Nutraceuticals in Patients With Heart Failure: A Systematic Review

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Nutraceuticals in heart failure patients: A systematic review Ingrid Hopper MBBS BMedSc(Hons) PhD FRACP , Cia Connell BPharm (Hons), Grad Cert Pharm Prac, M. Clin Pharm, MSHPA , Tom Briffa PhD , Carmine G. Depasquale BMBS (Hons), FRACP, PhD, FCSANZ , Andrea Driscoll NP, PhD, FAHA, FCSANZ, FACNP , Peter M. Kistler MBBS FRACP PhD , Peter S. Macdonald MBBS FRACP PHD MD FCSANZ , Andrew Sindone BMed(Hons), MD, FRACP, FCSANZ , Liza Thomas MBBS (Hons), FRACP, PhD , John J. Atherton MBBS, PhD, FRACP, FCSANZ, FESC PII: DOI: Reference:

S1071-9164(19)30715-8 https://doi.org/10.1016/j.cardfail.2019.10.014 YJCAF 4440

To appear in:

Journal of Cardiac Failure

Received date: Revised date: Accepted date:

30 June 2019 7 October 2019 29 October 2019

Please cite this article as: Ingrid Hopper MBBS BMedSc(Hons) PhD FRACP , Cia Connell BPharm (Hons), Grad Cert Pharm Prac, M. Clin Pharm, MSHPA , Tom Briffa PhD , Carmine G. Depasquale BMBS (Hons), FRACP, PhD, FCSANZ , Andrea Driscoll NP, PhD, FAHA, FCSANZ, FACN Peter M. Kistler MBBS FRACP PhD , Peter S. Macdonald MBBS FRACP PHD MD FCSANZ , Andrew Sindone BMed(Hons), MD, FRACP, FCSANZ , Liza Thomas MBBS (Hons), FRACP, PhD , John J. Atherton MBBS, PhD, FRACP, FCSANZ, FESC , Nutraceuticals in heart failure patients: A systematic review, Journal of Cardiac Failure (2019), doi: https://doi.org/10.1016/j.cardfail.2019.10.014

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Nutraceuticals in heart failure patients: a systematic review Ingrid Hopper MBBS BMedSc(Hons) PhD FRACP Affiliations: Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia, Heart Centre, The Alfred Hospital, Melbourne, Australia Nil Relevant relationships with industry Cia Connell: BPharm (Hons), Grad Cert Pharm Prac, M Clin Pharm, MSHPA Affiliation: National Heart Foundation of Australia, Melbourne, Australia Nil relevant relationships with industry. Tom Briffa PhD Affiliations: Centre for Health Services Research and Cardiovascular Research Group, School of Population Health, University of Western Australia, Perth, Australia Nil relevant relationships with industry. Carmine G. Depasquale BMBS (Hons), FRACP, PhD, FCSANZ Affiliations: Department of Cardiovascular Medicine, Flinders Medical Centre & Flinders University, Adelaide, Australia Relationships with industry: Sponsored Advisory Board: Novartis (entresto), Astra Zeneca (dapagliflozin, ZS-9) Sponsored Educational Presentation; Novartis, Servier, Vifor, PCM Scientific, Bristol-Myers Squibb, Biotronic, Boehringer Ingelheim, Lily Sponsored Heart Failure Educational Programme National Leader (CORE): PCM Scientific (through Novartis unrestricted grant) Sponsored Pharmaceutical Industry (in house) Educational Lecture: Boehringer Ingelheim Lily Andrea Driscoll NP, PhD, FAHA, FCSANZ, FACNP Affiliations: Department of Cardiology, Austin Health, Melbourne, Australia, School of Nursing and Midwifery, Faculty of Health, Deakin University, Melbourne, Australia Relationships with industry: Consultancies and speaker fees:Novartis, Australian Centre for Heart Health Nursing Advisory Board: Novaritis Peter M. Kistler MBBS FRACP PhD Affiliations: Heart Centre, The Alfred Hospital, Melbourne, Australia, Department of Medicine, University of Melbourne, Melbourne, Australia Relationships with industry: Sponsored Lectures; St Jude/Abbott. Royalties; Up to date, Online Medical Journal Peter S. Macdonald MBBS FRACP PHD MD FCSANZ Affiliations: St Vincent’s Hospital, Victor Chang Cardiac Research Institute, University of New South Wales, Sydney

Page 2 of 43 Relationships with industry: Advisory boards: Novartis, Astra-Zeneca Speaker Fees: Novartis, Servier, Health Pty Ltd. Novartis Research Grant – paid to St Vincent’s Hospital Servier Research Grant – paid to Victor Chang Cardiac Research Institute Andrew Sindone BMed(Hons), MD, FRACP, FCSANZ, Affiliations: Heart Failure Unit and Department of Cardiac Rehabilitation, Concord Hospital, Sydney, Australia University of Sydney, Sydney, Australia Relationships with industry: Professor Sindone has received honoraria, speaker fees, consultancy fees, is a member of advisory boards or has appeared on expert panels for: Alphapharm, Amgen, Aspen, Astra Zeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, CSL, HealthEd, Menarini, Merck Sharp and Dohm, Mylan, National Cardiac Monitoring, Novartis, Otsuka, Pfizer, Sanofi, Servier, Vifor Liza Thomas MBBS (Hons), FRACP, PhD Affiliations: Department of Cardiology, Westmead Hospital, Department of Medicine, University of Sydney, Department of Medicine, University of New South Wales Nil Relevant relationships with industry John J. Atherton. MBBS, PhD, FRACP, FCSANZ, FESC Affiliations: Department of Cardiology, Royal Brisbane and Women’s Hospital, Brisbane, Australia, Faculty of Medicine, University of Queensland, Brisbane, Australia, Faculty of Science, Health, Education and Engineering, University of Sunshine Coast, Australia, Faculty of Health, Queensland University of Technology, Brisbane, Australia Relationships with industry: Advisory boards for Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Otsuka, Vifor Pharma. Speaker fees from Bristol-Myers Squibb, Menarini, Novartis, Servier. Travel/ accommodation support from Bayer, Boehringer Ingelheim, Novartis, Vifor Pharma. Funding: The literature search was funded by the National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand.

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ABSTRACT Background: Nutraceuticals are pharmacologically active substances extracted from vegetable or animal food and administered to produce health benefits. We recently reviewed the current evidence for nutraceuticals in patients diagnosed with heart failure as part of the writing of the Australian Guidelines for the prevention, diagnosis and management of heart failure.

Methods: A systematic search for studies that compared nutraceuticals to standard care in adult patients with heart failure was performed. Studies were included if > 50 patients were enrolled, with ≥ 6 months follow up. If no studies met criteria then studies < 50 patients and < 6 months follow up were included. The primary outcomes included mortality/survival, hospitalisation, quality of life, and/or exercise tolerance. Iron was not included in this review as its role in HF is already well established. Results: Forty studies met the inclusion criteria. The strongest evidence came from studies of polyunsaturated fatty acids, which modestly decreased mortality and cardiovascular hospitalisations in patients with mostly New York Heart Association (NYHA) II and III heart failure across a range of left ventricular ejection fraction. Co-enzyme Q10 may decrease mortality and hospitalisation, but definite conclusions cannot be drawn. Studies that examined nitrate rich beetroot juice, micronutrient supplementation, hawthorn extract, magnesium, thiamine, vitamin E, vitamin D, Larginine, L-carnosine and L-carnitine were too small or underpowered to properly appraise clinical outcomes. Conclusion: Only one nutraceutical, omega-3 PUFA, received a positive recommendation in the Australian heart failure guidelines. Although occasionally showing some promise, all other nutraceuticals are inadequately studied to allow any conclusion on efficacy. Clinicians should favour other treatments that have been clearly shown to decrease mortality.

