Heart failure: looking beyond the guidelines

During my career, heart failure with reduced ejection fraction (HFrEF) has changed from a disease that was rapidly fatal to a chronic condition that now requires long-term, team management. The chance of survival has improved in symptomatic heart failure patients and in those discharged from hospital with modern therapies.^1-7

A UK registry study showed a 75% reduction in sudden death in symptomatic heart failure from before 2000 to after 2005 following the recommendation of early beta blocker (B-blocker) therapy and angiotensin converting enzyme (ACE) inhibitor therapy.^3,4

More recent research, published in the BMJ last year, used the UK Clinical Practice Research Datalink from January 2000 to the end of December 2017, which was linked to inpatient Hospital Episodes Statistics and the Office for National Statistics mortality data, to estimate short- and long-term survival rates in people with diagnosed heart failure and assess trends over time. It showed that overall, one, five and ten-year survival rates increased, by 6.6% between 2000 and 2016, 7.2% between 2000 and 2012 and 6.4% between 2000-2007 respectively.

The researchers noted the improvement in survival was greater in patients not requiring admission to hospital at the time of diagnosis (median difference 2.4 years; p<0.001). Worryingly though, there was a deprivation gap in median survival, of 0.5 years between the least and most deprived groups (4.6 vs 4.1 years; p=<0.001). The authors concluded that survival after a diagnosis of heart failure has shown only modest improvement in the 21st century and falls behind other serious conditions such as cancer. They call for new strategies in primary care, to achieve timely diagnosis and treatment initiation for all socioeconomic groups.^8,9

NICE guidance on heart failure

The latest NICE guidance on the diagnosis and management of adults with heart failure¹⁰ is helpful in this regard, by putting greater emphasis on multidisciplinary working, shared decision making, care planning, lifestyle advice and interventions, comorbidities, and end of life care.

N-terminal pro-B type natriuretic peptide (NT-proBNP) is recommended as the biomarker of choice in the diagnosis (and monitoring if appropriate) of people with heart failure Importantly, a mineralocorticoid receptor antagonist (MRA) should be offered, in addition to an ACE inhibitor/angiotensin receptor blocker (ARB), and B-blocker, to people with HFrEF who remain symptomatic.

Early diagnosis is important and the recommendation is to refer people with suspected HF and NT-proBNP >400ng/L, for specialist assessment and transthoracic echocardiography within six weeks.

Exercise-based cardiac rehabilitation should be offered to patients with stable heart failure, in an easily accessible setting and format. Patients with high NT-proBNP levels, >2000ng/L, should receive urgent specialist assessment and an echocardiogram within two weeks.¹⁰

Following referral to the multidisciplinary team (MDT), a summary should be written for each person with heart failure to form the basis of their care plan. This should include follow-up care and rehabilitation, access to social care, symptoms to look out for in case of deterioration, and the process for access to further advice from the MDT. There should be a named healthcare coordinator as a contact, which is usually a specialist heart failure nurse.

Monitoring of heart failure patients

The frequency of monitoring should be related to the clinical status and comorbidities. If the clinical condition or medication changes, the monitoring interval should be short (i.e. days or two weeks). The monitoring interval for stable heart failure should be at least 6-monthly.¹⁰

Clinical monitoring of heart failure involves assessment of functional capacity, fluid status, cardiac rhythm, cognitive status, nutritional status, and a medication review. Measurement of NT-proBNP should be considered, if appropriate, as part of a treatment optimisation protocol.¹⁰

Drug therapy for heart failure

ACE inhibitors, ARBs and MRAs should be started at low doses and titrated upwards at short intervals, until the target/maximum tolerated dose is reached. Renal function should be assessed prior to starting treatment, one to two weeks after treatment initiation, and after each dose change. Blood pressure should also be measured before and after each dose change.

In patients with a reduced eGFR <45mls/min/1.73m2, consider lower doses and slower titration of HF medication. In patients with an eGFR <30mls/min/1.73m2, consider consultation with a renal physician, and beware of hyperkalaemia.¹⁰

NICE provide a useful algorithm on the management of chronic HF (CHF).¹⁰ Standard therapy for heart failure involves the use of inotropic agents, such as digoxin, and loop diuretics, plus ivabradine for sinus rhythm with a heart rate >75 and EF <35% and consideration of hydralazine and/or a nitrate (particularly if of African-Caribbean descent).

These can be used in combination with ACE inhibitor, MRAs and Î²-blockers, which are all initial evidence-based therapies.

Despite this cocktail of drugs, data from the CPRD suggests there is still an unmet need for new pharmaceuticals and new approaches to the management of HF.^8,9

The 2016 European Society of Cardiology guidelines recommended sacubitril/valsartan for all patients meeting the inclusion criteria and who remain symptomatic despite treatment with an ACEi/ARB, a Î²-blocker and an MRA.¹¹ This is mirrored in the NICE algorithm.

