) vs. 1.20 (1.09–1.31), p = 0.1499; no urea difference. Neutral functional-capacity result; randomized; 6-month intervention.
López-Clemente 2025 [52]6MWT +48.69 ± 32.76 m (p = 0.005); HRQoL +4.08 ± 12.29 points (p = 0.03); no echocardiographic change.Transient creatinine increase/eGFR decline normalized after discontinuation; no observed change in HF decompensation or mortality at follow-up. Hypothesis-generating exploratory open-label evidence only.
Abbreviations: 6MWT, 6-min walk test; AT, anaerobic threshold; eGFR, estimated glomerular filtration rate; HF, heart failure; HRQoL, health-related quality of life; IQR, interquartile range; MVC, maximum voluntary contraction; VO2, oxygen uptake.
Table 4. Outcome-level evidence map and pooling decision.
Table 4. Outcome-level evidence map and pooling decision.
OutcomeRandomized
Evidence		Why No Meta-AnalysisSynthesis RuleResult
Functional capacityKuethe [50]; Carvalho [51]Different trial structures/time points;
crossover paired variance unavailable;
heterogeneous measures		Prioritize randomized between-group end-of-treatment resultsNo consistent benefit
Muscle strength/
endurance		Gordon [48]; Andrews [49]; Kuethe [50]Non-equivalent constructs/scales
(knee endurance, peak torque, handgrip, and sphygmomanometer strength)		Direction + magnitude;
no vote counting by p value		Preliminary
favorable signal
Quality of lifeKuethe [50]Too few comparable randomized dataRandomized evidence only for causal inferenceNo established benefit
Cardiac functionGordon [48]; Kuethe [50]Few small studies; different assessmentsNarrative randomized evidenceNo consistent benefit
Safety/
renal outcomes		Randomized reports sparseDifferent definitions; few events;
inconsistent denominators		Distinguish not reported from no eventVery uncertain
Hospitalization/
mortality		No adequately powered
randomized evidence		Insufficient eventsExploratory onlyUnknown
Quantitative pooling was not performed because comparable randomized data were too sparse and heterogeneous. The synthesis is therefore narrative and supported by outcome-level GRADE judgments.
Table 5. GRADE summary of findings for critical outcomes.
Table 5. GRADE summary of findings for critical outcomes.
OutcomeStudies/
Participants		Effect SummaryGRADE Domains and DowngradingCertainty
Functional
capacity		2 RCTs; up to
53 randomized
(Kuethe 20; Carvalho 33)		No consistent benefit. Carvalho: peak VO2 difference of 0.30 mL/kg/min (95% CI −3.47 to 4.08);
6MWT difference of 25.29 m (95% CI −19.33 to 69.92).
Kuethe reported no benefit; paired CI unavailable.		RoB: −1 (attrition/reporting);
inconsistency: 0 (directionally neutral across RCTs); indirectness: 0;
imprecision: −2 (small information size and intervals compatible with benefit/no benefit);
publication bias: 0 (too few studies to assess; not downgraded).		Very low
Muscle/
energetics		3 RCTs;
up to 57 randomized		Directionally favorable selected peripheral muscle outcomes but measured with non-equivalent tests and without demonstrated patient-centered benefit.RoB: −1; inconsistency: 0 (favorable direction, different constructs);
indirectness: −1 (surrogate/peripheral outcomes);
imprecision: −1 (small studies);
publication bias: 0 (too few studies to assess; not downgraded).		Very low
HRQoL1 randomized crossover trial;
n = 20 randomized, 13 completers		No established randomized benefitRoB: −1; inconsistency: not assessable;
indirectness: 0; imprecision: −2;
publication bias: 0 (not assessable; not downgraded).		Very low
Cardiac
function		2 RCTs; up to 37 randomizedNo consistent improvement in LVEFRoB: −1; inconsistency: 0; indirectness: 0;
imprecision: −2;
publication bias: 0 (not assessable; not downgraded).		Very low
Safety/renalRandomized evidence sparse;
denominators inconsistently reported		Sparse randomized data; Carvalho showed no significant creatinine/urea difference, while Kuethe reported substantial attrition and limited event attribution.RoB: −1; inconsistency: −1 (inconsistent reporting);
indirectness: −1 (short follow-up and non-event-focused trials);
imprecision: −2 (few participants/events);
publication bias: 0 (not assessable; not downgraded).		Very low
Hospitalization/