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Abbreviations AMSTAR Assessing the Methodological Quality of Systematic Reviews CHF

Chronic heart failure

HF

Heart failure

HFrEF Heart failure with reduced ejection fraction LVEF

left ventricular ejection fraction

NYHA New York Heart Association PUFA

Omega-3 polyunsaturated fatty acid

RCT

Randomised controlled trial

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INTRODUCTION Heart failure (HF) prevalence continues to rise, partly due to an aging population.1 Recent Australian guidelines outline recommendations for the prevention, detection and management of HF, highlighting treatments which improve clinical outcomes, including pharmacological and devicebased therapy and improvements in systems of care.2 We included recommendations on nutraceuticals. The term nutraceutical is a neologism derived from “nutrient” and “pharmaceutical”, referring to pharmacologically active substances extracted from vegetable or animal food, concentrated and administered in pharmaceutical form to produce health benefits.3 Nutraceuticals are commonly consumed by patients with cardiovascular disease4, 5.

HYPOTHESIS AND PURPOSE We sought to review current evidence for nutraceuticals in patients with HF.

METHODS The systematic review was funded by the Heart Foundation and Cardiac Society of Australia and New Zealand. Joanna Briggs Institute conducted the initial literature search in August 2017, and it was re-run in August 2018 by the authors.

Trial design We searched for randomized controlled trials (RCTs) and systematic reviews of RCTs comparing nutraceuticals with standard care in adult patients (≥18 years) with HF, published between January 1980 to August 2018. Grey literature and opinion papers were excluded. Studies were included if ≥50 patients and follow-up ≥ six months.

Agents investigated The agents selected for this review were based on the authors’ knowledge of nutraceuticals tested clinically and in research studies, and also additional terms following an initial review of

Page 6 of 43 nutraceuticals studies conducted in heart failure. We considered studies assessing nutraceuticals including vitamin D, A, C, E, B6, and B12, folate, thiamine, selenium, St John’s Wort, hawthorn, celery extract, magnesium supplements, co-enzyme Q10, polyunsaturated fatty acids (PUFA), fish oil, olive oil, beetroot juice, L-arginine, L-carnitine, L-carnisone, probiotics, or antioxidants. Antioxidants included antioxidant enzymes (superoxide dismutase, glutathione peroxidase, glutathione reductase, catalases), antioxidant vitamins A, C, and E, folic acid, beta-carotene, and antioxidant phytochemicals (carotenoids, flavonoids, allyl sulphides, polyphenols, resveratrol). Iron was not included in this review as its role in HF is already well established.6

Outcomes evaluated Outcomes evaluated included mortality/survival, hospitalisation, quality of life, and/or exercise tolerance.

Search methodology We searched CINAHL via EBSCO, EMBASE, MEDLINE via PubMed, and references of included studies. The search strategy combined key words and MeSH terms related to HF, nutraceuticals (including dietary supplements, herbal food, medicinal food), and names of classes and individual nutraceuticals (see appendix 1 for full search strategy). Where no studies met the initial criteria, RCTs and systematic review of RCTs with < 50 subjects and < six months’ follow-up were considered eligible for inclusion. No language restrictions applied. Titles and abstracts of all citations were screened, potentially relevant studies retrieved, and full texts reviewed to determine eligibility.

Critical appraisal All included studies were critically appraised by reviewers independently. The Assessing the Methodological Quality of Systematic Reviews (AMSTAR) checklist and the Joanna Briggs Institute checklist were used for systematic reviews and quasi-experimental studies respectively. RCTs were appraised with the Cochrane Risk of Bias tool. Disagreement between reviewers was resolved by discussion and a third reviewer opinion if consensus wasn’t achieved.

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Citations identified through database searching (n = 3246)

Duplicate records removed (n = 301)

(2351 from primary search, 895 from iterative search)

Titles/abstracts screened (n = 2945)

Citations excluded (n = 2643)

Articles published in LOTE* awaiting full text retrieval (n=1)

Full-text articles assessed for eligibility (n=302)

Articles awaiting full text retrieval (n=2)

Full-text articles included in summary

Full-text articles excluded with reasons (n=265)

(n=35)

Full-text articles included in 2017 summary (n=35)

Literature search re-run for August 2017 – 2018 (n=5 additional studies identified)

Full-text articles included in summary *

Figure 1: Flow diagram (n=40)of systematic review. LOTE = Language other than English

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RESULTS Forty studies met inclusion criteria (see figure 1), including seven systematic reviews; 29 RCTs; one quasi-experimental (Figure 1). Interventions included: beetroot juice (n=5); coenzyme Q10 (n=9); hawthorn extract (n=5); magnesium (n=1), (PUFA) including fish oil (n=6); thiamine (n=1); vitamin C (n=1), vitamin D (n=6), vitamin E (n=1), combination interventions (n=2), L-arginine (n=1), Lcarnosine (n=1) and L-carnitine (n=1). The ‘additional inclusion criteria’ described above were applied to allow for studies on beetroot juice, thiamine, vitamin C and vitamin E. No studies met inclusion criteria for vitamin A, B6, B12, folate, selenium, St John’s wort, celery extract, olive oil, and probiotics. Table 1 summarises included studies, and Figure 2 summarises the findings. Appendix 2 details the critical appraisal of included studies.

Figure 2 Nutraceuticals in heart failure – evidence for clinical outcome benefit.

Figure 2. Nutraceuticals in heart failure - evidence for clinical outcome benefit

Evidence of benefit Omega-3 polyunsaturated fatty acid

Trend towards benefit Coenzyme Q10

Insufficient evidence of benefit Beetroot juice Hawthorn extract Magnesium Vitamin C Vitamin D Vitamin E Combination nutraceuticals L-arginine L-carnosine L-carnitine No studies Vitamin A Vitamin B6 Vitamin B12 Folate Selenium St John’s Wort Celery extract Olive Oil Probiotics

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Omega-3 polyunsaturated fatty acids PUFA may positively impact chronic HF (CHF) through impacting the structure and function of the mitochondrial membrane.7 Three studies (one systematic review; two RCTs) including 133 to 7,046 participants informed this intervention. Dosages administered varied. Comparators included olive oil, gelatine or matching placebo. Follow-up ranged from 3 months to 3.9 years. Outcomes included exercise capacity, mortality and hospitalization. The quality of the systematic review and the RCTs was moderate, due to inconsistent reporting to determine bias across the RCTs. The findings are mainly influenced by one large RCT, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiaca (GISSI-HF trial8-10, a double-blind, placebo-controlled RCT comparing PUFA 1g daily with placebo in 7,046 patients with CHF regardless of aetiology or left ventricular ejection fraction (LVEF). Over 90% of patients had LVEF 40% or below.11 PUFA was associated with significantly reduced time to death (adjusted hazard ratio [HR] 0.91 [95.5% CI 0.8330.998], p=0.041), time to death or cardiovascular hospitalization (adjusted HR 0.92, 99% CI 0.8490.999, p=0.009), and cardiovascular hospitalizations (adjusted HR 0.93, 95% CI 0.87-0.99, p=0.049).11 Three studies examined exercise capacity (one systematic review and two RCTs)12. Both RCTs 9, 13

were included in the systematic review and meta-analysis involving 199 patients with HF

associated with reduced LVEF (HFrEF), showing that fish oil significantly increased peak VO2 in patients with non-ischaemic HF12. The evidence favouring PUFA in patients with HF is weak. There may be a modest benefit of PUFA in patients with HF in improving cardiovascular outcomes, however the confidence intervals suggest the treatment effect is not clinically significant. It’s unclear whether these effects would be maintained with contemporary therapy, with only 65% of patients receiving beta-blockers in the

