Cristiana and Giuseppe MC: Medical Treatment of Heart Failure with Reduced Ejection Fraction — Improving Clinical Status and Functional Capacity.

Introduction

The improvement of functional capacity is one of the main goals of treatment in patients with HFrEF.[1] In the past, despite significant effects on exercise capacity some drugs (e.g. ibopamine, flosequinan) have shown detrimental effects on long-term outcomes in patients with HFrEF.[2,3] It is perhaps notable that both of these drugs had shown signals of increased safety concerns during the earlier clinical phases of their development.[4,5] The challenge is to encourage a timely identification of effective treatments that can enhance functional performance in HF without the more difficult and more expensive path to prove all drugs also reduce mortality. It is valuable to have approved and effective treatments that can do the first without the need for the second in all cases, provided adequate safety can be assured.

It is now clear that stabilisation or improvement of exercise capacity reflects the ability of effective treatments to slow or prevent progressive worsening of HF and are important patient related outcomes. Amongst the drugs effective in improving prognosis in patients with heart failure some have a neutral or sometime negative effect on exercise capacity while some others have shown a significant improvement in exercise capacity. ACEi, ARBs and MRAs have a neutral effect on exercise capacity in patients with HFrEF while beta-blockers tend to reduce exercise tolerance. There are no data available on the effect of LCZ696 on exercise capacity in patients with HFrEF.

The only pharmacological treatments with a significant effect on cardiovascular prognosis that have consistently shown to improve exercise capacity are ivabradine, trimetazidine, intravenous iron and diuretics. Amongst devices CRT has been consistently shown to improve prognosis and improve exercise capacity in patients with HFrEF, and cardiac contractility modulation (CCM) have been shown to improve exercise capacity in one study and a comprehensive individual patient data meta-analysis.[6-7]

Figure 1.

Effect of ACE inhibitors in HFrEF in the Cilazapril captopril study9

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Figure 2.

Effect of candesartan on exercise capacity in HFrEF.11

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There are no adequate surrogate measures for mortality in heart failure, however once the drug has been shown to have a positive effect on prognosis it is important to assess its effect on well being. This can be difficult because of both patient and researchers biases in assessing well-being. Indeed, patients’ perceptions may be affected by their state of health, by their expectations, by related co-morbidities and by their personal priorities. Similarly, the medical assessment of patient general status is influenced consciously or unconsciously by information on the severity of the disease derived from investigations, and the doctors’ perceptions of likely prognosis derived from these. Exercise capacity, when reliably measured, represents a good measure of the effect of a given treatment on functional status of patients with heart failure.

Exercise tests using both bicycle or treadmill have been used to assess the effects of therapy in heart failure.[8] More objective assessment of true maximal exercise capacity utilising respiratory gas exchange to establish a close to maximal effort improves reliability of exercise capacity assessment. This allows the assessment of maximal oxygen consumption as the best available measure of functional capacity. This has been used for the pre-transplant assessment of patients with heart failure and assessing the effects of heart failure interventions. However, exercise testing and assessment of gas exchange may be difficult to administer in all patients as patients may be unable to exercise on a bicycle or to breathe into a gas exchange mask. Heart failure patients, however, can perform a self-paced 6 min walk test (6MWT). This test has long been used as an outcome measure in clinical trials and its results have been shown to be concordant with changes in symptoms, suggesting that it is a good indicator for symptom benefit.[8] A significant increase in 6MWT has been observed with cardiac resynchronization and CCM for example.[6–7]

ACE-inhibitors and ARBs

Despite their prognostic benefits ACE inhibitors have failed to show significant effects on functional capacity and no difference between ACE-I and ARBs has been ever demonstrated.

In general the adequately sized studies aimed at assessing the effect of ACE- I on exercise capacity have reported a neutral effect on functional status. One large multicentre, placebo-controlled trial testing captopril and cilazapril failed to show any effect of ACE-inhibition.[9] (Figure 1) One study testing the effect of perindopril showed a significant improvement in exercise capacity.[10] One adequately sized study compared candesartan with placebo and showed no effect (Figure 2).[11] Four studies have compared the effect of ARBs with the ACEI enalapril, and found no differences in functional capacity nor on patient reported outcomes.[12–15]Therefore, the overall effect of RAAS inhibitors on functional capacity and symptoms appears to be neutral.

