Drug intolerance was common during the trial. During the run-in period, just over 10% of participants (1138/10 513) discontinued because of an adverse event to one of the study treatments. After randomisation, a similar proportion discontinued sacubitril/valsartan because of an adverse event.2 The most common events relating to the combination included hypotension (17.61%), hyperkalaemia (11.61%) renal impairment (10.14%) and cough (8.78%).
Hypotension was more common with sacubitril/ valsartan than with enalapril (17.61% vs 11.97%). The risk of it occurring is higher in older age (≥75 years), low baseline systolic blood pressure, renal disease, use of high-dose diuretics, diarrhoea and vomiting. Blood pressure should be monitored at baseline and during dose titration. If hypotension persists despite adjusting the dose of other treatments (e.g. diuretics), reduce the sacubitril/valsartan dose or temporarily discontinue.
Renal function should be checked before and during treatment, especially in those with renal artery stenosis. Decrease or interrupt the sacubitril/valsartan dose if renal function declines.
Because of the risk of hyperkalaemia, serum potassium should be monitored and treatment should not be started if concentrations are more than 5.4 mmol/L. Hyperkalaemia is more likely to occur in patients with severe renal impairment, diabetes, hypoaldosteronism or on a high potassium diet.
Neprilysin is involved in the clearance of amyloid-beta. Increased concentrations were found in the cerebrospinal fluid of healthy adults taking sacubitril/valsartan. The clinical relevance of this is currently unknown.
Angioedema was found to be a serious adverse event with previous combination therapies that inhibit neprilysin and the renin–angiotensin system simultaneously.3 Although rare in the PARADIGM-HF trial, angioedema was more common with sacubitril/ valsartan than with enalapril (0.5% vs 0.2%).2 If angioedema occurs, treatment should be permanently stopped. Sacubitril/valsartan is contraindicated in patients with a history of angioedema with an ACE inhibitor or other angiotensin receptor antagonist, and in those with hereditary angioedema.
Concomitant use of an ACE inhibitor is contraindicated because of the risk of angioedema. A washout period of 36 hours is recommended before sacubitril/ valsartan is initiated in patients switching from an ACE inhibitor. Angiotensin receptor antagonists should not be taken with sacubitril/valsartan.
Sacubitril/valsartan has numerous other drug interactions. Co-administration of potassium-sparing diuretics may lead to increased serum potassium. Use of non-steroidal anti-inflammatory drugs may increase renal impairment, and there is a theoretical risk of lithium toxicity with concomitant use. Other drugs that may interact with the combination include aldosterone antagonists, frusemide, rifampicin, cyclosporin, ritonavir, metformin, statins and sildenafil.
Following oral administration, the combination dissociates into sacubitril and valsartan, and sacubitril is metabolised to the active metabolite (LBQ657) by esterases. Steady-state drug concentrations are reached after three days of twice daily dosing. Up to 68% of sacubitril (mainly as LBQ657) and 13% of valsartan are excreted in the urine with the rest excreted in the faeces. The elimination half-lives of sacubitril, LBQ657 and valsartan are 1.4, 11.5 and 9.9 hours.
The recommended starting dose of sacubitril/ valsartan is 49 mg/51 mg twice daily. A lower starting dose (24 mg/26 mg) should be considered in patients not currently taking an ACE inhibitor or angiotensin receptor antagonist, or who have risk factors for hypotension such as those aged 75 years and over or with low systolic blood pressure. A lower dose is also recommended for patients with severe renal impairment or moderate hepatic impairment. Valsartan is more bioavailable in this formulation than in other valsartan products. This should be considered for patients switching over to this formulation.
The drug is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and cholestasis. It should also not be used in pregnancy.
The combination of sacubitril and valsartan lowered the risk of death or hospitalisation due to worsening heart failure compared to enalapril in a large phase III trial. However, the enalapril dose (20 mg/day) in the trial was at the lower end of the recommended dose (20–40 mg/day) in Australia. This raises the question of whether it was a valid comparator. Another concern about the trial design was that many patients discontinued because they could not tolerate the drug during the run-in period and after randomisation so the patients that completed the trial may not be representative of the general population of patients with heart failure. Patient monitoring is very important, particularly when treatment is initiated and during dose titration and when there is a change in the patient’s other medicines. Before starting this drug in patients switching from an ACE inhibitor, there should be a washout period of at least a day to reduce the risk of angioedema.