Page 10 of 43 GISSI-HF study. The strength of recommendation for PUFA in patients with CHF in the Australian guidelines was therefore weak.2

CoQ10 Coenzyme Q10 (CoQ10) is an essential lipid present in all cellular membranes, has roles in mitochondrial ATP generation and is antioxidant. Decreased plasma CoQ10 is an independent predictor of mortality in patients with CHF.14 Three systematic reviews15-17, five RCTs18-22 and one quasi-experimental study23 were included. Sample sizes ranged from 55 to 641 participants, and follow-up six months to two years. Most studies evaluated patients with HFrEF. Dosages varied. Overall, the methodological quality of the systematic reviews was moderate. The Q-SYMBIO study was a placebo-controlled RCT21 evaluating CoQ10 supplementation and major adverse cardiovascular events in 420 patients with HF and average LVEF 31%. It reported a decrease in deaths in the CoQ10 group compared to placebo [HR 0.51 (95% CI 0.30-0.89), p=0.018). A recent systematic review of CoQ10 supplementation in CHF combined the Q-Symbio Study with six other studies in a meta-analysis, finding a 31% reduction in all-cause mortality.16 Morisco et al evaluated CoQ10 in 641 patients with advanced HF, reporting a statistically significant decrease in hospitalisations compared to placebo. This trial was conducted prior to widespread use of neurohormonal antagonists.20 The Q-SYMBIO study reported lower HF hospitalisation in the intervention group [HR 0.51(95% CI 0.27-0.95), p=0.033].21 There is some evidence that Coenzyme Q10 may decrease mortality and hospitalization, but definite conclusions cannot be reached given the size and quality of the studies.

Beetroot juice Beetroot is rich in inorganic nitrate, and increases circulating NO bioavailability.24 HF is associated with reduced nitric oxide bioavailability, and inability to up-regulate NO contributes to impaired

Page 11 of 43 functional capacity and reduced exercise tolerance in HF. Beetroot has been investigated as a means to improve exercise capacity in HF. All five included RCTs were double blind, randomized, placebo controlled, cross-over design trials.25-29 Four studies were conducted in patient with HFrEF25-28 and one in HFpEF29. Overall, the quality of the studies was moderate25-29, however sample sizes were small (20 subjects or less). Varied doses of nitrate rich beetroot juice were compared to nitrate depleted beetroot juice. Three studies reported statistically significant improvements in exercise capacity following NO3supplementation.25, 28, 29 Two studies reported no statistically significant improvement in exercise capacity.26, 27 The evidence on beetroot juice is conflicting and currently insufficient to support beetroot juice supplementation in patients with HF.

Hawthorn extract Hawthorn extract may confer cardiac benefits through positive inotropy and improved coronary blood flow.30, 31 Five studies including two systematic reviews and three RCTs informed this intervention. Sample sizes ranged from 30 to 2681 participants, and ran from 3 weeks to 24 months, with various doses of hawthorn extract. One systematic review was moderate32 and one high quality.33 A small RCT involving 120 patients reported no significant difference between hawthorn and placebo in mortality based on only seven events.34 A RCT involving 2,681 patients, reported no difference in the time to first cardiac event between hawthorn and placebo based on 761 events.35 One systematic review and one RCT evaluated exercise tolerance, both reporting improvement in the working capacity.33, 36 Zick et al found no statistical difference in functional capacity with hawthorn extract.34 There is insufficient evidence to recommend hawthorn extract supplementation in patients with HF.

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Magnesium High magnesium diet is associated with reduced cardiovascular risk,37 and the anion of magnesium orotate is an intermediate of pyrimidine biosynthesis with potential cardioprotective effects.38 One RCT involving 70 participants informed this intervention.39 The study was high risk for bias. At 12 months 76% of the intervention group and 52% of the placebo group were alive (p=0.048), however this finding should be viewed with caution as 11 patients were excluded from mortality evaluation.39 There is insufficient evidence to support magnesium supplementation in patients with HF.

Thiamine Thiamine deficiency is present in some patients with HF on furosemide therapy, and thiamine deficiency may contribute to the development of HF. Theoretically, repletion of thiamine may therefore benefit these patients. There was one RCT with 30 participants,40 which comprised intravenous therapy, followed by oral therapy versus placebo. Study quality was moderate. There was no difference in mortality, and mean NYHA class decreased in the thiamine group. The study was under-powered for clinical outcomes. There is insufficient evidence to support routine thiamine supplementation in patients with HF.

Vitamin C The anti-oxidant properties of vitamin C may protect the myocardium from oxidative stress41, which is augmented in patients with HF. One RCT with 40 subjects was included.41 Participants received either vitamin C 4000mg daily for four weeks followed by placebo for six weeks, or in reverse order with placebo followed by Vitamin C. The study was moderate quality. A significant improvement in exercise capacity was reported at four weeks (P<0.001) and at 10 weeks (P=0.005). The study was under-powered for clinical outcomes.

Page 13 of 43 There is insufficient evidence to support vitamin C supplementation in patients with HF.

Vitamin D Vitamin D deficiency is associated with a number of cardiovascular issues42. This forms the basis for studies to determine whether vitamin D supplementation impacts these outcomes, or whether vitamin D deficiency is a confounder for other mechanisms of poorer outcome. Vitamin D supplementation was investigated in four RCTs43-47 and one systematic review48, including between 64 to 934 participants, with follow-up for 20 weeks to three years. The intervention dosage varied significantly. The overall quality of the systematic review was moderate48, two RCTs were low risk of bias43, 44, and other RCTs varied quality45-47. RCTs and meta-analysis44-46 reported no statistically significant difference in exercise capacity with Vitamin D supplementation, overall quality of life43 or survival45, 47. Zitterman et al reported a higher need for mechanical circulatory support implantation in patients randomized to receive Vitamin D.47 Caution should be exercised in interpreting these results due to inadequate power to detect significant treatment differences. Overall, there is insufficient evidence to support vitamin D supplementation in patients with HF.

Vitamin E Oxidative stress is increased in HF, which may contribute to disease progression and may be secondary to depletion of endogenous antioxidants such as vitamin E. One high quality, doubleblind, placebo controlled RCT was included49, with 56 participants with severe HF (NYHA class III or IV), followed for 12 weeks. No change in quality of life was observed in either group. Evidence is insufficient to recommend vitamin E supplementation in HF.