Beta-blockers

Beta-blockers have a neutral or negative effect on exercise capacity.[8] A small effect has been shown with carvedilol in some studies but this effect has not been consistently demonstrated and confirmed. Only 3 of 20 trials and only one of five multicentre studies investigating the effect of beta-blockers on 6MWT showed an improvement.[8,16–20] When detected, this effect has been marginal (Figure 3). Two trials compared the effect of metoprolol and carvedilol on 6MWT and showed no difference between these two beta-blockers.[21,22] Carvedilol and bisoprolol have consistently been shown to be inferior to ivabradine in their effects on symptomatic improvement and on exercise capacity in separate well sized studies.[23,24]

Therefore, despite their prognostic benefits beta-blockers do not improve symptoms and functional tolerance in patients with heart failure, but other treatments may do so. Higher doses of beta-blockers are associated with fatigue and with reduced exercise tolerance and therefore it is unlikely that merely increasing the dose of beta-blockade will improve functional capacity in HF patients. Therefore, we may consider down-titration of beta-blocker dose in patients reporting fatigue or a decrease in exercise capacity and replacing this with the alternative heart rate reducing agent, ivabradine that does not decrease (and may actually increase) exercise capacity in HF patients.

Figure 3.

Overall effect of beta-blockers on exercise capacity in HFrEF [16–24]

icfj.2017.10.22-g003.jpg

Figure 4.

Ivabradine plus bisoprolol compared to up-titration of bisoprolol on exercise capacity (Amosova et al. ACC. 2010)

icfj.2017.10.22-g004.jpg

Figure 5.

Ivabradine plus carvedilol compared to uptitration of carvedilol on exercise tolerance and symptoms23

icfj.2017.10.22-g005.jpg

Figure 6.

CARVIVA-HR: Effect of ivabradine carvedilol or combination on exercise capacity.24 (* P < 0.01 vs baseline. † P < 0.01, †† P < 0.02 vs carvediolol)

icfj.2017.10.22-g006.jpg

Ivabradine

The prognostic benefits of ivabradine in patients with heart failure are coupled with a significant improvement in functional capacity and well-being. In one early randomised study in patients with underlying coronary artery disease, the combination of ivabradine and bisoprolol was found to be more effective at improving exercise capacity than doubling the bisoprolol dose in patients receiving bisoprolol 5 mg at baseline (Figure 4). A further study showed a similar effect with ivabradine added to carvedilol being more effective than uptitrating the dose of cavedilol in patients with HFrEF (Figure 5).[23]

Figure 7.

Effect of trimetazidine in patients with HFrEF (derived from Marazzi G et al. Eur J Heart Fail. 2016 (Suppl 1): 51)

icfj.2017.10.22-g007.jpg

In another large randomised study Volterrani et al compared the effect of heart rate reduction with carvedilol, ivabradine, and their combination on exercise capacity in patients with HFrEF receiving maximal dose of ACE inhibitors.[24] The maximal dose of study treatment was more frequently tolerated in patients receiving ivabradine than in those receiving carvedilol. Heart rate was reduced in all three groups, but to a greater extent by combination therapy and the distance walked on the 6-min walking test improved significantly only in patients receiving ivabradine alone or in association with carvedilol while it did not change with carvedilol.(Figure 6) The effects observed on the 6MWT were mirrored by similar improvements on MVO2. Patients receiving ivabradine alone or in combination had better quality of life compared with carvedilol that did not change quality of life compared to baseline values.[24]