The advice is to stop ACE inhibitors at least 36 hours before the first intake of sacubitril/valsartan. This is because both substances, neprilysin and ACE inihibitor, degrade bradykinin, and using them simultaneously can increase the risk of angioedema.¹² There are gains to be had though, because in the PARADIGM-HF trial, treatment with salcubitril/valsartan led to a reduction in repeat hospitalisations, and the incidence of overt diabetes and hyperkalaemia.^13-15

In patients with low blood pressure, this treatment combination was associated with a better prognosis than treatment with enalapril.¹⁶ There is also evidence that the rate of ventricular tachyarrhythmias is lower with salcubitril/valsartan than with standard ACE’ or ARB treatment.¹⁷ From the patients point of view, quality of life is significantly better with salcubitril/valsartan treatment than with enalapril.¹⁸

Looking beyond the guidelines

Initiating salcubitril/valsartan instead of an ACE inhibitor/ARB may be appropriate for patients hospitalised with acute heart failure, to reduce the short-term risk of adverse events and simplify management by eliminating the need to titrate the ACE inhibitor first and then switch.¹⁹

Patients with chronic heart failure often have iron deficiency (ID).²⁰ ID is not only associated with poor performance, it is also a strong independent predictor of unfavourable outcome.^11,21

In a recent meta-analysis, intravenous iron substitution in patients with HF, was associated with a fewer hospitalisations.²² Iron supplementation may be a useful therapeutic approach in symptomatic patients with proven ID, to improve functional status, heart failure symptoms, quality of life and prognosis.^21,22

Type 2 diabetes mellitus may affect 30-40% of HF patients and is associated with a higher risk of heart failure hospitalisation, and all-cause and cardiovascular mortality.²³ Recent trials with SGLT2 inhibitors have shown definite benefit. The 2016 ESC guideline recommends considering empagliflozin in patients with type 2 diabetes, to prevent or delay the onset of heart failure and prolong life.¹¹

A 2019 ESC Expert Consensus recommends also considering canagliflozin or dapagliflozin for patients with type 2 diabetes and either established cardiovascular disease (CVD) or a high cardiovascular (CV) risk, in order to prevent or delay the onset of HF and hospitalisations for heart failure.²⁴

The latest trial to be presented is the DAPA-HF trial. This phase 3 placebo-controlled trial included 4,744 patients with NYHA class II, III or IV heart failure and an EF ‰¤40%, who were randomly assigned to receive either dapagliflozin 10mg daily or placebo, in addition to recommended therapy.

The primary outcome was a composite of worsening HF (requiring hospitalisation or an urgent visit resulting in intravenous HF therapy) or CV death. Over a median 18.2-month period, the primary outcome occurred in 16.3% of patients taking dapagliflozin versus 21.2% of those taking placebo (hazard ratio (HR) 0.75; 95% confidence interval (CI), 0.65-0.85; p<0.001).

A first worsening heart failure event occurred in 10% of patients taking dapagliflozin versus 13.7% of those taking placebo (HR 0.70; 95% CI, 0.59-0.83). Death from CV causes occurred in 9.6% of patients taking dapagliflozin versus 11.5% of those taking placebo (HR 0.82; 95% CI, 0.69-0.98). The findings were similar between patients with diabetes and those without, and there was no difference between the groups in the frequency of adverse events related to renal dysfunction, volume depletion and hypoglycaemia.²⁵

A further analysis of the DAPA-HF trial found that in patients with HfrEF, dapagliflozin also improved symptoms, physical functioning and quality of life.²⁶

Multiple mechanisms have been proposed to explain the cardiorenal benefits of the sodium-glucose cotransporter 2 inhibitors (SGLT2is) including haemodynamic, metabolic, hormonal and direct cardiac and renal effects. They may be related to a reduction in sodium and water retention, which leads to reduced ventricular filling pressure and cardiac workload, or a change in cardiorenal fuel energetics, related to a shift in cardiorenal metabolism away from fatty acids and glucose oxidation towards ketone bodies, which are a more energy efficient fuel. A reduction in intracellular sodium may also be a factor.²⁷

Patients with central abdominal obesity or type 2 diabetes are also at risk of testosterone deficiency, and such patients are at risk of poor clinical outcomes and reduced exercise capacity.²⁸ The authors of this meta-analysis concluded that there were unmet clinical needs and testosterone appeared promising therapy to improve functional capacity. Short term studies have shown neither benefit or harm, but a long term RCT needs to be performed to demonstrate benefit in a similar manner to the statin trials.²⁹

In patients with coronary or peripheral artery disease, the use of rivaroxaban 2.5mg twice daily in addition to low dose aspirin has been shown to reduce the risk of vascular events in patients without HF and those with mild or moderate HF.30 In patients with advanced HF however, myocardial dysfunction and congestion may determine the outcome as opposed to vascular events.