Combination nutraceuticals

Page 14 of 43 Low micronutrient levels are observed in HF, and amino acids act as a substrate for protein synthesis and or intermediary metabolism. The ease and safety of oral multiple micronutrient supplementation has resulted in studies of combination nutraceuticals. Two studies were included. McKeag et al reported a double blind, placebo-controlled RCT of combination micronutrient supplementation in 74 patients with HFrEF.50 This study was of high methodological quality. Limitations include patients having mild HF and groups insufficiently matched. At 12 months, there were no statistically significant differences for either exercise capacity or quality of life. BonillaPalomas et al performed a randomized controlled trial in 120 patients with acute HF51. A nutritional intervention was delivered lasting 6 months to patients where nutritional goals had not been reached51, 52. Total mortality was significantly reduced (hazard ratio 0.45; 95% CI, 0.19-0.62, p=0.0004)51. Low study quality makes interpretation difficult. There is insufficient evidence to support routine combination micronutrient supplementation in patients with HF.

L-arginine L-arginine is an amino acid, and the substrate of endothelial nitric oxide synthetase and the precursor of nitric oxide, and may improve endothelial-mediated vasodilation. Its administration may offset reduced nitric oxide synthesis and bioavailability in HF patients. (ref 6 in paper – check). One study was included. Fontanive et al performed a double-blind, placebo-controlled RCT comparing L-arginine with placebo in 68 participants with HFrEF.53 The study was of high methodological quality. At 12 weeks, a significant improvement in NYHA class was seen, with a decrease from NYHA III, to class I or II, in 77% active and 20% placebo (p=0.03). No improvement in quality of life or 6MWT was seen. There is insufficient evidence to recommend routine use of Larginine in chronic heart failure.

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L-carnosine L-carnosine is a cytoplasmic dipeptide molecule comprising two amino acids, beta-alanine and histidine, which is present in highest concentration in skeletal muscle. Muscle carnosine is a major contributor to H+ buffering during high-intensity exercise, and can be increased in muscle cells by oral supplementation. One study was included. Lombardi et al performed an open label, randomised controlled parallel group study comparing 500mg per day of L-carnosine or standard treatment.54 The study was at high risk of bias. At 6 months, an improvement was seen in 6MWT distance (p=0.014) and quality of life by EQ-5D (p=0.018) and VAS (p<0.0001). Peak VO2 also increased in the treatment group but not in the control group (p<0.0001), VO2 at anaerobic threshold (p=0.003), peak exercise workload (p=0.033). Limitations in this study include the open label design. There is insufficient evidence to recommend routine use of L-carnosine in chronic heart failure.

L-carnitine L-carnitine is a vitamin-like and modified amino acid that plays an important role in supporting metabolic activities. One systematic review was found55 which included 17 RCTs with 1625 participants, and ran from 7 days to 3 years. Sample size ranged from 51 to 261 participants, with doses from 1 to 6mg. This was assessed as moderate quality. Meta-analysis of four RCTs showed no statistical difference in mortality, based on 29 events in 414 patients. Meta-analysis of two RCTs found no difference in functional capacity. There is insufficient evidence to recommend L-carnitine supplementation in patients with HF.

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Other nutraceuticals There were no studies that met the inclusion criteria for vitamin A, B6, B12, folate, selenium, St John’s wort, celery extract, olive oil, and probiotics.

DISCUSSION We found limited evidence supporting benefits of nutraceuticals for patients with HF. There was weak evidence from a study of PUFA, which modestly decreased mortality and cardiovascular hospitalisations in patients with mostly NYHA II and III HFrEF, with low numbers of patients receiving beta-blockers and mineralocorticoid receptor antagonists at baseline. The evidence reviewed suggested co-enzyme Q10 decreases mortality and hospitalisation, but definite conclusions cannot be drawn. Studies that examined nitrate-rich beetroot juice, micronutrient supplementation, hawthorn extract, magnesium, thiamine, vitamin E, vitamin D, L-arginine, L-carnosine and L-carnitine were too small or underpowered to adequately appraise clinical outcomes. One study of vitamin D supplementation suggested harm, with a higher need for mechanical circulatory support, however this study was under-powered to detect significant treatment differences. The major weaknesses in the evidence include the small number of studies performed, the small number of participants, diminished study quality with a high risk of bias, and that most were performed before the widespread use of neurohormonal antagonists. Consequently, only one nutraceutical, PUFA, received a recommendation in the Australian HF guideline - a weak recommendation with low quality of evidence - to be used in patients with persistent HFrEF despite best practice treatment to decrease mortality and cardiovascular hospitalization.2 Our practice advice was that clinicians should favour other treatments that have been clearly shown to decrease mortality. This is the first systematic review of the literature on nutraceuticals in HF focussed on clinical parameters of importance to treating clinicians and patients. We concentrated on nutraceuticals

Page 17 of 43 encountered in daily practice, and translated the findings from this review directly into guidelines. This review builds on the previous work by Cicero et al56, which focussed on the effect of nutraceuticals on surrogate endpoints of HF, and potential mechanisms of benefit. They reported favourable effects on LVEF and cardiac output with some nutraceuticals. Unfortunately, with the possible exception of PUFA, there is insufficient clinical trial evidence to demonstrate that this translates to improvements in clinical outcomes. Furthermore, we have not comprehensively evaluated the potential health risks associated with nutraceuticals. Nutraceuticals are of interest in cardiovascular disease prevention and treatment. Expert opinion and consensus documents have been published57-59, however none relating to HF. This is the first time nutraceuticals have been addressed as a class in HF guidelines, although previous guidelines have included recommendations for PUFA, and listed nutraceuticals as a potential cause of decompensated HF. We did not include iron in our review given it is considered established therapy in HF, and that intravenous administration is required60. Although the evidence is not strong, there are promising signals with some nutraceuticals. Ongoing trials are evaluating effects of PUFA and vitamin D in HF. Continued research efforts are needed to clarify whether nutraceuticals will have a greater role in guideline-directed care in the future. It is important to acknowledge the role of a nutrient-rich anti-oxidant diet in promoting good health for patients with HF, and indeed nutrition in patients with heart failure has recently been the subject of a consensus statement.61 The need for a whole-diet approach, rather than singlecompound supplementation, likely underlies the disconnect between various observational studies suggesting an association between a dietary component and survival, followed by a subsequent nutraceutical intervention study using the same component but with neutral findings.

Conclusion The evidence for the effect of nutraceuticals in HF was reviewed for the Australian HF guidelines. Only PUFA received a weak recommendation. Other studies were small and mostly

Page 18 of 43 underpowered, and often performed before the widespread use of neurohormonal antagonists. It remains imperative that medications which decrease mortality receive the highest priority in HF care. Further research is needed to establish whether other nutraceuticals may have a role in HF.

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adjunctive in the treatment of chronic congestive heart failure. The Q10 Study Group. J Card Fail 1995;1:101-7. 19.

Khatta M, Alexander BS, Krichten CM et al. The effect of coenzyme Q10 in patients with

congestive heart failure. Ann Intern Med 2000;132:636-40. 20.

Morisco C, Trimarco B, Condorelli M. Effect of coenzyme Q10 therapy in patients with

congestive heart failure: a long-term multicenter randomized study. Clin Investig 1993;71:S134-6. 21.

Mortensen SA, Rosenfeldt F, Kumar A et al. 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;2:641-9. 22.

Zhao Q, Kebbati AH, Zhang Y, Tang Y, Okello E, Huang C. Effect of coenzyme Q10 on the

incidence of atrial fibrillation in patients with heart failure. J Investig Med 2015;63:735-9. 23.

Adarsh K, Kaur H and Mohan V. Coenzyme Q10 (CoQ10) in isolated diastolic heart failure in

hypertrophic cardiomyopathy (HCM). BioFactors (Oxford, England). 2008;32:145-9. 24.

Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology

and therapeutics. Nat Rev Drug Discov 2008;7:156-67. 25.

Coggan AR, Broadstreet SR, Mahmood K et al. Dietary Nitrate Increases VO2peak and

Performance but Does Not Alter Ventilation or Efficiency in Patients With Heart Failure With Reduced Ejection Fraction. J Card Fail 2018;24:65-73. 26.

Coggan AR, Leibowitz JL, Spearie CA et al. Acute Dietary Nitrate Intake Improves Muscle

Contractile Function in Patients With Heart Failure: A Double-Blind, Placebo-Controlled, Randomized Trial. Circ Heart Fail 2015;8:914-20.

Page 21 of 43 27.

Hirai DM, Zelt JT, Jones JH et al. Dietary nitrate supplementation and exercise tolerance in

patients with heart failure with reduced ejection fraction. Am J Physiol Regul Integr Comp Physiol 2017;312:R13-R22. 28.

Kerley CP, O'Neill JO, Reddy Bijjam V, Blaine C, James PE, Cormican L. Dietary nitrate

increases exercise tolerance in patients with non-ischemic, dilated cardiomyopathy-a double-blind, randomized, placebo-controlled, crossover trial. J Heart Lung Transplant 2016;35:922-6. 29.

Zamani P, Rawat D, Shiva-Kumar P et al. Effect of inorganic nitrate on exercise capacity in

heart failure with preserved ejection fraction. Circulation 2015;131:371-80. 30.

Chang Q, Zuo Z, Harrison F, Chow MS. Hawthorn. J Clin Pharm 2002;42:605-12.

31.

Loew D. Phytotherapy in heart failure. Phytomedicine 1997;4:267-71.

32.

Daniele C, Mazzanti G, Pittler MH, Ernst E. Adverse-event profile of Crataegus spp.: a

systematic review. Drug Saf 2006;29:523-35. 33.

Guo R, Pittler MH, Ernst E. Hawthorn extract for treating chronic heart failure. Cochrane

Database Syst Rev 2008:CD005312. 34.

Zick SM, Vautaw BM, Gillespie B, Aaronson KD. Hawthorn Extract Randomized Blinded

Chronic Heart Failure (HERB CHF) trial. Eur J Heart Fail 2009;11:990-9. 35.

Holubarsch CJ, Colucci WS, Meinertz T, Gaus W, Tendera M. The efficacy and safety of

Crataegus extract WS 1442 in patients with heart failure: the SPICE trial. Eur J Heart Fail 2008;10:1255-63. 36.

Schmidt U, Kuhn U, Ploch M, Hubner WD. Efficacy of the Hawthorn (Crataegus) preparation

LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II. Phytomedicine 1994;1:17-24. 37.

Gartside PS, Glueck CJ. The important role of modifiable dietary and behavioral

characteristics in the causation and prevention of coronary heart disease hospitalization and mortality: the prospective NHANES I follow-up study. J Am Coll Nutr 1995;14:71-79 38.

Richards SM, Conyers RA, Fisher JL, Rosenfeldt FL. Cardioprotection by orotic acid:

metabolism and mechanism of action. J Mol Cell Cardiol 1997;29:3239-50 39.

Stepura OB, Martynow AI. Magnesium orotate in severe congestive heart failure (MACH). Int

J Cardiol 2009;134:145-7 40.

Shimon I, Almog S, Vered Z et al. Improved left ventricular function after thiamine

supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med 1995;98:485-90 41.

Ho C. Effects of antioxidant on cardiovascular performance ec, and functional status in

patients with chronic heart failure. Case Western Reserve University, 2007.

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Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D(3) is a negative

endocrine regulator of the renin-angiotensin system. J Clin Investig 2002;110:229-38. 43.

Boxer RS, Hoit BD, Schmotzer BJ, Stefano GT, Gomes A, Negrea L. The effect of vitamin D on

aldosterone and health status in patients with heart failure. J Card Fail 2014;20:334-42. 44.

Boxer RS, Kenny AM, Schmotzer BJ, Vest M, Fiutem JJ, Pina IL. A randomized controlled trial

of high dose vitamin D3 in patients with heart failure. JACC Heart Fail 2013;1:84-90. 45.

Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D

supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2006;83:754-9. 46.

Witte KK, Byrom R, Gierula J et al. Effects of Vitamin D on Cardiac Function in Patients With

Chronic HF: The VINDICATE Study. J Am Coll Cardiol 2016;67:2593-603. 47.

Zittermann A, Ernst JB, Prokop S et al. Effect of vitamin D on all-cause mortality in heart

failure (EVITA): a 3-year randomized clinical trial with 4000 IU vitamin D daily. Eur Heart J 2017;38:2279-2286. 48.

Jiang WL, Gu HB, Zhang YF, Xia QQ, Qi J, Chen JC. Vitamin D Supplementation in the

Treatment of Chronic Heart Failure: A Meta-analysis of Randomized Controlled Trials. Clin Cardiol 2016;39:56-61. 49.

Keith ME, Jeejeebhoy KN, Langer A et al. A controlled clinical trial of vitamin E

supplementation in patients with congestive heart failure. Am J Clin Nutr 2001;73:219-24. 50.

McKeag NA, McKinley MC, Harbinson MT et al. The effect of multiple micronutrient

supplementation on left ventricular ejection fraction in patients with chronic stable heart failure: A randomized, placebo-controlled trial. JACC: 2014;2:308-317. 51.

Bonilla-Palomas JL, Gámez-López AL, Castillo-Domínguez JC et al. Nutritional Intervention in

Malnourished Hospitalized Patients with Heart Failure. Arch Med Res 2016;47:535-540. 52.

Gámez-López AL, Bonilla-Palomas JL, Anguita-Sánchez M et al. Justificación y diseño del

estudio PICNIC: Programa de IntervenCión Nutricional en pacientes hospitalizados por Insuficiencia Cardiaca desnutridos. Rev Esp Cardiol 2014;67:277-282. 53.

Fontanive P, Saponati G, Iurato A, et al. Effects of L-arginine on the Minnesota Living with

Heart Failure Questionnaire quality-of-life score in patients with chronic systolic heart failure. Med Sci Mon. 2009;15:Cr606-11. 54.

Lombardi C, Carubelli V, Lazzarini V, Vizzardi E, Bordonali T, Ciccarese C, Castrini AI, Dei Cas

A, Nodari S and Metra M. Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition 2015;31:72-8.

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Song X, Qu H, Yang Z, Rong J, Cai W and Zhou H. Efficacy and Safety of L-Carnitine Treatment

for Chronic Heart Failure: A Meta-Analysis of Randomized Controlled Trials. BioMed research international. 2017;2017:6274854. 56.

Cicero AFG and Colletti A. Nutraceuticals and Dietary Supplements to Improve Quality of Life

and Outcomes in Heart Failure Patients. Curr Pharm Des. 2017;23:1265-1272. 57.

Banach M, Patti AM, Giglio RV, et al. The Role of Nutraceuticals in Statin Intolerant Patients.

JACC. 2018;72:96-118. 58.

Cicero AFG, Grassi D, Tocci G, Galletti F, Borghi C and Ferri C. Nutrients and Nutraceuticals

for the Management of High Normal Blood Pressure: An Evidence-Based Consensus Document. High Blood Press Cardiovasc Prev 2019;26: 9-25. 59.

