Year 2018
July 2018
10 July 2018

Heart Failure - Recent Advances in Treatment

Heart failure is a serious disease that affects the most important organ in the body after the brain. Heart is a pump that circulates blood around the body, nourishing our organs with oxygen and nutrients. When it fails, our body becomes starved of energy. This results in feeling tired, breathless, dizzy, and having swelling of the legs and abdomen. This will eventually lead to death. Heart failure is a dreaded disease as survival is poor once the diagnosis is made. Overall, only 50% of those diagnosed with heart failure survive beyond 5 years. In severe heart failure, the prognosis is worse with up to 80% dying within 5 years of diagnosis.1 Worldwide, heart failure is a growing epidemic that results in 5 million hospitalisations every year. In Singapore, heart failure hospitalisations have been growing at a rate of 10% every year, surpassing the 5% increase in all-cause hospitalisations every year.2 Last year, there were about 6,000 heart failure hospitalisations in the restructured hospitals.3 There are no data for heart failure hospitalisations in private hospitals, but an estimate is an additional 30% of the public load. The cardinal symptoms and signs of heart failure are dyspnea (breathlessness), fatigue, decreased effort tolerance, orthopnea, paroxysmal nocturnal dyspnea, and fluid retention (swelling). The Framingham Criteria for Diagnosis of Heart Failure require the presence of 2 major criteria, or 1 major + 2 minor criteria [Figure 1].4

Heart failure pharmacotherapy

The aim of heart failure treatment is to increase life expectancy and to improve quality of life, not least by keeping patients well enough to avoid hospitalisation. This involves getting the right combination of medications to maximise the chances of recovery of heart function, and minimize side effects.

The pillars of heart failure pharmacotherapy are 3 classes of medications – namely RAAS inhibitors, beta-blockers, and mineralocorticoid antagonists. Each of these agents have been shown to provide an increment of 30% to 40% improvement in survival.5 They have been key to treating heart failure in the last 20 years. In that time though, there have been no similar major advances in heart failure pharmacotherapy.

Using this evidence-based approach, we can significantly improve patient’s survival in real-world practice. Even so, one-year mortality remains fairly high at 11%.6 There is still a long way to go before we can “cure” heart failure.

One of the major pathophysiological mechanisms in heart failure is activation of RAAS system leading on to vasoconstriction in response to decreased cardiac output. This is to maintain perfusion pressure of the organs despite a decreased volume of blood reaching the target organs. However, this sets up a vicious cycle where increased systemic vascular resistance results in increased afterload against which the heart has to pump against, thereby increasing myocardial work and oxygen consumption. This explains why some patients with severe heart failure initially have only mild myocardial dysfunction. A classic example is someone who had an inferior myocardial infarction, which often is welltolerated with little or no decrease in left ventricular ejection fraction. However, the deceptively calm surface hides a roiling proliferation of adverse neurohormones.

Thus vasodilation was thought to be important in breaking this cycle of vasoconstriction, increased afterload, and worsening cardiac function.

Clinical evidence in heart failure treatment

A series of trials in the 1980s and early 1990s provided the evidence to support this mode of therapy. The pioneering Veterans Heart Failure Trial I (V-HeFT I) which ran from 1980 to 1985 showed that, compared to placebo, the combination of isosorbide dinitrate (ISDN) and hydralazine improved survival by a whopping 34% in male heart failure patients in the USA. The absolute mortality of the patients in the placebo arm was 34.3% over 2 years, while that of the ISDN/hydralazine arm was 25.6% over 2 years. A third arm using the alpha-blocker prazosin showed higher mortality than placebo, hence pure alphablockers are not recommended in Heart Failure.7

A follow-up study comparing the angiotensin-converting enzyme inhibitor (ACE-I) enalapril to the ISDN/hydralazine combination (the V-HeFT II Study) from 1986 to 1991 showed superior survival in the enalapril arm by 18%. The absolute mortality of patients in the ISDN/ hydralazine arm was similar to

that in the V-HeFT I Study (25% at 2 years), suggesting that enalapril was truly superior to the other vasodilators available then.8 A slew of contemporary trials cemented enalapril as a lifesaving drug for all degrees of heart failure – from NYHA III & IV patients with advanced heart failure (CONSENSUS Trial)9, to NYHA II & III patients with Moderate Heart Failure (SOLVD Study)10, and to NYHA I patients with asymptomatic left ventricular dysfunction (SOLVD Study).11

That is why ACE-I are the main drug used in clinical practice to treat heart failure. However, there is still a place for the ISDN/ hydralazine combination. The ACE-I is associated with raised serum potassium levels, and may worsen pre-existing renal dysfunction. In patients who cannot tolerate ACE-I, one can use the ISDN/hydralazine combination. Certain patients may also not present with a high-renin state. In these patients, the ACE-I effect is attenuated and thus not as effective as ISDN/Hydralazine, as shown in the A-HEFT Trial.12-14

Angiotensin-receptor blockers (ARB) work similarly to the ACE-I, by blocking the receptor at the end of the renin-angiotensin pathway. As it does not block the breakdown of bradykinin, it is not associated with bradykinin accumulation leading to the well-known “ACE-I Cough”. The CHARM Study showed that in patients who did not tolerate ACE-I, using an ARB (Candesartan) was superior to placebo in the primary end-point of cardiovascular death or heart failure hospitalisation.15

There are no major head-to-head trials of ACE-I vs ARB in heart failure to establish the relative efficacies of these two similar drug classes. However, the general consensus is that ACE-I is probably superior to ARB in HF outcomes. In patients who cannot tolerate ACE-I, ARB is a reasonable alternative. The addition of ARB to ACE-I in an attempt to increase reninangiotensin blockade is not recommended due to the higher incidence of hyperkalaemia and worsening renal function.

Promising new agent for heart failure

A promising new agent is the novel angiotensin receptor blocker cum neprilysin inhibitor (ARNI), code-named “LCZ696”, and newly christened with the name “Entresto”.16 This is a novel agent with two molecules “cocrystallised” together in a 1:1 molar ratio.

One molecule is valsartan, which is an established angiotensin receptor blocker used to treat Heart Failure. The other molecule is sacubitril, which is a neprilysin inhibitor.

Evolution of pharmacologic approaches in HF:
LCZ696 as a new alternative to an ACEI or ARBs in patients with HFrEF1

Up to 40% of patients with heart failure have little or no impairment of systolic contraction, but have diastolic dysfunction.19 The myocardium is stiff, and thus is unable to relax fully, and therefore stroke volume is reduced. This phenomenon is called diastolic heart failure, also known as “Heart Failure with Preserved Ejection Fraction” (HFPEF).   

Sacubitril (AHU377) works by inhibiting the breakdown of natriuretic peptides, which are beneficial in the heart failure state by promoting vasodilation, natriuresis and [Figure 2].17

In a landmark study (the “”PARADIGM” Study) published in the New England Journal of Medicine in Sep 2014, it was shown to improve survival and hospitalisations by 20% over and above the stalwart of the 1990s, enalapril (an ACE-Inhibitor).18 Bear in mind that this degree of effect is similar to the clinical difference between enalapril and ISDN/ hydralazine combination in the 1991 study which established enalapril as the superior therapy. The US Food and Drug Administration (FDA) subsequently approved Entresto for clinical use on July 7, 2015.

I had the privilege to play a part in the PARADIGM Study, leading one of the study sites in Singapore. As a result of this experience, Singapore has been approved for early access to this potentially life-saving therapy.

Up to 40% of patients with heart failure have little or no impairment of systolic contraction, but have diastolic dysfunction.19 The myocardium is stiff, and thus is unable to relax fully, and therefore stroke volume is reduced. This phenomenon is called diastolic heart failure, also known as “Heart Failure with Preserved Ejection Fraction” (HFPEF). Entresto is also being studied for HFPEF, with promising results in an early (Phase 2) trial called the PARAMOUNT Study.20,21 The definitive phase 3 PARAGON Study is currently in progress globally, including in Singapore.

In severe heart failure, when the heart gets progressively weaker and patients require hospitalisation every few weeks, tablets may be insufficient. One of the newer options available is inodilator therapy with the new calcium-sensitising medications. Although it may not increase lifespan, it can improve the quality of patients’ precious remaining life.22,23

For those with end-stage heart failure, the left ventricular assist device (LVAD) is literally a life-saver. It is a miniature heart pump that is implanted into the apex of the heart, taking over the heart’s function. It has been implanted in more than 18,000 patients worldwide, including Singapore.24 Many patients at death’s door have been given a new lease of life, and are back to living busy and productive lives – working and enjoying their hobbies.

Heart failure was previously a death sentence. Thankfully, we have better tools to treat patients with heart failure. While cost is certainly a factor to consider, the opportunity cost of not utilising the tools available may be higher. Let’s give our patients the best chance possible.