The effect of ivabradine on exercise capacity and maximal oxygen consumption was confirmed by another randomised study in patients with ischemic heart failure receiving background beta-blockers. In this study exercise capacity increased doubled and maximal oxygen consumption increased by nearly 30% with ivabradine.[25] These data show that heart rate reduction with ivabradine leads to a better exercise capacity compared to beta blockers alone and that the association of ivabradine with a beta-blocker is effective in improving functional capacity and quality of life compared to beta-blocker alone suggesting that combination therapy is more beneficial than simple beta-blockade. The better effect of ivabradine compared to beta blockers on exercise capacity seems related not only to heart rate reduction, but may also be due to the differing effects of ivabradine and beta-blockers on skeletal muscle perfusion and performance during exercise. It is well known that beta-blockers impair the alpha-adrenergic-mediated dilation that occurs during exercise while ivabradine preserves the exercise-induced increase in blood flow.[26–28] These effects reflect a better muscle performance during exercise with ivabradine compared to beta-blockers. Given the prognostic effect of ivabradine and its effect on functional capacity and patients related outcomes this drug should always be considered for the treatment of patients with HFrEF. It should always be considered in patients in sinus rhythm. Furthermore, its implementation, associated with an adjustment of the beta-blocker dose, in patients receiving full beta-blockade, especially when reporting fatigue or limited exercise tolerance, may lead to an improved functional status.

Figure 8.

Effect of trimetazidine on exercise capacity in patients with HFrEF

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Figure 10.

CONFIRM HF study – change in 6-minutes walking test with ferric carboxymaltose [49]

icfj.2017.10.22-g010.jpg

ARNI – Angiotensin receptor neprilysin inhibitor

There are no data on the effect of LCZ696 on functional capacity in patients with heart failure. The PARADIGM-HF study showed that the drug was associated with a reduction of the worsening of functional status as assessed by KCCQ change from baseline to month 8. During the first eight months of the study patients receiving LCZ696 had a worsening of the clinical score of –2.99 points compared to –4.63 points in the enalapril group with a significant between-group difference of 1.64 points.[29]

Mineralocorticoid/aldosterone receptor antagonists [MRAs]

While the effect of MRAs on exercise capacity in patients with HFpEF has been extensively investigated, this effect has not been systematically tested in patients with HFrEF. In one randomised study the adjunct of spironolactone to ACEi and diuretics did not increase exercise capacity in HFrEF.[30]

Digoxin and other digitalis glycosides

The effect of digoxin on exercise capacity is neutral. Indeed, only one of four trials showed an improvement in exercise capacity.[31-34] Of importance, the largest of these studies that by itself included more patients than all other studies together (580 patients), did not show any benefit of digoxin on exercise capacity compared to placebo.[35] Whether the effect of digoxin differs between patients in sinus rhythm and those in atrial fibrillation has not been investigated.

Diuretics

Diuretics improve symptoms of congestion in patients with HFrEF.[1] The available data from small trials suggest that in patients with HFrEF conventional diuretics appears to improve exercise capacity when compared to a placebo or to an active comparator. Four trials compared diuretics to active control and showed that diuretics improved exercise capacity in participants. [36-39] Whether the effect of diuretics on exercise capacity was dependent upon the degree of congestion at baseline is not known. All these studies have reported an improvement in symptoms with diuretic therapy.

Metabolic agents

It is well known that altered cardiac metabolism plays an important role in the pathophysiology of heart failure. In particular, chronic HF may be conceived as “a ketosis-prone state” with a switch towards free fatty acid utilisation in the heart. Trimetazidine is an inhibitor of free fatty acid oxidation that shifts cardiac metabolism from free fatty acids to glucose utilisation resulting into a greater production of high-energy phosphates. This translates into a greater myocardial efficiency. Trimetazidine added to standard therapy improves symptoms and exercise capacity in patients with HFrEF of ischaemic and non ischaemic aetiology.

