An eight-week study by Ruilope et al. published in 2010 in the Lancet33 included 1328 patients with mild-to-moderate hypertension randomized to one of eight regimens: sacubitril/valsartan 100, 200 or 400 mg; valsartan 80, 160 or 320 mg; sacubitril 200 mg; or placebo.

The 200 mg and 400 mg doses of sacubitril/valsartan provided greater reductions in blood pressure than valsartan at doses of 160 mg and 300 mg, respectively.

Sacubitril/valsartan reduced systolic more markedly than diastolic blood pressure, thereby inducing reduced pulse pressure (PP) compared to valsartan. This is significant, given that reducing PP is beneficial owing to the association of higher PP with arterial stiffness and risk of stroke, myocardial infarction, congestive heart failure and cardiovascular death.

The PARAMOUNT trial34 assessed the efficacy and safety of sacubitril/valsartan in patients with HF and preserved ejection fraction (HFpEF). It included patients in New York Heart Association (NYHA) classes II and III, with left ventricular ejection fraction (LVEF) ≥45% and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml. One hundred and forty-nine patients were randomized to sacubitril/valsartan and 152 to valsartan. Sacubitril/valsartan was titrated up to 200 mg twice daily and valsartan up to 160 mg twice daily. Patients were treated for 36 weeks. Reductions in NT-proBNP from randomization until week 12, the primary aim, were greater in the sacubitril/valsartan group than in the valsartan group (p=0.005). Sacubitril/valsartan was well tolerated and the occurrence of adverse events was similar in both study groups. Given the positive outcome of the PARAMOUNT trial in this area in which, until then, no drug had been able to show a reduction in mortality, the PARAGON trial (ClinicalTrials.gov identifier NCT01920711) was started with the aim of assessing the impact of sacubitril/valsartan on the composite endpoint of cardiovascular mortality and total hospitalizations due to HF.

The PARADIGM-HF trial35–37 belongs, without a doubt, to the rare category of historic trials in medicine that definitively changed the way patients with HFrEF are treated. It was terminated early, in accordance with prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit of sacubitril/valsartan over enalapril had been crossed.

It is the largest trial conducted to date in the context of HFrEF, with 8442 patients. Eligibility requirements at screening included age at least 18 years, NYHA class II-IV, and LVEF≤40% (which was changed to ≤35% by an amendment to the protocol on December 15, 2010). Patients were required to have a plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml (or NT-proBNP≥60 pg/ml) or, if they had been hospitalized for HF within the previous 12 months, BNP of at least 100 pg/ml (or NT-proBNP≥400 pg/ml). Patients taking any dose of an ACEI or ARB were considered for participation, but for at least four weeks before screening, patients were required to take a stable dose of a BB and an ACEI or ARB equivalent to at least 10 mg of enalapril daily. Exclusion criteria included symptomatic hypotension, systolic blood pressure (SBP)<100 mmHg at screening or 95 mmHg at randomization, estimated glomerular filtration rate (eGFR)<30 ml/min/1.73 m2 of body surface area at screening or at randomization or a decrease in eGFR of more than 25% (amended to 35%) between screening and randomization, serum potassium>5.2 mmol/l at screening (or >5.4 mmol/l at randomization), or a history of angioedema or unacceptable side effects during treatment with ACEIs or ARBs.35

These patients were randomized to sacubitril/valsartan 200 mg twice daily, or enalapril 10 mg twice daily, in addition to recommended therapy.35–37

The main aim of the TITRATION trial53 was to assess the tolerability of sacubitril/valsartan in two titration regimens, with a follow-up period of 11 weeks.

The drug was titrated gradually, from an initial dose of 50 mg twice daily, up to the target dose of 200 mg twice daily. The initial dose of 50 mg twice daily was administered over a five-day open-label run-in. Patients who tolerated this phase were then randomized to one of two titration regimens up to 200 mg twice daily: a ‘condensed’ regimen, of 100 mg twice daily for two weeks followed by 200 mg twice daily, and a ‘conservative’ regimen, of 50 mg twice daily for two weeks, 100 mg twice daily for three weeks, followed by 200 mg twice daily. Tolerability criteria were hypotension, renal dysfunction, hyperkalemia, and angioedema. The analysis was stratified according to prior treatment with ACEIs/ARBs: high doses (>160 mg of valsartan or >10 mg enalapril, or equivalent) and low doses (≤160 mg of valsartan or ≤10 mg enalapril, or equivalent).

Four hundred and ninety-eight patients with chronic HF, NYHA classes II-IV and LVEF≤35% were included. In 93% of cases patients were receiving ACEIs or ARBs before inclusion in the study; at admission, these drugs were replaced by sacubitril/valsartan according to the algorithm subsequently adopted by international guidelines.

The tolerability of the two titration regimens, ‘condensed’ and ‘conservative’, was similar: there was no statistically significant differences between the study arms in the incidence of hypotension (9.7% vs. 8.4%), renal dysfunction (7.3% vs. 7.6%), hyperkalemia (7.7% vs. 4.4%), or angioedema (0% vs. 0.8%).

In the group receiving low-dose ACEIs/ARBs before the study began, the ‘condensed’ titration of sacubitril/valsartan led to a higher rate of hypotension than the ‘conservative’ titration. In patients receiving high-dose ACEIs/ARBs before the study began, the tolerability of the two titration regimens was similar.

A study by Gaziano et al. published in JAMA Cardiology assessed the cost-effectiveness of sacubitril/valsartan compared with enalapril in the USA.54 In eligible patients with HFrEF, a Markov model showed that sacubitril/valsartan would increase life expectancy with an incremental cost-effectiveness ratio comparable to that of other high-value accepted cardiovascular interventions. Sensitivity analyses showed that sacubitril/valsartan would remain cost-effective vs. enalapril.

Since sacubitril/valsartan is a non-generic drug, the cost to the patient compared to ACEIs/ARBs may, for some patients, be a hurdle. However, in view of the magnitude of the prognostic gain associated with sacubitril/valsartan, policy-makers may decide to adopt the same policy regarding this drug as that adopted for anti-diabetics, making it essentially free, at least for less well-off patients.

Sacubitril/valsartan is available in three doses: 50 mg (24 mg/26 mg), 100 mg (49 mg/51 mg) and 200 mg (97 mg/103 mg).

Co-administration of sacubitril/valsartan with an ACEI is contraindicated due to the increased risk of angioedema. Sacubitril/valsartan should only be started after 36 hours of washout of ACEIs.22,42,56

Given that valsartan is an ARB, sacubitril/valsartan should not be co-administered with another ARB.21 However, a washout period of a previously administered ARB is not necessary, and sacubitril/valsartan can be initiated at the time of the next dose.

During the process of titration, blood pressure and serum creatinine and potassium should be monitored.

Condensed titration: Patients who previously took high doses of ACEI (enalapril >10 mg/day or equivalent) or ARB (valsartan>160 mg/day or equivalent) can start sacubitril/valsartan at a dose of 100 mg (49 mg/51 mg) twice daily and after 3-4 weeks increase to 200 mg (97 mg/103 mg) twice daily.

Conservative titration: Patients who were not previously treated with ACEIs or ARBs, or those who previously took low doses of ACEI (enalapril≤10 mg/day or equivalent) or ARB (valsartan≤160 mg/day or equivalent), or who have SBP>100 and ≤110 mmHg, moderate to severe renal impairment, or moderate hepatic impairment, can begin sacubitril/valsartan at a dose of 50 mg (24 mg/26 mg) twice daily. After 3-4 weeks, the dose can be increased to 100 mg (49 mg/51 mg) twice daily and, if this dose is tolerated, can be increased further after 3-4 weeks to 200 mg (97 mg/103 mg) twice daily.56

The most frequently reported adverse reactions to sacubitril/valsartan compared to enalapril in the PARADIGM-HF trial36 were hypotension (16.7% vs. 10.6% of participants), hyperkalemia (20.4% vs. 22.9%), and renal dysfunction (4.8% vs. 6.5%). However, in most cases, these adverse events were classified as non-serious; hypotension was a serious adverse event in 1.4% of patients and renal failure in 1.02%. Angioedema occurred in 0.5% of these patients.

Another important point to take into consideration is that patients in clinical practice are often frailer and have more severe disease than the PARADIGM-HF study population. In fact, although the intrinsic risk of adverse events in real-world patients may be higher, this may actually result in a larger benefit of sacubitril/valsartan in absolute terms. This should be taken into account by physicians who are hesitating to begin or up-titrate sacubitril/valsartan in these patients.

