Pharmacological Interventions Effective in Improving Exercise Capacity in Heart Failure

Login or register to view PDF.
Abstract

Heart failure (HF) is characterised by exercise intolerance, which substantially impairs quality of life (QOL) and prognosis. The aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF. Ivabradine, trimetazidine and intravenous iron are the only drugs included in the European Society of Cardiology HF guidelines that have consistently been shown to positively affect functional capacity in HF. The beneficial effects on HF symptoms, physical performance and QOL using these pharmacological approaches are described.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Giuseppe Rosano, Centre for Clinical and Basic Research, IRCCS San Raffaele Pisana, via della Pisana 235, 00163 Rome, Italy. E: giuseppe.rosano@sanraffaele.it
Received date
07 February 2018
Accepted date
07 March 2018
Citation
Cardiac Failure Review 2018;4(1):25–7.
DOI
https://doi.org/10.15420/cfr.2018:8:2

Exercise intolerance is a typical symptom of heart failure (HF), impairing patients’ ability to perform activities of daily living and affecting quality of life (QOL).1 Chronic HF is characterised by a progressive reduction in exercise capacity, increasing fatigue and shortness of breath.2 In addition, exercise intolerance is often accompanied by increased blood pressure and chronotropic incompetence.1

According to European Society of Cardiology (ESC) guidelines on HF,1 the goals of treatment are to improve functional capacity and QOL, as well as clinical status, in order to prevent hospital admission and reduce mortality. For these reasons, pharmacological and non-pharmacological interventions have been developed to improve exercise capacity in HF. According to ESC guidelines, exercise training is an integral component of the management of patients with this HF.1 In fact, there is considerable evidence that exercise not only is safe but also leads to physical and psychological benefits in HF patients.3

As for pharmacological intervention, in past decades this has been mainly focused on improving mortality and morbidity, and has added little to exercise capacity and QOL in people with HF. Interventions with effects on exercise capacity have not been considered in the therapeutic algorithm of HF, mainly because early interventions such as flosequinan and ibopamine have been associated with neutral or unfavourable outcomes.4,5 However, more recently, it has become evident that drugs with a positive effect on functional capacity may also positively affect prognosis in HF. With this in mind, the aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF.

Intravenous Iron

Iron deficiency is a common comorbidity of HF, affecting up to 50 % of patients.6–8 It can lead to anaemia and/or skeletal muscle dysfunction without anaemia in HF patients. Iron is a critical component of peroxide- and nitrous oxide-generating enzymes that are critical for mitochondrial function. As a consequence of iron insufficiency, impaired oxygen transport occurs, altering the metabolism of cardiac and skeletal muscle. Owing to these effects on skeletal muscle, iron deficiency is associated with reduced exercise capacity and poor prognosis. In fact, increased morbidity and mortality is associated with this condition.7

For these reasons, the ESC guidelines indicate that ferric carboxymaltose (FCM; intravenous iron) should be considered in symptomatic patients (serum ferritin <100 μg/l, or serum ferritin 100–299 μg/l with transferrin saturation <20 %).1 This recommendation is based on evidence showing that treatment with intravenous FCM decreases symptoms and improves functional capacity and QOL in HF patients.

Earlier studies suggested that in anaemic patients with chronic HF, iron alone (without erythropoietin) increased haemoglobin count, reduced symptoms and improved exercise capacity.9,10 In patients with moderate-to-severe congestive HF and chronic kidney insufficiency, improvements in New York Heart Association (NYHA) class and echocardiographic indices were observed.10

Consistently with this, a double-blind, randomised, placebo-controlled study in anaemic patients with chronic HF and renal insufficiency demonstrated that FCM reduced N-terminal probrain natriuretic peptide (NT-proBNP) levels, and that this reduction was associated with an improvement in exercise capacity as well as left ventricular ejection fraction (LVEF), NYHA functional class, renal function and QOL.11 In addition, the Effect of FCM on Exercise Capacity in Patients with Iron Deficiency and Chronic HF (EFFECT-HF) study further clarified that FCM led to repletion of iron stores and improved HF severity and QOL.12

A single-blind, randomised controlled study demonstrated that FCM improved exercise tolerance, functional class and HF symptoms in patients with chronic HF and evidence of abnormal iron metabolism, with these effects being more evident in anaemic patients.13