Poli A, Barbagallo CM, Cicero AFG, et al. Nutraceuticals and functional foods for the control

of plasma cholesterol levels. An intersociety position paper. Pharmacol Res. 2018;134:51-60. 60.

von Haehling S, Ebner N, Evertz R, Ponikowski P and Anker SD. Iron Deficiency in Heart

Failure: An Overview. JACC Heart failure. 2019;7:36-46. 61.

Vest AR, Chan M, Deswal A, et al. Nutrition, Obesity, and Cachexia in Patients With Heart

Failure: A Consensus Statement from the Heart Failure Society of America Scientific Statements Committee. J Card Fail 2019;25:380-400.

Page 24 of 43

Table 1. Results and characteristics of included studies. Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Polyunsaturated fatty acid Xin et al 2012

Systemati c review

825

Fish Oil dosage ranged from 600 to 4300 mg/day with the ratio of EPA to DHA varying from 0.60 to 1.53

Placebo (olive oil 4 studies, gelatine 2 studies, not reported 2 studies)

Duration of investigation varied from 3 to 12 months

Peak Oxygen Consumption:  3 studies with 4 study arms, which included 199 nonischaemic CHF patients exclusively, investigated peak VO2 in the exercise test.  No significant heterogeneity detected (I2 =0, p=0.67).  One study (Nodari 2011) mainly informed the pooled analysis (weighted 66.1%).  Pooled results indicated fish oil significantly increased peak Vo2 in non-ischaemic CHF patient (WMD=1.68 ml/kg min, 95% CI 0.52 to 2.84, p= 0.005).

I

Finzi et al, 2011

Sub study of GISSIHF (randomiz

566

1 capsule/day of 1g n3PUFA

Matching placebo; 288 participants received

Data were prospectively collected from September 2004 to December 2007.

Total mortality: 26.6% in the n-3PUFA group vs 24.3% in the placebo group (adjusted HR 1.25, 95%CI 0.89-1.75, P=.19). Hospitalisation

II

Cardiovascular hospitalisations: 63.0%in the n-3 PUFA group vs 71.5% in the placebo group. Adjusted HR0.87,

Page 25 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

assigned to patients in a test group; 278 participants received n3PUFA

placebo

Median follow up duration was 928 days.

95% CI 0.71-1.07, P=0.18

608

1g/day of n-3 PUFA; n=312 patients randomized to n-3 PUFA group.

Matching placebo; n=296 patients received placebo.

Median follow up period 48 months (39-55)

Death from any cause (secondary endpoint): 67 patients (21.5%) in the n-3 PUFA group vs 77 (26%) in the placebo group.

II

7046

n-3PUFA; patients were randomly allocated to receive treatment 1g/day

Matching placebo

Median duration of 3.9 years

All cause death: 27% of patients in the n-3PUFA group vs 29% in the placebo group (adjusted HR: 0.91; 95.5 CI: 0.833–0.998; p = 0.041). Absolute risk reduction 1.8% (95% CI 0.3-3.9) All cause death or admission to hospital for cardiovascular reasons: 57% n3-PUFA group vs 59% in the placebo group (adjusted HR: 0.92; 99% CI: 0.849–0.999; p = 0.009). Hospitalisation for cardiovascular reasons: Absolute risk reduction 2.3% (0.0—4.6) The reduction of death for cardiovascular cause, of hospital admission, admission for any or a cardiovascular cause, and of

II

ed placebo controlled clinical trial)

Ghio et al, 2010

Marchioli et al, 2009

Sub study of GISSI-HF (randomize d placebo controlled clinical trial) Double blind placebo controlled randomize d clinical trial

NH MR C leve l of evid enc e

Page 26 of 43 Author

Tavazzi et al, 2008

Study type

Randomize d doubleblind placebo controlled trial; Part of the GISSI-HF trial

Coenzyme Q10

Number of particip ants

7046

Intervention

1g n-3 PUFA per day

Comparison

Matching placebo

Length of follow up

Median duration of 3.9 years

Outcome measures / results

the combined point of cardiovascular death or admission for any cause were significantly lower in the n-3 PUFA group than the placebo group. Results were adjusted for variables significantly out of baseline balance between the two groups (p<0.1) as indicated in the study protocol. However specific differences between the groups at baseline were not noted. Both adjusted and unadjusted results are presented below. Death from cardiovascular cardiovascular cause: 20.4% in the n3 PUFA group (n=712) vs 22.0% in the placebo group (n=765); [HR 0.90, 95%CI (0.81-0.99), p=0.045] Cardiovascular death or admission for any cause: 61.7% in the n-3 PUFA group (n=2157) vs 63.3% placebo group (n=2202); [HR 0.94, 95% CI (0.89-0.99), p=0.043] Hospitalisation for any reason: 56.8% in the n-3 PUFA group (n=1986), vs 58.3% in the placebo group (n=2028); (HR 0.94,[95% CI 0.88-1.00], p=0.049) Cardiovascular hospitalisation: 46.8% in the n-3 PUFA group (n=1635) vs 48.5% in the placebo group (n=1687); (HR 0.93, [95% CI 0.87-0.99], p=0.026) Heart failure hospitalisation: HR 0.94, 95% CI [0.86-1.02], p=0.147

NH MR C leve l of evid enc e

II

Page 27 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Fotino et al 2013

Systematic review (with metaanalysis) Systematic review (with metaanalysis)

395

Coenzyme CoQ10 dosage varied from 60mg to 300 m daily CoQ10 dosage varied from 30mg to 200mg

Placebo

Varied from 2 weeks to 28 weeks

Hospitalisation for heart failure was indicated as a primary outcome for the systematic review, however, authors reported that none of the included studies reported on changes in the number or rate of hospitalisations for heart failure.

I

Placebo

No information provided in the review on the follow-up duration for included studies

Death/Mortality

I

Lei et al 2017

2149



A meta-analysis was conducted but as it included a study with healthy participants the results are not presented here; the data presented below has been extracted from the meta-analysis forest plot

Study

Number of Events in CoQ10 group

Number of Events in Placebo group

Hofman-Bang 1995

3/79

4/79

Khatta 2000

2/28

1/27

Morisco 1993

16/282

21/281

Mortensen 2014

21/202

39/218

0/30

1/30

Watson 1999

Page 28 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

Zhao 2015 Madmani et al 2014

Cochrane Systematic Review (with metaanalysis)

914

Coenzyme CoQ10 dosage varied from 50mg to 150mg

Placebo

Six months or less for included studies, except for Morisco (1993) with one year follow-up.

6/62

NH MR C leve l of evid enc e 8/66

Mortality/Survival: Only one included trial (Adarsh 2008) reported data on mortality - 2.2% in the CoQ10 group vs 2.4% in the placebo group; no significant change in mortality between the two groups; No statistical test mentioned, no P-value indicated.

I

Hospitalisation: one study (Morisco 1993) reported data on hospitalisation - 40% in the placebo group and about 20% in the coenzyme Q10 group. Note: No statistical test mentioned; it was indicated that P value < 0.01. Exercise capacity (meta-analysis of two studies; 85 participants; Mean Difference MD = 12.79 with 95% CI from -140.12 to 165.70). HofmanBang et al, 1995

RCT, crossover trial

79

100 mg coenzyme Q10 daily (added to conventional therapy)

Placebo (added to conventiona l therapy)

6 months

Mortality/Survival: 3 in the CoQ10 period and 4 in the placebo period Quality of life: The total score for the quality of life assessment increased from 107 during the placebo period to 113 during the CoQ10 period (P <0.05; Note: unclear details about this statistical analysis)

II

Page 29 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Khatta et all 2000

RCT; ‘doubleblind’

55

200 mg of coenzyme Q10 per day;

Placebo

6 months

Mortality/Survival: 1 in the placebo group vs 2 in the coenzyme Q10 group.

II

RCT; doubleblind

641

Coenzyme Q10 at the dosage of 2 mg/kg per day (i.e. 50 mg two or three times daily)

Placebo

CoQ10 100 mg 3 times daily (in addition to standard

Placebo (in addition to standard therapy)

Morisco et al 1993

Mortense RCT net al 2014

420

Exercise Tolerance: mean exercise duration was 8.5 ± 3.2 minutes before treatment and 9.1 ± 3.4 minutes after treatment; in the placebo group, exercise duration was 7.7 ± 3.2 minutes before treatment and 7.5 ± 2.9 minutes after 6 months. 12 months

Mortality: 16 patients in the CoQ10 group vs 21 in the control group.

II

Hospitalisation for worsening heart failure: 73 in CoQ10 group vs 118 in the control group (P<0.001);

2 years

Death from any cause: 21 (10%) in the CoQ10 group vs 39 (18%) in the placebo group (p = 0.036, HR 0.51, 95% CI from 0.30 to 0.89). Cardiovascular death: 18 (9%) in the CoQ10 group vs 34 (16%) in the placebo group (p = 0.039, HR 0.51, 95% CI

II

Page 30 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

therapy)

Outcome measures / results

NH MR C leve l of evid enc e

from 0.28 to 0.92) Major adverse cardiovascular events: 30 (15%) in the CoQ10 group vs 57 (26%) in the placebo group (p = 0.005, HR 0.50, 95% CI from 0.32 to 0.80) Heart failure hospitalisation: 17 (8%) in the CoQ10 group vs 31 (14%) in the placebo group [HR 0.51(95% CI 0.270.95), p=0.033).

Zhao et al 2015

RCT; ‘doubleblind’

128

30 mg/d of CoQ10;

Placebo

12 months

Mortality: 6(9.67%)in the CoQ10 group vs 8 (12.12%) in the control group; no statistical analysis reported by authors on mortality data.

II

Adarsh et al 2008

QuasiExperime ntal (nonrandomiz ed experime ntal) study;

87

CoQ10 100 mg twice daily

Placebo

9.4 months to 27.5 months (mean of 14.5 months);

Mortality: 1 in the CoQ10 group vs 1 in the control group;

III

Beetroot juice

Improvement in QoL: 37 (80.4%) in the CoQ10 group vs 17 (41.5%) in the control group (P < 0.005)

Page 31 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Coggan et al 2015

Doubleblind, placebo controlled randomiz ed crossover design

9

Subjects ingested 140mL concentrate d beetroot juice supplement containing 11.2mmol of No-3

Same subjects ingested 140mL of placebo (No3 depleted beetroot juice) 1 to 2 weeks following the first treatment (washout period)

Duration of investigation lasted 2 weeks approximately (follow up period unclear)

Exercise Capacity: 6 min walk distance between the intervention and placebo groups did not change significantly (528±30m intervention; 517±31m placebo; P=0.29)

II

Hirai et al 2017

Doubleblind, randomiz ed crossover

13

Subjects consumed 2x70mL bottles of nitrate rich juice

nitrate depleted (placebo) beetroot juice,

Follow up period unclear

No significant difference in duration of exercise tolerance between nitrate and placebo (495 ± 53 vs. 489 ± 58 s, respectively; P>0.05)

II

Page 32 of 43 Author

Study type

Number of particip ants

study

Zamani et al 2015

Double blind, randomiz ed crossover study

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Identical nitrate depleted placebo

Not specified, but indicated that the procedure ranged up to 42 days

Exercise capacity:

II

containing 6.45mmol (0.4g) of nitrate daily (one in the morning and one in the evening) for 9 consecutive days.

20

A single dose of inorganic nitrate is given to subjects in the form of concentrate d beetroot juice

  

Peak Vo2 12.6±3.7 in beetroot juice group vs 11.6±3.1mL O2 kg-1 min-1 in placebo group; mean difference 1.0±1.2mL O2 kg-1 min-1, P=0.0051) total work performed 55.6±35.3 vs 49.2 ±28.9kJ; mean difference 6.5±11.9 kJ; P=0.04 exercise duration 15.3±4.9 vs 14.5±4.4 minutes; mean difference 0.8±1.3 minutes; P=0.02

Page 33 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

Same volume of NO3− depleted BRJ

3 hours

VO2 peak improvement of 8 ± 2% with beetroot juice compared to placebo (from 21.4 ± 2.1 to 23.0 ± 2.3 mL.min−1.kg−1, p<0.05).

Nitratedepleted

8 days

Mean intermittent shuttle walk test (ISWT) distance increased by 65 +/- 41 meters (431 to 496 meters, 15%) in

containing 12.9mmol NO3- in 140mL Coggan et al 2018

Doubleblind, randomiz ed crossover study

8

140 mL of a concentrate d BRJ supplement (Beet It Sport, James White Drinks, Ipswich, UK) containing 11.2mmol of NO3−

Kerley et al 2016

Doubleblind,

12

.

140 ml of nitrate-rich

NH MR C leve l of evid enc e

Page 34 of 43 Author

Study type

Number of particip ants

randomiz ed crossover study

Intervention

Comparison

beet-root juice (NO3 – ; 12.9 mmol nitrate)

beet-root juice (PL;o 0.5 mmol nitrate)

Tailored diet optimization , and nutritional supplements

Not described

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

the beetroot juice group vs a decrease of 5+/-35 meters (437 to 433 meters, 1%) after placebo (p=0.0056).

Combination nutraceuticals BonillaPalomas et al 2016;

RCT

120

12 months

Mortality: 20.3% of patients died in the intervention group vs 47.5% in the control group (HR 0.37; 95% CI, 0.19-0.72, p=0.003) Readmission for worsening HF: 10.2% in the intervention group vs 36.1% in the control group (HR 0.21; 95% CI, 0.090.52, p=0.001) All-cause death or readmission: 27.1% of in the intervention group vs 60.7% in the control group (HR 0.45; 95% CI, 0.19-0.62, p=0.0004)

McKeag et al 2014

Randomiz ed, double blind placebo

79

Multiple micronutrien t supplement containing 1

Placebo

12 months

Quality of life: Mean change 5.3, 95% CI -1.1 to 11.8, p=0.103 Physical Function Measured as distance walked over 6 minute: Mean change 10.3, 95% CI -14.9 to 35.5, p=0.418

II

Page 35 of 43 Author

Study type

Number of particip ants

controlled parallelgroup study

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Forceval® tablet and 2 X 25-µg vitamin D3 tablets

Hawthorn extract Daniele et al 2006

Systematic review

5577

Daily dose of hawthorn monoprepar ations ranged from 160 to 1800mg.

Placebo

3 weeks to 2 years

166 adverse events reported, most were mild to moderate. Eight severe adverse events reported with LI 132 extract. The most frequent adverse events were dizziness/vertigo (n=15), gastrointestinal complaints (n=24), headache (n=9), migraine (n=8) and palpitation (n=11).