The effect of trimetazidine on symptoms and functional capacity has been tested in several studies in patients with HFrEF. Three meta-analyses of the available data suggest that Trimetazidine improves symptoms, exercise capacity and prognosis in patients with HFrEF.[40-42] The effect of trimetazidine on exercise capacity and symptoms are concordant in all studies and suggest an additive effect on top of medical therapy and on top of cardiac rehabilitation programmes. (Figure 7 and 8) It has been observed that trimetazidine improves skeletal muscle metabolism.[43–45] This suggests that the main effect of trimetazidine on functional capacity in patients with heart failure may be dependent upon cardiac metabolic effects more than by other mechanisms. Given its positive effect on prognosis in patients with heart failure and its significant effect on symptoms and functional capacity trimetazidine should be always considered in the treatment of patients with heart failure to improve symptoms, quality of life, exercise capacity and prognosis.

Figure 9.

FAIR-HF change in exercise capacity and KCCQ with ferric carboxymaltose in patients with HFrEF [47]

icfj.2017.10.22-g009.jpg

Figure 11.

Effect of testosterone on functional capacity in men and women with HFrEF [50-51]

icfj.2017.10.22-g011.jpg

Iron supplementation

Iron deficiency occurring in patients with heart failure is associated with impaired functional capacity, poor quality of life, and increased mortality.[4647] The effect of correction of iron deficiency on exercise capacity has been tested in a few clinical studies. The Ferric Iron Sucrose in Heart Failure (FERRIC-HF) study was one of the first placebo-controlled studies that used iron sucrose to replenish iron stores, irrespective of the presence of anaemia. Thirty-seven patients were randomised in a 2 to 1 ratio (either iron sucrose or placebo) according to their haemoglobin values. Therapy was continued until iron status was normalised. Patients with iron deficiency who received intravenous iron improved their exercise capacity by a mean change in maximal oxygen uptake of almost 2 mL/kg/min.

More recently intravenous administration of ferric carboxymaltose has been consistently shown to improve exercise capacity in patients with HFrEF and low ferritin levels regardless of the presence of anaemia in the FAIR-HF and in the CONFIRM-HF studies (Figure 9 and 10).[4849] The FAIR HF study reported a significant improvement with ferric carboxymaltose in the quality of life as measured by the self-reported Patient Global Assessment, improvement (20 metres) in exercise capacity and in the assessment of quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ).[48] The CONFIRM-HF study showed that ferric carboxymaltose administration in iron-deficient HFrEF patients with and without anaemia caused a sustained improvement in functional capacity over a 12 month period. Of importance patients treated with ferric carboxymaltose showed a significantly reduced risk of hospital admission due to worsening HF during a 1-year follow-up.

A recent meta-analysis of the studies conducted with ferric carboxymaltose in patients with HFrEF with or without anaemia has suggested that this iron formulation reduces re-hospitalisation rates. Therefore, intravenous administration of ferric carboxymaltose is indicated in all patients with HFrEF with ferritin levels <299 μg/l. Oral administration of iron is inadequate to correct low ferritin levels and should not be considered as an alternative to intravenous iron.

Testosterone

Testosterone supplementation in patients with HFrEF has been shown to improve exercise capacity regardless of the baseline testosterone levels in both men and women.[50–51] (Figure 11) Randomised controlled studies have shown that the effect of testosterone supplementation is related to the improvement in muscle strength and not to any effect on central haemodynamics. A meta-analysis of the available data support the significant benefit of testosterone supplementation in improving exercise capacity in patients with heart failure.[52] The effect is more evident when testosterone supplementation is associated with cardiac rehabilitation programmes. Supra-physiological and supra-therapeutic testosterone supplementation does not have any additional effect on functional capacity and may worsen clinical status. Testosterone supplementation can be considered in patients with muscle wasting or with cachexia. Supplementation therapy will need adequate monitoring of prostate health and fluid retention.

Calcium channel blockers.

Worsening of heart failure has been reported with all classes of calcium channel blockers. An early small study suggested that amlodipine had a minimal effect on exercise tolerance in heart failure. However, 2 subsequent multicentre studies including patients assessed the effect of amlodipine on exercise capacity and quality of life in patients with HFrEF. Although no statistically significant excess of adverse events were reported the episodes of worsening heart failure were higher in amlodipine-treated patients (10% vs 6.3%). Amlodipine had no effect on exercise tolerance, increasing exercise time less than placebo (53 ± 9 seconds vs 66 ± 9 seconds).[53] Therefore, calcium channel blockers have no effect on exercise tolerance in patients with heart failure. These drugs should not be used in patients with heart failure unless there is a compelling need.