mortality		No adequately powered randomized evidenceEffect unknownSevere imprecision and absence of event-powered randomized evidenceVery low (effect not estimable)
Table 6. RoB 2 domain-level judgments for the primary randomized evidence and the principal outcome domains assessed in each study.
Table 6. RoB 2 domain-level judgments for the primary randomized evidence and the principal outcome domains assessed in each study.
StudyRandomizationDeviationsMissing DataOutcome
Measurement		Selection of
Reported Result		Period/Carry-Over
Effects		Overall
Gordon 1995 [48] Muscle/energetics; cardiac functionSome concernsLowSome concernsLowSome concernsN/A
(parallel-group trial)		Some concerns
Andrews 1998 [49] Muscle endurance/metabolismSome concernsLowSome concernsLowSome concernsN/A
(parallel-group trial)		Some concerns
Kuethe 2006 [50] Functional capacity; muscle strength; HRQoL; cardiac functionSome concernsLowHigh (13/20 completed)LowSome concerns; paired-period and carry-over reporting incompleteSome concerns: washout plausible, but period-specific paired estimates and formal carry-over testing incompletely reportedHigh
Carvalho 2012 [51] Functional capacitySome concernsLowSome concernsLowSome concernsN/A
(parallel-group trial)		Some concerns
Table 7. Study-level safety reporting matrix. NR = not reported in the accessible report or not extractable for this review.
Table 7. Study-level safety reporting matrix. NR = not reported in the accessible report or not extractable for this review.
StudyRenal
Markers		Adverse EventsDiscontinuation/
Attrition		HF Hospitalization/
Mortality		Safety
Interpretation
Gordon 1995 [48]Not adequately reportedNot adequately reportedNRNRToo short/small for clinical safety
Andrews 1998 [49]NRNRNRNRSafety cannot be inferred
Kuethe 2006 [50]NR in reportOne participant reported transient mild gastric pain during creatine intake; no other adverse event was specifically attributed to creatine in the accessible report7/20 discontinued (3 during creatine, 4 during placebo); reasons: cold (1), death (1), breast cancer (1), acute decompensation (1), and unstated (3)One death and one acute HF decompensation occurred among withdrawals; treatment-period attribution not reportedSubstantial attrition and limited attribution preclude a safety conclusion
Carvalho 2012 [51]Creatinine 1.31 mg/dL (95% CI 1.21–1.42) vs. 1.20 (1.09–1.31), p = 0.1499; no significant urea differenceNo systematic adverse-event denominator reportedNRNRRenal laboratory data reassuring over 6 months but trial underpowered for clinical events
López-Clemente 2025 [52]Transient creatinine increase/eGFR decline; normalized after discontinuationReported descriptivelyOpen-label; no randomized attrition comparisonNo observed change in HF decompensation or mortality during follow-upExploratory, non-randomized
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Epelde, F.; Martínez López, M.P. Efficacy and Safety of Oral Creatine Supplementation in Patients with Heart Failure: A PRISMA 2020 Systematic Review and Narrative Evidence Synthesis. Int. J. Environ. Res. Public Health 2026, 23, 1130. https://doi.org/10.3390/ijerph23091130

AMA Style

Epelde F, Martínez López MP. Efficacy and Safety of Oral Creatine Supplementation in Patients with Heart Failure: A PRISMA 2020 Systematic Review and Narrative Evidence Synthesis. International Journal of Environmental Research and Public Health. 2026; 23(9):1130. https://doi.org/10.3390/ijerph23091130

Chicago/Turabian Style

Epelde, Francisco, and María Pilar Martínez López. 2026. "Efficacy and Safety of Oral Creatine Supplementation in Patients with Heart Failure: A PRISMA 2020 Systematic Review and Narrative Evidence Synthesis" International Journal of Environmental Research and Public Health 23, no. 9: 1130. https://doi.org/10.3390/ijerph23091130

APA Style

Epelde, F., & Martínez López, M. P. (2026). Efficacy and Safety of Oral Creatine Supplementation in Patients with Heart Failure: A PRISMA 2020 Systematic Review and Narrative Evidence Synthesis. International Journal of Environmental Research and Public Health, 23(9), 1130. https://doi.org/10.3390/ijerph23091130

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop