The evidence in heart failure and reduced left ventricular ejection fraction
PARADIGM-HF1 was a double-blind, randomised-controlled trial in which 8,442 patients with chronic symptomatic heart failure (New York Heart Association [NYHA] class II–IV) and a reduced left ventricular ejection fraction (LVEF) <40% (changed to ≤35% during the course of the study) were randomised to receive enalapril (10 mg twice daily) or sacubitril/valsartan (200 mg twice daily)*. Entry criteria also included a raised natriuretic peptide (NP) level (brain natriuretic peptide [BNP] ≥150 pg/ml or N-terminal proBNP [NTproBNP] ≥600 pg/ml, although for patients who had been hospitalised for heart failure in the previous 12 months, a slightly lower cut-off was used for BNP [≥100 pg/ml] or NTproBNP [≥400 pg/ml]). Exclusions included significant valvular heart disease; systolic blood pressure below 100 mmHg at screening; an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2; and hyperkalaemia.
All patients had to tolerate 10 mg enalapril twice daily followed by sacubitril/valsartan 100 mg twice daily, up-titrated to 200 mg twice daily, during a six-week run-in period before they could be randomised. During this run-in period, 2,079 patients discontinued the study, most commonly because of side effects or abnormal blood tests secondary to enalapril (n=657) or the subsequent sacubitril/valsartan treatment (n=605).
The mean age of the patients was 64 years, 22% were female, mean systolic blood pressure was 122 mmHg, and median NTproBNP plasma level was around 1,600 ng/L. More than 90% were treated with a beta blocker, the vast majority were taking a diuretic (80%) and 55% were also on mineralcorticoid antagonists.
The study was interrupted early (in March 2014) because of the benefit in the sacubitril/valsartan arm after a median follow-up of 27 months. The results were presented in September 2014 at the Congress of the European Society of Cardiology.2 Compared with patients randomised to enalapril, the use of sacubitril/valsartan led to a 20% risk reduction (4.7% absolute risk reduction [ARR]) in the primary end point (a composite of death from cardiovascular causes or hospitalisation for heart failure; figure 1), a 20% risk reduction in death from cardiovascular causes (3.2% ARR), a 21% risk reduction for the first hospitalisation for worsening heart failure (2.8% ARR), and a 16% risk reduction for death of any cause (2.8% ARR).
The most common adverse event was symptomatic hypotension, which was more frequent in patients taking sacubitril/valsartan (14%) than enalapril (9.2%, p<0.001). Those taking enalapril were more likely to have a rise in creatinine (≥2.5 mg/dL; 4.5% vs. 3.3%, p=0.007) or potassium (>6.0 mmol/L; 5.6% vs. 4.3%, p=0.007) and to have a cough (14.3% vs. 11.3%, p<0.001). There was no difference in the (very low) incidence of angioedema between the groups.
There have been further analyses from the PARADIGM-HF study.
PARADIGM-HF recruited patients across a wide age range. Older patients were more likely to be female, had higher systolic blood pressure and circulating NTproBNP plasma levels, worse symptoms and renal function, and were more likely to have ischaemic heart disease or atrial fibrillation.3 Despite these differences, the effect of sacubitril/valsartan was similar across all ages (ranges defined post hoc: <55 years, 55–64 years, 65–74 years, >75 years). The hazard ratio (HR) was in favour (<1) of sacubitril/valsartan in all age categories for all the end points considered. The incidence of adverse events (apart from angioedema) increased with age, and the most common were again symptomatic hypotension, reported in 17.7% of patients older than 75 years in the sacubitril/valsartan group (vs. 11.9% in the enalapril group), and hyperkalaemia (more common in those taking enalapril).
Mode of death
During the trial, 1,546 patients died, including 711 in the sacubitril/valsartan arm and 835 patients in the enalapril group.4 Around 81% of deaths were attributed to cardiovascular causes, the majority of which were related to worsening heart failure or had happened suddenly; for 66 deaths the cause was not available. Fatal myocardial infarction and fatal stroke were rare events (<1%). Those who died were older, more likely to be male, and had more features of advanced heart failure than those who survived. The reduction in mortality seen with sacubitril/valsartan compared with enalapril was mainly due to the lower incidence of sudden death and death related to worsening heart failure. Sacubitril/valsartan had no effect on the incidence of non-cardiovascular death compared with enalapril.
Worsening heart failure
Sacubitril/valsartan was superior to enalapril in preventing symptoms and disease progression.5 Compared with patients randomised to enalapril, those receiving sacubitril/valsartan required intensification of anti-heart failure treatment less frequently, including the need for intravenous inotropic support, or the need for emergency department visits. Furthermore, patients in the sacubitril/valsartan arm were less likely to be hospitalised multiple times. Patients in the sacubitril/valsartan group had significantly lower levels of circulating troponin and NTproBNP, evident within four weeks of starting the trial and sustained after eight months of treatment.
