Managing Heart Failure in India with Sacubitril Valsartan: Lessons from Clinical Trials

Chronic Heart Failure (CHF) is a complex syndrome in which the heart cannot provide adequate cardiac output to meet the body's metabolic requirements and accommodate a venous return. (1)

Heart failure is often due to myocardial dysfunction and is broadly classified by left ventricular ejection fraction. When the left ventricular ejection fraction is less than 40%, it is heart failure with a reduced ejection fraction. Some underlying causes include cardiovascular causes such as myocardial ischemia or infarction, uncontrolled hypertension, valvular disease, atrial fibrillation and tachycardia, and pulmonary embolism. There could also be systemic contributory factors like infection, thyroid dysfunction, anemia, poorly controlled diabetes, previous chemotherapy or radiotherapy, and peripartum cardiomyopathy; idiopathic or genetic causes include dilated cardiomyopathy, hypertrophic obstructive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. (1) Even with appropriate medical care, individuals with advanced CHF have significant mortality and morbidity (2).

Heart Failure - Indian scenario- India is home to 16% of the world's population and 25% of the world's coronary heart disease (CHD) burden, which is a significant cause of heart failure (HF). (3) Research reveals a significant and continuous rise in the estimated prevalence and incidence rates of heart failure (HF) in India; becoming a major public health concern, with main risk factors including a high prevalence of cardiovascular (CV) and metabolic illnesses. (4)For almost 25 years, the mainstay of therapy for heart failure and reduced ejection fraction (EF) has been angiotensin-converting enzyme (ACE) inhibitors. (5) Despite using these standard medicines, the outcomes in HF patients continue to remain dismal, with high mortality, high rehospitalization rates, poor quality of life, malignant arrhythmia, and renal impairment. (6)

How Indian HF Patients are Different?

• In India, as compared to other parts of the world, the male-to-female ratio presenting with HF is different. This may be because, in contrast to the West, more men in India seek medical attention than women.
• Indian patients present with HF at a younger age
• In India, high blood pressure is distinctly highly pervasive
• Ischaemic heart disease (IHD) is the most prevalent cause of HF in both the USA and India, but rheumatic heart disease (RHD) also contributes significantly to the HF burden in India.
• Indians are significantly more susceptible to risk factors like diabetes mellitus than their western counterparts.
• The prognosis of HF appears to be worse in Indian patients than in those in the West.

Because HF appears roughly a decade earlier in Indians, it usually affects patients in their prime. (7)

ARNIs- Game Changes in Heart Failure Care

Novel therapeutics have evolved as a result of a better knowledge of the biology of heart failure. Among these are angiotensin receptor/neprilysin inhibitors (ARNIs), which cardiologists now regard as "game-changers."(2)

Sacubitril /valsartan, categorized as an Angiotensin receptor neprilysin inhibitor (ARNI) has been proven to reduce mortality and morbidity in individuals with HFrEF without increasing the risk of angioedema (4). It was initially designed to treat individuals with refractory Chronic Heart Failure with a low Ejection Fraction (CHFrEF). (2)

The 2016 European Society of Cardiology(ESC) guidelines (3)recommend (sacubitril/valsartan) as an alternative for ACE inhibitors in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), who remain symptomatic despite optimal medical therapy with an ACE inhibitor/angiotensin receptor blocker (ARB), beta-blockers, and Mineralocorticoid receptor antagonists (MRA). The 2021 ESC re-affirms the above statement while adding an important update- an ARNI may also be considered as a 'first-line therapy' instead of an ACE-I in ACE-I naive (i.e. de novo) patients with HFrEF.(8)

Considering the evolving therapy horizons in managing heart failure, a review of angiotensin receptor/neprilysin inhibitors (Sacubitril /Valsartan), their mechanism of action, and a review of recent studies on this relatively novel drug therapy for HF patients are much needed.

ARNI for Management of Chronic Heart Failure: Consensus Statement from Indian Cardiologists (7)

• Experts highlight that ARNI is a new therapeutic class of medicine that works by inhibiting both the renin-angiotensin system (RAAS) and the neutral endopeptidase system.
  
• The first and only medicine in this class that has been authorized for usage is sacubitril-valsartan. While sacubitril is a neprilysin inhibitor (NI), Valsartan is a kind of ARB.
• Sacubitril-valsartan has been demonstrated to be more effective than ACE inhibitors (enalapril) in terms of mortality reduction and morbidity.
• Instead of an ACE inhibitor/ARB, sacubitril-valsartan can be utilized, in patients where affordability resource is not a constraint.
• ARNIs should not be used in conjunction with an ACE inhibitor/ARB. Given the possibility of angioedema, an ACE inhibitor and an ARNI should be separated by at least 36 hours.