I

Guo et al 2008(35)

Systematic review of interventio ns

855

Two brands of hawthorn extract WS 1442 and LI132 were used; seven

Placebo

8 weeks and 26 weeks (not reported for some included trials)

Maximal workload: Significant increase in patients receiving hawthorn extract compared to placebo group [IV 5.35 (95% CI 0.71, 10.00), P<0.02, n=380).

I

Exercise tolerance: increase in favour of the treatment; (IV 122.76, 95% CI [32.74 to 212.78], p=.0075, n=98)

Page 36 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

of eight trials used WS 1442.

Outcome measures / results

NH MR C leve l of evid enc e

6 min walk test: IV -8.00, (95% CI -34.49 to 18.49), p=0.55

Daily dose ranged from 160mg to 1800mg.

Holubars ch et al 2008

Schmidt et al 1994

Randomiz ed, doubleblind, placebo controlled study

3601

Multicent er placebo controlled doubleblind trial

78

900mg/day of WS® 1442

Placebo

2 years

Cardiac event: Cardiac death (sudden cardiac death, death II due to progressive heart failure, fatal myocardial infarction), non-fatal myocardial infarction or hospitalisation due to progressive heart failure: 27.9% (373 of 1338) and 28.9% (388 of 1343) in the WS® 1442 and placebo groups respectively. The average time to first cardiac event: 620 and 606 days in the WS® 1442 and placebo groups respectively (p=0.51)

600mg of Crataegus extract LI 132/ day

Placebo

8 weeks

Working capacity: test group (28 watt) vs placebo group (5 watt), p<0.001

II

Page 37 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Zick et al 2009

Randomiz ed doubleblind placebo controlled trial

120

Crataegus Special Hawthorn extract WS 1442: 450mg of hawthorn twice a day

Placebo

6 months

Exercise Capacity (6MWT): No significant differences found between groups (p=0.61)

II

Functional capacity: No significant differences found between groups (p=0.22) Quality of Life: no significant differences found between groups (total p=0.62; emotional p=0.83; physical p=0.53) Hospitalisation: no significant difference between either total (p=0.07) or CHF-related (p=0.11) hospitalisations Mortality: No significant difference in total deaths due to CHF (p=0.92 or CVD (p=0.99) between treatment groups.

Magnesium Stepura et al 2009

Prospectiv e, randomiz ed, doubleblind,

79

6000mg magnesium orotate for one 3000mg thereafter

Placebo

12 months

Patients still alive at 12 months: Intervention n= 28/37, Control n= 16/31; p=0.0458

II

Page 38 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Randomiz ed, double blind trial

30

2 daily doses of IV 100mg Thiamine HCl for one week followed by oral thiamine 200mg daily

Placebo IV for one week followed by oral thiamine 200mg daily

6 weeks

Mortality: two in the intervention group and one in the placebo

II

Cross-over RCT

40

Vitamin C 4000 mg daily for 4 weeks followed by placebo for 6 weeks

Placebo for 6 weeks followed by Vitamin C 4000 mg daily for 4 weeks

10 weeks

placebocontrolled study Thiamine Shimon et al 1995

Mean NYHA class decreased from 2.6 ± 0.6 at baseline to 2.2 ± 0.7 (
Vitamin C Ho 2007

Exercise Capacity: A significant difference between the groups was found at 4 and 10 weeks (P<0.001, and p=0.005)

II

Page 39 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Jiang et al 2016(50)

Systematic Review

576

Conventional treatment

20 weeks to 6 months

Exercise Capacity (6MWT): No significant heterogeneity (I2 =0.0%, p=0.846). Vitamin D supplementation was not superior to conventional treatment (WMD: 8.90 m, 95% CI:−48.47 to 66.26, P = 0.76)

I

Boxer et al 2013

Parallel randomize d controlled double blind placebo trial Randomize d Controlled double blind placebo trial Double blind RCT

64

Vitamin D dose varied from 50 000 IU/wk to 100 000 IU at baseline and 10 wk Vitamin D3 50, 0000 IU weekly for 6 months; Calcium citrate 800mg daily

Placebo weekly for 6 months; Calcium citrate 800mg daily

6 months

Exercise tolerance: There was no statistically significant difference between the groups in terms of peak Vo2 (p=0.3), 6MWD (p=0.9), TGUG (p=0.3) and isokinetic muscle testing (extension 60o s-1 p=0.9; 120o s-1 p=0.2; Flexion 60o s-1 p=0.3; 120 o s-1 p=0.2)

II

Vitamin D3 50, 0000 IU weekly for 6 months; Calcium citrate 800mg daily Daily supplement of

Placebo weekly for 6 months; Calcium citrate 800mg daily

6 months

Quality of life: There was no statistically significant difference between the groups. There was a clinically relevant change (≥ 5 points) in all domains

II

Placebo

9 months

Survival Rates: 85.7% and 88.2% respectively; p=0.836

II

Vitamin D

Boxer et al 2014

Schleithoff et al 2006

64

123

Page 40 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

50 µg (2000 IU) cholecalciferol Witte et al 2016

Zitterman n et al 2017

Outcome measures / results

NH MR C leve l of evid enc e

Maximal oxygen intake (Vo2 max): There was no statistically significant change (p=0.429)

Randomize d placebocontrolled trial Single center, prospectiv e randomize d, placebo controlled clinical trial

223

100 µg cholecalciferol (4000 IU daily)

Placebo

12 months

There was no statistically significant improvement in 6MWT; no other data presented.

II

934

4000IU vitamin D3

Placebo

3 years

Mortality: 19.6% (n=39) in the vitamin D group and 17.9% (n=36) in the placebo group; HR 1.09; 95% CI: 0.69–1.71; P=0.726

II

Double blind RCT

56

335.6 mg (500IU) RRR-α tocopherol

Placebo

12 weeks

Quality of life: no significant changes in the quality of life.

II

Double blind RCT

68

2g tds of Larginine

Placebo

12 weeks

Functional class: Decrease from NYHA class III, to class I-II in 77% of active and 20% placebo (p=0.03).

II

Hospitalisation: 67.4% (n=126) and 60.0% (n=112) in patients assigned to vitamin D and placebo, respectively; HR 1.26, 95% CI (0.98 to 1.63), p=0.075

Vitamin E Keith et al 2001

L-arginine Fontanive et al 2009

Page 41 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Quality of life: There was no statistically significant difference between the groups (p=0.205) Exercise Capacity (6MWT): No significant differences found between groups L-carnosine Lombardi et al 2015

Open label RCT

50

500mg per day of orodispersibl e Lcarnosine

Usual care

Dosage varied 1 to 6mg per day

Placebo

6 months

Exercise capacity: Improvement in 6MWT distance (p=0.014), increase in peak VO2 (p<0.0001), VO2 at anaerobic threshold (p=0.003), peak exercise workload (p=0.033).

II

Quality of life: Improved in L-carnosine group compared with placebo. EQ-5D (p=0.018) and EuroQoL Visual Analogue Scale score (p<0.0001)

L-carnitine Song et al 2017

Systematic review (with metaanalysis)

1625

7 days to 3 years

Mortality: No difference in mortality (p=0.08) Exercise capacity: No difference in 6MWD (p=0.14)

I

Page 42 of 43 Author

Study type

Number of particip ants

Intervention

Comparison

Length of follow up

Outcome measures / results

NH MR C leve l of evid enc e

Page 43 of 43