In conclusion, ivabradine, trimetazidine, ferric carboxymaltose and diuretics have consistently shown to improve functional capacity and symptoms in patients with HFrEF because of their effect on long term prognosis these drugs should always be considered in patients with heart failure. Diuretics improve functional capacity and should be prescribed in patients with signs and symptoms of congestions. Cardiac resynchronisation therapy improves functional capacity in patients with HFrEF in whom it is appropriately applied (QRS >130/150 msec according to morphology).

Declarations of Interest

The authors declare no conflicts of interest.

Acknowledgements

The authors state that they abide by the requirements for ethical publishing in biomedical journals. [53]

References

1. 

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P 2016; ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016; May20

2. 

Massel D Ibopamine and survival in severe congestive heart failure: PRIME II. Lancet. 1997; Jul12350(9071)147

3. 

Kamali F, Edwards C Possible role of metabolite in flosequinan-related mortality. Clin Pharmacokinet. 1995; Dec29(6)396–403

4. 

Massie BM, Berk MR, Brozena SC, Elkayam U, Plehn JF, Kukin ML, Packer M, Murphy BE, Neuberg GW, Steingart RM et al Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET). Circulation. 1993; Aug88(2)492–501

5. 

Packer M, Narahara KA, Elkayam U, Sullivan JM, Pearle DL, Massie BM, Double-blind Creager MA placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. J Am Coll Cardiol. 1993; Jul22(1)65–72

6. 

Kuschyk J, Roeger S, Schneider R, Streitner F, Stach K, Rudic B, Weiß C, Schimpf R, Papavasilliu T, Rousso B, Burkhoff D, Borggrefe M Efficacy and survival in patients with cardiac contractility modulation: long-term single center experience in 81 patients. Int J Cardiol. 2015; Mar15183: 76–81

7. 

Giallauria F, Vigorito C, Piepoli MF, Stewart Coats AJ Effects of cardiac contractility modulation by non-excitatory electrical stimulation on exercise capacity and quality of life: An individual patient’s data meta-analysis of randomized controlled trials. Int J Cardiol. 2014; Aug1175(2)352–7 10.1016/j.ijcard.2014.06.005

8. 

Olsson LG, Swedberg K, Clark AL, Witte KK, Cleland JG Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review. Eur Heart J. 2005; Apr26(8)778–93

9. 

The Cilazapril-Captopril Multicenter Group. Comparison of the effects of cilazapril and captopril versus placebo on exercise testing in chronic heart failure patients: a double-blind, randomized, multicenter trial. Cardiology. 1995; 86: (Suppl. 1)34–40

10. 

Hutcheon SD, Gillespie ND, Crombie IK et al Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomized double blind placebo controlled trial. Heart. 2002; 88: 373–377

11. 

Granger CB, Ertl G, Kuch J et al Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J. 2000; 139: 609–617

12. 

Dickstein K, Chang P, Willenheimer R et al Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol. 1995; 26: 438–445

13. 

Lang RM, Elkayam U, Yellen LG et al Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. The Losartan Pilot Exercise Study Investigators. J Am Coll Cardiol. 1997; 30: 983–991

14. 

McKelvie RS, Yusuf S, Pericak D et al Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. The RESOLVD Pilot Study Investigators. Circulation. 1999; 100: 1056–1064

15. 

Willenheimer R, Helmers C, Pantev E et al Safety and efficacy of valsartan versus enalapril in heart failure patients. Int J Cardiol. 2002; 85: 261–270

16. 

Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation. 1995; 92: 212–218

17. 

Australia/New Zealand Heart Failure Research Collaborative Group. Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet. 1997; 349: 375–380

18. 

Packer M, Colucci WS, Sackner-Bernstein JD et al Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996; 94: 2793–2799

19. 