  1. Owan T et al. N Engl J Med 2006; 355:251-259
  2. Health Facts Si­­­­ngapore 2011 – Health Information Division, Ministry of Health, Singapore
  3. MOH Website – moh_web/home/costs_and_financing/HospitalBillSize/ heart_failure.html
  4. McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971; 285:1441-6.
  5. Leslie SJ. J R Coll Physicians Edinb 2006; 36:249-252.
  6. Poh Shuan Daniel Yeo, Ping Chai, Hean Yee Ong, Amanda Koh, Rose Shiow Ling Low. Successful Implementation of ACCF/AHA Performance Measures for Adults With Heart Failure Reduces Mortality in South-East Asian Patients with Chronic Heart Failure. Circulation 2013; 128:A9240.
  7. Cohn JN, Archibald DG, Ziesche S et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration cooperative study. N Engl J Med 1986; 314: 1547-1552
  8. Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-310.
  9. CONSENSUS Trial Study Group. N Engl J Med 1987; 316: 1429.
  10. SOLVD Investigators. N Engl J Med 1991; 325: 293.
  11. SOLVD Investigators. N Engl J Med 1992; 327: 685.
  12. Materson BJ, Reda DJ, Cushman WC et al, N Engl J Med 1993; 328: 914
  13. Am J Hypertens 1995; 8:189.
  14. A-HEFT Study. Taylor AL, Ziesche S, Yancy C et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351: 2049.
  15. CHARM Study. The Lancet 2003: 362:772-776
  16. Gu et al. J Clin Pharmacol 2010; 50:401–14.
  17. Waeber & Feihl. Lancet 2010; 375:1228-1229.
  18. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. N Eng J Med 2014; 371:993-1004.
  19. Yap J, Sim D, Lim CP, Chia SY, Go YY, Jaufeerally FR, Sim LL, Liew R, Ching CK. Predictors of two-year mortality in Asian patients with heart failure and preserved ejection fraction. Int J Cardiol 2015; 183C:33–38.
  20. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012; DOI:10.1016/ S0140-6736(12)61227-6. Available at: http://www.
  21. Solomon, S. PARAMOUNT: Efficacy and safety of LCZ696, a First-in-class angiotensin receptor neprilysin inhibitor, in patients with heart failure and preserved ejection fraction: Primary results from the PARAMOUNT study. European Society of Cardiology 2012 Congress; August 26, 2012; Munich, Germany.
  22. PSD Yeo et al. J Card Fail 2012; 18:S108.
  23. PSD Yeo, et al. J Card Fail 2013, 19:S43.
  24. Data on file. September 2014. Pleasanton, CA. Thoratec Corp.

A Specialist’s Point of View – Written by Dr Daniel Yeo

Dr Daniel Yeo
is a Cardiologist at Gleneagles Hospital Singapore. He completed a Fellowship in Heart Failure & Cardiac Transplantation at The Cleveland Clinic in Ohio, USA in 2009.  Prior to private practice, Dr Daniel Yeo led the Heart Failure Service at Tan Tock Seng Hospital from 2008-2014 and was the Director of the National Healthcare Group Heart Failure Disease Management Program from 2011-2014. He was active in Research, leading many Investigator-initiated (SHOP, ASIAN-HF, PRACTICE-ASIA-HF) and Industry-initiated trials at TTSH (IMPROVE-IT, EMPHASIS-HF, LEPHT, PARADIGM, SOCRATES). He has presented his research at numerous major international Conferences (ACC, AHA, HFSA, ISHLT) as well as local Conferences (Singapore Cardiac Society, National Healthcare Group Annual Scientific Congress, Singapore Health & Biomedical Congress). He has published his work in major journals including Journal of the American College of Cardiology, Journal of Cardiac Failure, European Heart Journal, European Journal of Heart Failure, The Lancet, Annals of the Academy of Medicine, Singapore, Singapore Medical Journal, International Journal of Cardiology. He is a regular reviewer for Peer-Reviewed Journals and the NMRC Singapore.

In his clinical practice as a heart specialist, he performs coronary angiography and stenting, pacemaker implantation, trans-oesophageal echocardiography, ultrasound-guided pericardiocentesis, haemodynamic tailored therapy for heart failure, iron-repletion therapy and endomyocardial biopsy. He also performs evaluation for suitability for left ventricular assist device implantation. In his clinic, Dr Yeo provides on-site ECG, treadmill stress test, echocardiography, stress echocardiography, 24-Hour ECG monitoring (Holter), and 24-Hour Ambulatory Blood Pressure monitoring and the full range of Cardiology tests and procedures at Gleneagles Hospital.

Dr Yeo’s passion is to understand the patient’s concerns and to care for the patient as a unique individual. He practices evidence-based and collaborative medicine so as to achieve the best possible results for his patients, and ultimately achieve a healthy heart.

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