Sacubitril/valsartan in Heart Failure -Review of Indian studies -Recent data from several trials indicate the effectiveness and safety of sacubitril/valsartan in HFrEF patients.

1. Sacubitril/valsartan in Hospitalized Heart Failure Patients: In a major Indian study investigating the long-term safety and efficacy of angiotensin receptor/neprilysin inhibitors (ARNI, all patients hospitalized in medical wards and ICU with CHF with decreased ejection fraction (EF) (who were symptomatic in the form of NYHA CLASS II or above) were included. To begin, one group received ARNI 50mg twice daily. A control group received Angiotensin-converting enzyme inhibitors (ACEI) instead of ARNI. Better improvement in EF was observed among the ARNI group, with 58% in the ARNI group showing a 5 to 10% increase rate of EF, in comparison, only 18% in the ACEI group showed the same improvement rate. 8 % in the ARNI group led to more than a 10% increase in EF, whereas the ACEI group showed no improvement.ARNI showed encouraging effects with improved performances and fewer hospitalizations. The team also highlighted the need for randomized control research to comprehend this new molecule's true potential in India. (2)

2. Sacubitril/valsartan in Heart Failure with Border-line reduced Ejection Fraction: Another Indian study comparing the angiotensin receptor neprilysin inhibitor (sacubitril- valsartan) with enalapril, in maximal tolerable dose, in patients who had heart failure with a borderline reduced ejection fraction, concluded that sacubitril/valsartan group has significant improvements in ejection fraction, and symptoms, with better quality of life and reduced number of hospitalization, over enalapril group. The team also highlighted that Sacubitril/valsartan group has an average of 9% improvements in EF against 2% in the enalapril group, which is statistically significant. Interestingly, there is little information available on patients with EFs between 40 and 50 percent. This unique study made an effort to fill up this gap by assessing a group of patients with borderline impaired EF and discovered that sacubitril/Valsartan patients had significantly shorter hospital stays and improved EF when compared to enalapril patients. (5)

3. Sacubitril/valsartan on Left Ventricular Function in Heart Failure: Yet another study was undertaken to evaluate the effect of Sacubitril Valsartan on left ventricle function in patients with HFrEF compared to pre-treatment baseline values while on optimum medical treatment. These results indicated that Sacubitril Valsartan significantly improved EF, provided a longer symptom-free period, and hence improved quality of life. It decreased the number of hospital readmissions and is hence economically and clinically valuable. (3)

4. Sacubitril/valsartan Improves Clinical Outcomes in Heart Failure Patients: Expert findings of a PARADIGM-HF sub-analysis that assessed the effectiveness and safety of sacubitril/valsartan in Indian patients with chronic HFrEF noted that compared to enalapril, sacubitril/valsartan had better efficacy in reducing the risks of CV death, HF hospitalization, and all-cause mortality in Indian population. Adverse events (78.4% vs.82.2%) were comparatively lower in the sacubitril/valsartan than in the enalapril group. (4)

Sacubitril/Valsartan: Overview of Landmark Global Studies

1. Sacubitril/valsartan reduced the risk of CV death and HF hospitalization compared to enalapril in patients with chronic HFrEF, in Prospective comparison of ARNI with ACEi to Determine the Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF). Notably, this was the largest clinical study ever undertaken, globally, to treat chronic heart failure, and affirmed that sacubitril/valsartan is more successful than enalapril and that it may be used to treat chronic heart failure, instead of ACE inhibitors, or angiotensin II receptor blockers. (4)

2. The TRANSITION research, published in 2018, showed that sacubitril/valsartan may be started safely and shortly after an acute heart failure event, both in the hospital and in an out-patient environment, and a wide spectrum of hemodynamically stabilized acute heart failure patients. (9)

3. The results of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) trial, revealed that patients with HFrEF treated with sacubitril/valsartan experienced rapid reductions in NT-proBNP, an established biomarker for heart failure severity and prognosis. Improvements in heart volume and function parameters at 12 months were also noted, with the reverse cardiac remodeling at one year. (10)