Severity of heart failure
The MAGGIC score6 was used to define categories of baseline risk for the patients in PARADIGM-HF.7 An increase of one in the score is associated with an increase in the risk of the primary end point of 6%. Sacubitril/valsartan conferred a similar relative risk reduction across all the levels of risk, although the absolute benefit was markedly greater for those in the highest risk group.
A potential concern about the clinical use of sacubitril/valsartan is the speed of up-titration. In PARADIGM-HF, there was quite a long run-in period, and patients only received sacubitril/valsartan once they had already been tolerant of enalapril 10 mg twice daily.
The randomised, double-blind, TITRATION study8 assessed the safety and tolerability of up-titrating sacubitril/valsartan from 50 mg twice daily to the target dose of 200 mg twice daily over three weeks (condensed strategy) or six weeks (conservative strategy) in patients with heart failure and LVEF <35%. The study included inpatients pre-treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (11%), and also a small proportion of patients naïve to both drugs (7%).
Of the 540 patients enrolled in the short (five days) run-in phase, in which patients received open-label sacubitril/valsartan 50 mg twice daily, 498 were randomised (92%), and 429 (86%) finished the study.
There was no difference between the two regimens in any of the specified adverse events including hypotension, renal dysfunction, hyperkalaemia, angioedema, systolic blood pressure below 95 mmHg, potassium >5.5 mmol/L or >6.0 mmol/L (table 1).
There was no difference between the groups in the secondary end point of treatment success, defined as the number of patients achieving the sacubitril/valsartan 200 mg twice-daily target dose without any down-titration or dose interruption over 12 weeks. Success was achieved in 78% patients in the condensed strategy arm versus 84% in the conservative strategy arm (p=0.07), but the analysis excluded patients who discontinued sacubitril/valsartan because of death or ”non-adverse events”. The results should be considered preliminary; in particular, the exclusion of ”non-adverse events” is difficult to assess until the paper is published in full.9
- The PARADIGM-HF trial showed that, compared to enalapril, sacubitril/valsartan led to a 20% risk reduction (4.7% absolute risk reduction) in a composite end point of death from cardiovascular causes or hospitalisation for heart failure in patients with HFREF
- Benefits were consistent across different age ranges and risk profiles
- Compared to enalapril, sacubitril/valsartan lowered the incidence of sudden death and death related to worsening heart failure
- Sacubitril/valsartan was superior to enalapril in preventing the progression of heart failure
1. McMurray JJ, Packer M, Desai AS et al.; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004. http://dx.doi.org/10.1056/NEJMoa1409077
2. Clark AL, Pellicori P. Clinical trials update from the European Society of Cardiology meeting 2014: PARADIGM-HF, CONFIRM-HF, SIGNIFY, atrial fibrillation, beta-blockers and heart failure, and vagal stimulation in heart failure. ESC Heart Failure 2014;1:82–6. http://dx.doi.org/10.1002/ehf2.12012
3. Jhund PS, Fu M, Bayram E et al.; PARADIGM-HF Investigators and Committees. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J 2015;36:2576–84. http://dx.doi.org/10.1093/eurheartj/ehv330
4. Desai AS, McMurray JJ, Packer M et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J 2015;36:1990–7. http://dx.doi.org/10.1093/eurheartj/ehv186
5. Packer M, McMurray JJ, Desai AS et al.; PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation 2015;131:54–61. http://dx.doi.org/10.1161/CIRCULATIONAHA.114.013748
6. Pocock SJ, Ariti CA, McMurray JJ et al.; Meta-Analysis Global Group in Chronic Heart Failure. Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J 2013;34:1404–13. http://dx.doi.org/10.1093/eurheartj/ehs337
7. Simpson J, Jhund PS, Silva Cardoso J et al.; PARADIGM-HF Investigators and Committees. Comparing LCZ696 with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol 2015;66:2059–71. http://dx.doi.org/10.1016/j.jacc.2015.08.878
8. Pellicori P, Clark AL. Clinical trials update from the European Society of Cardiology – Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure. Eur J Heart Fail 2015;17:979–83. http://dx.doi.org/10.1002/ejhf.340
In clinical trials, sacubitril/ valsartan – initially known as the investigational agent LCZ696 – was used in 100 mg and 200 mg doses. These translate to the licensed doses of 49 mg sacubitril/51 mg valsartan and 97 mg sacubitril/103 mg of valsartan, respectively.
A smaller 50 mg dose, which equates to 24 mg sacubitril/26 mg valsartan, is also available.
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