Independently of the presence of anaemia, the Ferinject Assessment in Patients with Iron Deficiency and Chronic HF (FAIR-HF) trial showed the benefits of FCM on symptoms, functional capacity and QOL, with an acceptable side-effect profile.14 The Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic HF (CONFIRM-HF) trial showed that the observed improvements in functional capacity, symptoms and QOL were also associated with a decreased risk of hospitalisation for worsening HF at 1 year.15 Two meta-analyses in iron-deficient patients with systolic HF indicated that FCM improved HF symptoms, outcomes, exercise capacity and QOL,16 and that this intervention was associated with a reduction in recurrent cardiovascular hospitalisations.17

On the other hand, the recent Iron Repletion Effects on Oxygen Uptake in HF (IRONOUT-HF) trial, conducted in patients with HF and reduced ejection fraction (HFrEF) and iron deficiency, showed that high-dose oral iron did not improve exercise capacity over 16 weeks.18 These results suggest that oral intake does not provide adequate replacement of iron in HF patients.

Three recently initiated double-blind, placebo-controlled clinical trials (AFFIRM-AHF, FAIR-HF2 and HEART-FID) will investigate the effects of intravenous FCM versus placebo on morbidity and mortality outcomes and will further clarify the impact of intravenous FCM supplementation on functional capacity and clinical outcomes.

Ivabradine

The efficacy of ivabradine in HF is now well established.19–22 ESC guidelines indicate ivabradine for the treatment of HFrEF patients who are in sinus rhythm and who cannot tolerate a beta-blocker, and for those who already receive an angiotensin-converting enzyme inhibitor, a beta-blocker and a mineralocorticoid receptor antagonist and are still symptomatic.1

Clinical trials have demonstrated that ivabradine effectively improves functional capacity in patients with HFrEF. The carvedilol, ivabradine or their Combination on Exercise Capacity in Patients with HF (CARVIVA HF) trial found that ivabradine, alone or in combination with carvedilol, was more effective than carvedilol alone in improving exercise tolerance and QOL in HF patients.21 Patients receiving carvedilol and ivabradine in combination had better exercise performance than those receiving carvedilol alone. The effects of ivabradine on exercise capacity were associated with an improvement in isokinetic strength compared to carvedilol, and with a significant reduction in fatigue index. These data are in agreement with a subanalysis of the Systolic HF Treatment with the If Inhibitor Ivabradine Trial (SHIFT), conducted in 1944 patients, in which health-related QOL was found to be inversely associated with clinical events.19 Treatment with ivabradine was associated with improvements in QOL scores and better outcomes, due to the improvement in exercise capacity and symptoms.

These studies suggest that combined ivabradine and beta-blocker therapy is associated with a better functional capacity than beta-blockers alone, and that combination therapy provides better QOL than beta-blocker monotherapy.23 Furthermore, the combination of carvedilol and ivabradine leads to better control of heart rate and exercise capacity than uptitration of beta-blocker monotherapy. Furthermore, the addition of ivabradine to carvedilol in patients in sinus rhythm, ischaemic HF and heart rate ≥70 BPM was found to lead to a shorter beta-blocker uptitration period, higher final beta-blocker dose, greater heart rate reduction and better exercise capacity.22

Most of the effects of ivabradine on functional capacity are related to the haemodynamic improvements provided by ivabradine in HF, and not only through heart rate reduction.24 In fact, ivabradine provides an anti-remodelling effect, improves left ventricular structures and function, and reduces NT-proBNP levels.25 When compared with beta-blockers, ivabradine, for the same degree of heart rate reduction, does not impair the neuromuscular junction, thereby affecting muscular contraction. For all these reasons, ivabradine is effective in improving functional capacity, relieving symptoms and increasing QOL in patients with HF.26 These effects also translate into prognostic benefits.

Trimetazidine

Trimetazidine is a relatively old agent but relatively new in the treatment of HF. It has been shown to improve LVF, exercise capacity and prognosis in patients with mainly ischaemic HF.27–31

Trimetazidine improves cardiac metabolism by inhibiting free fatty acid oxidation and improving glucose utilisation. This metabolic switch leads to a greater production of high-energy phosphate per mol of oxygen and, therefore, to more energy for contraction. This improved metabolic efficiency translates into greater efficiency of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase and of the actin–myosin interactions.32,33

Several studies have shown that modulation of myocardial metabolism with trimetazidine and drugs acting on the same metabolic pathway, such as perhexiline, may improve left ventricular remodelling and prognosis in patients with HFrEF. Although metabolic modulators have been used in clinical practice for decades, they have been only recently introduced in HF management.