4. The PIONEER-HF study, a multicenter, randomized, double-blind, active-controlled experiment, looked at the impact of sacubitril/valsartan in HFrEF patients who were admitted to the hospital for acute decompensated HF. Sacubitril/valsartan was shown to be more efficacious than enalapril in lowering the risk of HF rehospitalization or cardiovascular mortality (9.2% vs. 15.2%; HR,0.58; 95% CI, 0.39 to 0.87; P 1⁄4 0.007) after an 8 week follow up. (11)

Safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF-Research documents that sacubitril/valsartan had fewer drug-related side effects than ACEIs/ARBs, including angioedema, hyperkalemia, cough, dizziness, renal failure, and arterial hypotension. (6)

Key pointers-

• Researchers have shown that sacubitril/valsartan reduces mortality and hospitalization risks, reverses cardiac remodeling, lowers HF biomarkers, improves the quality of life, reduces arrhythmia, improves renal dysfunction, and controls HF metabolism.
• Compared to ACEIs/ARBs, sacubitril/valsartan was safe and well-tolerated in patients with HFrEF or HFpEF.
• Sacubitril/valsartan usage has been recommended by the recent heart failure therapy guidelines, in the USA and Europe. (12)
• The 2021 American Academy of Cardiologists (ACC) expert consensus lists that sacubitril/valsartan to be used in HFrEF (EF< 40%), NYHA class II-IV HF, and as a combination with a guideline-directed medical treatment for HF (6)
• A growing body of Indian studies now affirms that Sacubitril valsartan is an effective alternative to conventional HF therapies.

Concluding Words-

• Supported by an overwhelming number of global and Indian studies, sacubitril/valsartan promises to be an effective agent in the treatment of heart failure.
• As this novel therapy revolutionizes the field of heart failure care, physicians may like to continue to understand the underlying mechanisms of the drug to its core and implement this drug therapy in heart failure patients rationally.
• With continuous research on Sacubitril Valsartan in India, this therapeutic continues to hold promise for better management of heart failure in the future.

References:

1. Hopper, I., & Easton, K. (2017). Chronic heart failure. Australian Prescriber, 40(4), 128.

2. Das, C. K., Tripathi, M. S., Minz, A., Bhanja, R. L., Royzada, A., & Chakraborty, G. K. (2018). Is ARNI exclusive in the management of chronic heart failure? 2 years of experience in a central hospital of Indian Railway. Indian Heart Journal, 70, S51.

3. Assessment of left ventricular function by two dimensional echocardiography and n-terminal pro-brain natriuretic peptide in patients of heart failure with reduced ejection fraction treated with angiotensin receptor neprilysisn inhibitor anup vineet mahajani, tripti deb. Apollo hospitals, jubilee hills, hyderabad, India.

4. Jain, A. R., Aggarwal, R. K., Rao, N. S., Billa, G., & Kumar, S. (2020). Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study. Indian heart journal, 72(6), 535-540.

5. Chatterjee, P. K., Majumder, B., Shukla, P., Sinha, P., Mitra, K. K., Chakroborty, S., & Chakrabarty, S. (2018). A comparative study of sacubitril/valsartan with enalapril in patients with borderline reduced ejection fraction-A single tertiary centre experience in eastern India. Indian Heart Journal, 70, S51.

6. Zhang, R., Sun, X., Li, Y., He, W., Zhu, H., Liu, B., & Zhang, A. (2022). The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review. Journal of Cardiovascular Pharmacology and Therapeutics, 27, 10742484211058681

7. Mishra, S., Mohan, J. C., Nair, T., Chopra, V. K., Harikrishnan, S., Guha, S., ... & Bahl, V. K. (2018). Management protocols for chronic heart failure in India. Indian heart journal, 70(1), 105-127.

8. European Heart Journal, Volume 42, Issue 36, 21 September 2021, Pages 3599–3726, https://doi.org/10.1093/eurheartj/ehab368 Published:27 August 2021

9. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019;21:998e1007.

10. Januzzi JL, Prescott MF, Butler J, et al. Association of change in N-terminal proeB-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. J Am Med Assoc. 2019;322:1085e1095.

11. Morrow DA, Velazquez EJ, DeVore AD, et al. Clinical outcomes in patients with acute decompensated heart failure randomly assigned to sacubitril/valsartan or enalapril in the PIONEER-HF Trial. Circulation. 2019;139(19):2285-2288.

12. Khder, Y., Shi, V., McMurray, J. J., & Lefkowitz, M. P. (2016). Sacubitril/valsartan (LCZ696) in heart failure. Heart Failure, 133-165.