Refsgaard J, Andreasen F, Gotsche O Divergent outcome between six minute walking test and maximal bicycle test during treatment with carvedilol in patients with mild to moderate heart failure. Eur J Heart Fail. 2000; 2: 95

20. 

Krum H, Sackner-Bernstein JD, Goldsmith RL et al Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation. 1995; 92: 1499–1506

21. 

Sanderson JE, Chan SK, Yip G et al Beta-blockade in heart failure: a comparison of carvedilol with metoprolol. J Am Coll Cardiol. 1999; 34: 1522–1528

22. 

Metra M, Giubbini R, Nodari S et al Differential effects of betablockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation. 2000; 102: 546–551

23. 

Bagriy AE, Schukina EV, Samoilova OV, Pricolota OA, Malovichko SI, Pricolota AV, Bagriy EA Addition of ivabradine to β-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther. 2015; Feb32(2)108–19

24. 

Volterrani M, Cice G, Caminiti G, Vitale C, D’Isa S, Perrone Filardi P, Acquistapace F, Marazzi G, Fini M, Rosano GM Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure (the CARVIVA HF trial). Int J Cardiol. 2011; Sep1151(2)218–24

25. 

Sarullo FM, Fazio G, Puccio D, Fasullo S, Paterna S, Novo S, Di Pasquale P Impact of ‘’off-label” use of ivabradine on exercise capacity, gas exchange, functional class, quality of life, and neurohormonal modulation in patients with ischemic chronic heart failure. J Cardiovasc Pharmacol Ther. 2010; Dec15(4)349–55

26. 

Baumgart D, Haude M, Gorge G et al Augmented alpha-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999; 99: 2090–7568.

27. 

Heusch G, Baumgart D, Camici P et al Alpha-adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000; 101: 689–94570.

28. 

Simon L, Ghaleh B, Puybasset L, Giudicelli JF, Berdeaux A Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995; 275: 659–66

29. 

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014; Sep11371(11)993–1004

30. 

Kinugawa T, Ogino K, Kato M, Furuse Y, Shimoyama M, Mori M, Endo A, Kato T, Omodani H, Osaki S, Miyakoda H, Hisatome I, Shigemasa C Effects of spironolactone on exercise capacity and neurohormonal factors in patients with heart failure treated with loop diuretics and angiotensin-converting enzyme inhibitor. Gen Pharmacol. 1998; Jul31(1)93–9

31. 

Packer M, Gheorghiade M, Young JB et al Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin converting-enzyme inhibitors. RADIANCE Study. N Engl J Med. 1993; 329: 1–7

32. 

Guyatt GH, Sullivan MJ, Fallen EL et al A controlled trial of digoxin in congestive heart failure. Am J Cardiol. 1988; 61: 371–375

33. 

Uretsky BF, Young JB, Shahidi FE et al Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol. 1993; 22: 955–962

34. 

Lader E, Egan D, Hunsberger S et al The effect of digoxin on the quality of life in patients with heart failure. J Card Fail. 2003; 9: 4–12

35. 

Lader E, Egan D, Hunsberger S et al The effect of digoxin on the quality of life in patients with heart failure. J Card Fail. 2003; 9: 4–12

36. 

Boccanelli A, Zachara E, Liberatore SM, Carboni GP, Prati PL Addition of captopril versus increasing diuretics in moderate but deteriorating heart failure: a double-blind comparative trial. Postgraduate Medical Journal. 1986; 62(Suppl 1)184–87

37. 

Haerer W, Hetzel M, Fehske KL, Fehske KL, Stauch M The impact of digoxin and diuretics on exercise tolerance in congestive heart failure: a placebo controlled randomised double-blind trial. Circulation. 1989; 80: 1698A

37. 

Cowley AJ, Stainer K, Wyne RD, Rowley JM, Hampton JR Symptomatic assessment of p8tients with heart failure: double-blind comparison of increasing doses of diuretics and captopril in moderate heart failure. Lancet. 1986; 2: 770–72

39. 