Metabolic agents improve cardiac metabolism without altering haemodynamics.34 Among metabolic agents acting on cardiac myocytes, only perhexiline and trimetazidine are available for clinical use. Trimetazidine is the metabolic agent with the most data in patients with HF, while only a few reports, mainly preclinical, are available for perhexiline.

In chronic HF, trimetazidine improves LVF, normalises myocardial metabolism and improves endothelial dysfunction.35–37 A collaborative, multicentre study has shown that trimetazidine improves mortality in patients with HFrEF.31 A meta-analysis investigating the effects of trimetazidine as add-on treatment in patients with chronic HF demonstrated that the agent improves clinical symptoms and cardiac function, reduces hospitalisations for cardiac causes, and decreases serum levels of BNP and C-reactive protein.30

Finally, there is evidence that modified trimetazidine may yield fewer benefits than the original form in terms of LVEF enhancement, which may be because of the difference in pharmacokinetics.38,39

Randomised clinical trials confirmed the efficacy of trimetazidine in patients with HF. Beneficial effects include improvements in NYHA functional class, exercise tolerance, QOL, LVEF and cardiac volume.31,35,40–42 A meta-analysis of 955 HF patients concluded that trimetazidine therapy significantly reduces left ventricular end-systolic volume and improves NYHA functional class and exercise duration, as well as decreasing all-cause mortality, cardiovascular events and hospitalisation rates.43 The 2016 ESC guideline indicates that trimetazidine may be considered for the treatment of stable angina pectoris with symptomatic HFrEF, when angina persists despite treatment with a beta-blocker (or alternative), to relieve angina (effective anti-anginal treatment, safe in HF), class IIb, level of evidence A.1 This recommendation is based on the body of evidence suggesting that trimetazidine may improve NYHA functional capacity, exercise duration and LVF in patients with HFrEF.

Conclusions

A substantial body of evidence for their beneficial effects supports the use of ivabradine, trimetazidine and intravenous iron to improve functional capacity and prognosis in HF.23 In particular, treatment with ivabradine up to 7.5 mg twice daily has been found to improve functional parameters and exercise capacity in HF patients,21 with improvements in QOL scores and better outcomes. Similarly, treatment with trimetazidine is associated with improvements in exercise tolerance, NYHA functional class, QOL, LVEF and cardiac volume. Intravenous FMC has been found to improve exercise capacity, functional class, HF severity and symptoms, and QOL, as well as reducing hospitalisation rates for worsening HF. Ongoing trials will further clarify the impact of intravenous FCM supplementation on functional capacity and clinical outcomes.