Conclusion

Managing heart failure is complex and requires a multidisciplinary approach, but early diagnosis and ongoing management require a systematic approach in primary care and this provides the opportunity to stress the importance and value of cardiac rehabilitation services.

Professor Mike Kirby is Visiting Professor to the Faculty of Health and Human Sciences at the University of Hertfordshire and past director of HertNet: the Hertfordshire Primary Care Network of 50 Practices.

References

Levy D, Kenchaiah S, Larson MG et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med 2002;347:1397€“1402
Owan TE, Hodge DO, Herges RM et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006;355:251€“259
Cubbon RM, Gale CP, Kearney LC et al. Changing characteristics and mode of death associated with chronic heart failure caused by left ventricular systolic dysfunction: a study across therapeutic eras. Circ Heart Fail 2011;4:396€“403
MacIntyre K, Capewell S, Stewart S et al. Evidence of improving prognosis in heart failure: trends in case fatality in 66 547 patients hospitalized between 1986 and 1995. Circulation 2000;102:1126€“1131
Shafazand M, Schaufelberger M, Lappas G et al. Survival trends in men and women with heart failure of ischaemic and non-ischaemic origin: data for the period 1987€“2003 from the Swedish Hospital Discharge Registry. Eur Heart J 2009;30:671€“ 678
Stevenson LW, Pande R. Witness to progress. Circ Heart Fail 2011;4:390€“392
Loh JC, Creaser J, Rourke DA et al. Temporal trends in treatment and outcomes for advanced heart failure with reduced ejection fraction from 1993-2010: findings from a university referral center. Circ Heart Fail 2013;6:411€“419
Taylor CJ, OrdÃ³Ã±ez-Mena JM, Roalfe AK et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. BMJ. 2019 Feb 13;364:l223
Erratum. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population-based cohort study. BMJ. 2019 Oct 8;367:15840
National Institute for Health and Care Excellence. Chronic heart failure in adults: diagnosis and management (NICE guideline NG106) 2018. Available at: https://www.nice.org.uk/guidance/ng106 [Accessed 03/02/20].
Ponikowski P, Voors AA, Anker SD et al. 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
Berliner D, Bauersachs J. New drugs: big changes in conservative heart failure therapy? Eur J Cardiothorac Surg 2019;55:i3€“i10
Mogensen UM, Gong J, Jhund PS et al. Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail 2018;20:760€“8
Seferovic JP, Claggett B, Seidelmann SB et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 2017;5:333€“40
Desai AS, Vardeny O, Claggett B et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol 2017;2:79€“85
Vardeny O, Claggett B, Kachadourian J et al. Incidence, predictors, and outcomes associated with hypotensive episodes among heart failure patients receiving sacubitril/valsartan or enalapril: the PARADIGM-HF Trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure). Circ Heart Fail 2018;11:e004745
de Diego C, Gonzalez-Torres L, Nunez JM, Centurion Inda R, Martin-Langerwerf DA, Sangio AD et al. Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm 2018;15:395€“402
Lewis EF, Claggett BL, McMurray JJV et al. Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail 2017;10
Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019;380:539-548. In: Christodorescu R. 2019 – A Fruitful Year in the Field of Heart Failure. E-journal of Cardiology Practice 2020;18(7). Available at: https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-18/2019-a-fruitful-year-in-the-field-of-heart-failure [Accessed 05/02/20]
Jankowska EA, Drozd M, Ponikowski P. Iron deficiency treatment in patients with heart failure. Handb Exp Pharmacol 2017;243:561€“76
Jankowska EA, Rozentryt P, Witkowska A et al. Iron deficiency: an ominous sign in patients with systolic chronic heart failure. Eur Heart J 2010;31:1872€“80
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
Seferovic PM, Petrie MC, Filippatos GS et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018;20:853-72
Seferovic PM, Ponikowski P, Anker SD ET AL. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21:1169-1186
McMurray JJV, Solomon SD, Inzucchi SE et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008
Kosiborod MN, Jhund PS, Docherty KF et al. Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction: Results From the DAPA-HF Trial. Circulation. 2020 Jan 14;141(2):90-99
Tamargo J. Sodium€“glucose Cotransporter 2 Inhibitors in Heart Failure: Potential Mechanisms of Action, Adverse Effects and Future Developments. Eur Cardiol 2019;14(1):23-32
Toma, Finlay A, McAlister et Al, Testosterone supplementation in heart failure a meta-analysis Circ heart fail.111.965632
Jones TH, Kelly DM Randomised controlled trials- mechanistic studies of testosterone and the cardiovascular system Asian J Androl. 2018 Mar-Apr;20(2):120-130.doi:10.4103/aja.aja_6_18.
30. Branch KR, Probstfield JL, Eikelboom JW et al. Rivaroxaban With or Without Aspirin in Patients With Heart Failure and Chronic Coronary or Peripheral Artery Disease. Circulation. 2019 Aug 13;140(7):529-537

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