Hypotension and hyperkalemia: Treatment should not be initiated if SBP<100 mmHg or serum potassium>5.4 mmol/l. If hypotension occurs during treatment, dose adjustment of diuretics and/or vasodilators and treatment of other causes of hypotension (e.g. hypovolemia) should be considered.

If hypotension is not corrected by these measures, or serum potassium falls below 5.4 mmol/l, discontinuation or temporary dose reduction of sacubitril/valsartan should be considered.56

Of note, PARADIGM-HF enrolled a large number of patients with low SBP, and those in the lowest SBP category (including those with SBP<100 mmHg) attained the same relative magnitude of benefit from sacubitril/valsartan as patients in the trial overall.58 Because such patients are at higher risk of adverse clinical outcomes, the same relative risk reduction with sacubitril/valsartan is expected to give a greater absolute risk reduction. Using a conservative up-titration regimen, the majority of patients are able to tolerate the target dose of sacubitril/valsartan, and even using a lower dose patients will still derive benefit compared with enalapril.59 These observations are reassuring and support the use of sacubitril/valsartan in patients with low SBP, even less than 100 mmHg. Therefore, physicians should not avoid prescribing this potentially life-saving treatment in HF patients. Titration should be conservative and may not achieve the target dose, but it should be attempted.60,61

Renal impairment and diabetes: In patients with mild renal impairment (eGFR 60-90 ml/min/1.73 m2) there is no need to adjust dosage. In patients with moderate (eGFR 30-60 ml/min/1.73 m2) or severe (eGFR<30 ml/min/1.73 m2) renal impairment a conservative titration should be performed. There is limited clinical experience in patients with eGFR<30 ml/min/1.73 m2 and these patients may be at greater risk of hypotension and hyperkalemia. Sacubitril/valsartan is not recommended in patients with end-stage renal disease.

If patients present clinically significant worsening of renal function during the use of sacubitril/valsartan, a temporary dose reduction or discontinuation should be considered.56

Sacubitril/valsartan, compared with enalapril, slowed the rate of decrease in eGFR and had favorable effects on cardiovascular and renal outcomes in patients with and without chronic kidney disease.62 The observed increase in the urinary albumin/creatinine ratio results from a block in the reabsorption of protein in the proximal renal tubule and is not related to an increased rate of decline in glomerular filtration, as it usually is with the use of RAAS inhibitors.63 This finding is important and has therapeutic implications, since conventional RAAS blockers are often withheld or withdrawn in patients with heart failure and renal dysfunction.

Diabetes is another frequent comorbid condition in HFrEF. In diabetic patients, sacubitril/valsartan has been shown to have additional benefits beyond its cardiovascular impact, attenuating the rate of decline in renal function and improving glycemic control.63,64

NYHA class IV: Clinical experience is very limited in this population.56 The HFN-LIFE trial will provide valuable insight into the practical use of sacubitril/valsartan in patients with advanced HF, prospectively comparing its effectiveness with valsartan alone, in a randomized, double-blind trial of approximately 400 subjects with NYHA class IV heart failure (ClinicalTrials.gov identifier NCT02816736).

Hepatic impairment: In patients with mild hepatic impairment (Child-Pugh class A) dose adjustment is not necessary. In patients with moderate hepatic impairment (Child-Pugh class B) or with aspartate aminotransferase/alanine aminotransferase values twice the upper limit of normal, caution and conservative titration are recommended. Sacubitril/valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh class C).56

Drug interactions: Sacubitril/valsartan may increase the serum concentration of atorvastatin, resulting in significantly greater blood pressure reduction if co-administered with phosphodiesterase type 5 inhibitors, including sildenafil, and may increase the risk of worsening of renal function if co-administered with non-steroidal anti-inflammatory drugs. Caution is recommended in these circumstances.56

Neprilysin hydrolyzes BNP but not NT-proBNP.65 Therapy with sacubitril/valsartan thus induces an increase in BNP levels as a result of neprilysin inhibition. NT-proBNP is therefore a useful biomarker to assess therapeutic effect and prognosis in patients treated with neprilysin inhibitors.65 However, currently available commercial assays for detection of NT-proBNP and BNP actually measure a mixture of the two peptides. Furthermore, it remains unclear whether degradation or oligomerization of either BNP or NT-proBNP impairs the accuracy of commercial assays used for their detection.66