References
  1. Ponikowski P, Voors AA, Anker SD, et al. ESC Scientific Document Group. 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 Heart J 2016;37:2129–200.
    Crossref | PubMed
  2. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847.
    Crossref | PubMed
  3. Piepoli MF, Conraads V, Corrà U, et al. Exercise training in heart failure: from theory to practice. A consensus document of the Heart Failure Association and the European Association for Cardiovascular Prevention and Rehabilitation. Eur J Heart Fail 2011;13:347–57.
    Crossref | PubMed
  4. Packer M, Narahara KA, Elkayam U, et al. Double-blind, 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;22:65–72.
    Crossref | PubMed
  5. Hampton JR, van Veldhuisen DJ, Kleber FX, et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators. Lancet 1997;349:971–7.
    Crossref | PubMed
  6. Klip IT, Comin-Colet J, Voors AA, et al. Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82.
    Crossref | PubMed
  7. Okonko DO, Mandal AK, Missouris CG, Poole-Wilson PA. Disordered iron homeostasis in chronic heart failure: prevalence, predictors, and relation to anemia, exercise capacity, and survival. J Am Coll Cardiol 2011;58:1241–51.
    Crossref | PubMed
  8. Cleland JG, Zhang J, Pellicori P, et al. Prevalence and outcomes of anemia and hematinic deficiencies in patients with chronic heart failure. JAMA Cardiol 2016;1:539–47.
    Crossref | PubMed
  9. Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol 2006;48:1225–7.
    Crossref | PubMed
  10. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J Nephrol 2008;21:236–42
    PubMed
  11. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol 2007;50:1657–65.
    Crossref | PubMed
  12. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. EFFECT-HF Investigators. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation 2017;136:1374–83.
    Crossref | PubMed
  13. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol 2008;51:103–12.
    Crossref | PubMed
  14. Anker SD, Comin Colet J, Filippatos G, et al. FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48.
    Crossref | PubMed
  15. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. 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;36:657–68.
    Crossref | PubMed
  16. Jankowska EA, Tkaczyszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail 2016;18:786–95.
    Crossref | PubMed
  17. Anker SD, Kirwan BA, van Veldhuisen DJ, et al. Effects of ferric carboxymaltose on hospitalisations and mortality rates in iron-deficient heart failure patients: an individual patient data meta-analysis. Eur J Heart Fail 2018;20:125–33.
    Crossref | PubMed
  18. Lewis GD, Malhotra R, Hernandez AF, et al. NHLBI Heart Failure Clinical Research Network. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA 2017;317:1958–66.
    Crossref | PubMed
  19. Ekman I, Chassany O, Komajda M, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 2011;32:2395–404.
    Crossref | PubMed
  20. Swedberg K, Komajda M, Böhm M, et al. SHIFT investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875–85.
    Crossref | PubMed
  21. Volterrani M, Cice G, Caminiti G, et al. Effect of carvedilol, ivabradine or their combination on exercise capacity in patients with heart failure (the CARVIVA HF trial). Int J Cardiol 2011;151:218–24.
    Crossref | PubMed
  22. Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to β-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther 2015;32:108–19.
    Crossref | PubMed
  23. Milinkovic´ I, Rosano G, Lopatin Y, Seferovic´ PM. The role of ivabradine and trimetazidine in the new ESC HF guidelines. Card Fail Rev 2016;2:123–9.
    Crossref | PubMed
  24. Rosano GM, Vitale C, Volterrani M. Heart rate in ischemic heart disease. The innovation of ivabradine: more than pure heart rate reduction. Adv Ther 2010;27:202–10.
    Crossref | PubMed
  25. Pereira-Barretto AC. Cardiac and hemodynamic benefits: mode of action of ivabradine in heart failure. Adv Ther 2015;32:906–19.
    Crossref | PubMed
  26. Sarullo FM, Fazio G, Puccio D, et al. 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;15:349–55.
    Crossref | PubMed
  27. Lim WY, Woldman S. Pharmacological management of chronic heart failure: old drugs, new drugs and new indications. Br J Hosp Med (Lond) 2013;74:C18–22.
    Crossref | PubMed
  28. Zhao Y, Peng L, Luo Y, et al. Trimetazidine improves exercise tolerance in patients with ischemic heart disease: a meta-analysis. Herz 2016;41:514–22.
    Crossref | PubMed
  29. Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol 2012;59:913–22.
    Crossref | PubMed
  30. Zhou X, Chen J. Is treatment with trimetazidine beneficial in patients with chronic heart failure? PLoS One 2014;9:e94660.
    Crossref | PubMed
  31. Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol 2013;163:320–5.
    Crossref | PubMed
  32. Kantor PF, Lucien A, Kozak R, Lopaschuk GD. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2000;86:580–8.
    Crossref | PubMed
  33. Zemljic G, Bunc M, Vrtovec B. Trimetazidine shortens QTc interval in patients with ischemic heart failure. J Cardiovasc Pharmacol Ther 2010;15:31–6.
    Crossref | PubMed
  34. Palaniswamy C, Mellana WM, Selvaraj DR, Mohan D. Metabolic modulation: a new therapeutic target in treatment of heart failure. Am J Ther 2011;18:e197–201.
    Crossref | PubMed
  35. Vitale C, Wajngaten M, Sposato B, et al. Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J 2004;25:1814–21.
    Crossref | PubMed
  36. Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol 2006;48:992–8.
    Crossref | PubMed
  37. Belardinelli R, Solenghi M, Volpe L, Purcaro A. Trimetazidine improves endothelial dysfunction in chronic heart failure: an antioxidant effect. Eur Heart J 2007;28:1102–8.
    Crossref | PubMed
  38. Barré J, Ledudal P, Oosterhuis B, et al. Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failure. Biopharm Drug Dispos 2003;24:159–64.
    Crossref | PubMed
  39. Génissel P, Chodjania Y, Demolis JL, et al. Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers. Eur J Drug Metab Pharmacokinet 2004;29:61–8.
    Crossref | PubMed
  40. Di Napoli P, Taccardi AA, Barsotti A. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005;91:161–5.
    Crossref | PubMed
  41. Rosano GM, Vitale C, Sposato B, et al. Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16.
    Crossref | PubMed
  42. Sisakian H, Torgomyan A, Barkhudaryan A. The effect of trimetazidine on left ventricular systolic function and physical tolerance in patients with ischaemic cardiomyopathy. Acta Cardiol 2007;62:493–9.
    Crossref | PubMed
  43. Gao D, Ning N, Niu X, et al. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart 2011;97:278–86.
    Crossref | PubMed