Richardson A, Bayliss J, Scriven AJ, Sutton GC, Poole-Wilson PA Double-blind comparison of captopril alone against furosemide plus amiloride in mild heart failure. Lancet. 1987; 2(8561)709–11

40. 

Zhao Y, Peng L, Luo Y, Li S, Zheng Z, Dong R, Zhu J, Liu J Trimetazidine improves exercise tolerance in patients with ischemic heart disease: A meta-analysis. Herz. 2015; Dec14 10.1007/s00059-015-4392-2(epub ahead of print)

41. 

Zhang L, Lu Y, Jiang H, Zhang L, Sun A, Zou Y, Ge J Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol. 2012; Mar659(10)913–22 10.1016/j.jacc.2011.11.027

42. 

Gao D, Ning N, Niu X, Hao G, Meng Z Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart. 2011; Feb97(4)278–86

43. 

Ferraro E, Pin F, Gorini S, Pontecorvo L, Ferri A, Mollace V, Costelli P, Rosano G Improvement of skeletal muscle performance in ageing by the metabolic modulator Trimetazidine. J Cachexia Sarcopenia Muscle. 2016; Jan5Published online 2016 Jan 5. 10.1002/jcsm.12097

44. 

Lopatin YM, Rosano GM, Fragasso G, Lopaschuk GD, Seferovic PM, Gowdak LH, Vinereanu D, Hamid MA, Jourdain P, Ponikowski P Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol. 2016; Jan15203: 909–15

45. 

Ferraro E, Giammarioli AM, Caldarola S, Lista P, Feraco A, Tinari A, Salvatore AM, Malorni W, Berghella L, Rosano G The metabolic modulator trimetazidine triggers autophagy and counteracts stress-induced atrophy in skeletal muscle myotubes. FEBS J. 2013; Oct280(20)5094–5108

46. 

Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, Borodulin-Nadzieja L, von Haehling S, Doehner W, Banasiak W, Polonski L, Filippatos G, Anker SD, Ponikowski P Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011; 17: 899–906

47. 

Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, von Haehling S, Macdougall IC, Weiss G, McMurray JJ, Anker SD, Gheorghiade M, Ponikowski P Iron status in patients with chronic heart failure. Eur Heart J. 2013; 34: 827–834

48. 

Anker SD, Colet JC, Filippatos G, Willenheimer R, Dickstein K, Drexler H Lüscher TF, Bart B, Banasiak W, Niegowska J, Kirwan BA, Mori C, von Eisenhart Rothe B, Pocock SJ, Poole-Wilson PA, Ponikowski P, for the FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361: 2436–2434

49. 

Ponikowski P, van Veldhuisen DJ, Comin-Colet J, Ertl G, Komajda M, Mareev V, McDonagh T, Parkhomenko A, Tavazzi L, Levesque V, Mori C, Roubert B, Filippatos G, Ruschitzka F, Anker SD CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†. Eur Heart J. 2015; Mar1436(11)657–668

50. 

Iellamo F, Volterrani M, Caminiti G, Karam R, Massaro R, Fini M, Collins P, Rosano GM Testosterone therapy in women with chronic heart failure: a pilot double-blind, randomized, placebo-controlled study. J Am Coll Cardiol. 2010; Oct1256(16)1310–1316

51. 

Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009; Sep154(10)919–927

52. 

Toma M, McAlister FA, Coglianese EE, Vidi V, Vasaiwala S, Bakal JA, Armstrong PW, Ezekowitz JA Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012; May15(3)315–321

53. 

Udelson JE, DeAbate CA, Berk M, Neuberg G, Packer M, Vijay NK, Gorwitt J, Smith WB, Kukin ML, LeJemtel T, Levine TB, Konstam MA Effects of amlodipine on exercise tolerance, quality of life, and left ventricular function in patients with heart failure from left ventricular systolic dysfunction. Am Heart J. 2000; Mar139(3)503–510

53. 

Shewan LG, Coats AJS, Henein M Requirements for ethical publishing in biomedical journals. International Cardiovascular Forum Journal 2015; 2: 2 10.17987/icfj.v2i1.4



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