A patient who seems to be doing well on conventional treatment will naturally be surprised and probably discomforted by the suggestion that his or her treatment should be changed, especially if this means an extra visit or two to the doctor or nurse, along with blood pressure checks and the taking of blood samples (and maybe the doctor or nurse looking after the patient might have similar thoughts!). Of course, those familiar with heart failure will know that the idea that a patient with heart failure is ‘doing well’ (or is ‘stable’) is a myth and that there is a high rate of disease progression, even with the currently best available treatment.
Sometimes, practitioners think they can wait until things get worse before needing to intervene. Unfortunately, the first manifestation of worsening may be death and, for many years, we have recognised that in patients with mild symptoms (i.e. the ones that might appear most stable), the most common mode of death is sudden, presumed arrhythmic, death. Why does all this matter? It matters because, if we wait, we may miss the boat. We won’t get warning. Our patient might not declare his or herself as someone in imminent danger.
Is this a real concern? In the PARADIGM-HF trial,1 in which the majority of patients had mild symptoms, we found 41% of ‘first events’ (or ‘end points’) in the trial were deaths and about half of those were sudden. So given the statistically overwhelming evidence that the angiotensin-receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan is superior to an evidence-based angiotensin-converting enzyme (ACE) inhibitor used in an evidence-based dose, in a broad spectrum of patients with heart failure and reduced ejection fraction (HFREF), I would argue that potentially all such patients treated with an ACE inhibitor or angiotensin-receptor blocker (ARB) should be considered for switching to the ARNI.
As with any drug, however, there are specific indications and contraindications and I will review these in the next section, taking account of the European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) product labelling for sacubitril/valsartan. As we have learnt with ACE inhibitors/ARBs and beta blockers, aiming for the evidence-based target dose of treatment is important. But we also know, with all treatments, adverse effects may limit dose titration or even result in treatment intolerance. Therefore, I will also review what we know about the adverse effects of sacubitril/valsartan and how to manage these.
Indications and contraindications
Sacubitril/valsartan is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction. The product labelling for sacubitril/valsartan largely reflects the inclusion and exclusion criteria for the PARADIGM-HF study. The key indications are symptomatic heart failure and reduced ejection fraction (≤40%). Thereafter, the major consideration is tolerability. Because the neprilysin inhibitor component of the molecule (sacubitril) results in additional blood pressure lowering (beyond that of the ARB valsartan alone), sacubitril/valsartan is only recommended in patients with a systolic blood pressure ≥100 mmHg.
Neprilysin, like ACE, breaks down bradykinin, the chemical substance that when it accumulates can rarely cause angioedema in susceptible patients. Consequently, no patient with a history of angioedema should receive sacubitril/valsartan (because neprilysin inhibition leads to an increase in bradykinin). Likewise, ACE inhibitor treatment should be stopped for at least 36 hours before switching to sacubitril/valsartan so as to avoid the possibility of simultaneous ACE and neprilysin inhibition (and greater accumulation of bradykinin).
Although not specifically mentioned, kidney function must be monitored when switching to sacubitril/valsartan because the ARB component of this molecule, as with any other renin–angiotensin system (RAS) blocker, may lead to a rise in creatinine in some patients. This is unlikely if switching from an evidence-based dose of another RAS blocker, especially since renal dysfunctions were less common with sacubitril/valsartan than with enalapril in PARADIGM-HF. The same considerations apply to potassium, and sacubitril/valsartan is not recommended in patients with a potassium of >5.4 mmol/L.
As alluded to above, hypotension may occur on switching from an ACE inhibitor or ARB to sacubitril/valsartan because the latter increases natriuretic peptides and other vasoactive substances, which lead to vasodilatation. Among the 8,399 patients randomised to sacubitril/valsartan in PARADIGM-HF, 14.0% reported hypotension (9.2% in the enalapril group). In 2.7%, this was accompanied by a systolic blood pressure <90 mmHg (1.4% in the enalapril group). However, only 0.9% of sacubitril/valsartan treated patients stopped the study drug because of hypotension (0.7% in the enalapril group). This demonstrates that although relatively common in patients with heart failure, hypotension rarely is severe enough to lead to treatment discontinuation. We knew this already from our experience with ACE inhibitors/ARBs and beta blockers and, certainly, in my own practice patients are often willing to accept hypotensive symptoms (which are often postural e.g. transient dizziness on rising quickly from a chair) if fully informed of the benefits of persisting with treatment (i.e. that the risks of death and hospitalisation may be reduced).
The incidence of hypotension (and need to discontinue life-saving therapy) can be minimised by stopping any unnecessary blood pressure lowering drugs – the main culprits are nitrates, calcium-channel blockers and alpha-adrenoceptor antagonists. I find the latter to be the biggest problem. If administered for prostatic symptoms, it may be possible to substitute a 5-alpha reductase inhibitor (e.g. finasteride). Likewise, the much less common problem of hyperkalaemia (which was less frequent in the sacubitril/valsartan group than in the enalapril group) can often be avoided by discontinuation of drugs causing hyperkalaemia. The obvious ones are potassium supplements and potassium-sparing diuretics (the latter category does not include mineralocorticoid receptor antagonists, such as spironolactone). Other drugs causing potassium problems include trimethoprim and dietary sources should also be considered, e.g. ‘low-sodium’ salt-substitutes and bananas.
How to use sacubitril/valsartan
The best evidence we have for the use of sacubitril/valsartan comes from PARADIGM-HF, which enrolled patients already treated with an ACE inhibitor or ARB. To be eligible, patients had to be taking the equivalent of enalapril 10 mg daily (see table 1 of equivalent ACE inhibitor and ARB doses). The recommended starting dose of sacubitril/valsartan in these patients is 49/51 mg (i.e. 100 mg LCZ696 as used in PARADIGM-HF), taken twice daily. As mentioned earlier, patients should have a systolic blood pressure ≥100 mmHg and a serum potassium concentration ≤5.4 mmol/L.
The target dose of sacubitril/valsartan is 97/103 mg twice daily and the dose should be increased two to four weeks after initiation of therapy, provided the patient does not experience symptomatic hypotension, hyperkalaemia (potassium >5.4 mmol/L) or significant deterioration in renal function. Deterioration in renal function is only likely in patients subjected to greater inhibition of the RAS than with their previous dose of ACE inhibitor or ARB, as a result of the valsartan component of sacubitril/valsartan. The valsartan component of the 49/51 mg dose of sacubitril/valsartan is equivalent to 80 mg of conventional valsartan. However, patients in PARADIGM-HF treated with sacubitril/valsartan had less renal dysfunction than those treated with enalapril, suggesting neprilysin inhibition protects the kidney to some extent.
In patients taking a lower dose of ACE inhibitor or ARB (or who have not previously been treated with one of these drugs), a lower starting dose of sacubitril/valsartan (24/26 mg) should be used, twice daily, and the dose doubled every three to four weeks with the aim of reaching the same target of 97/103 mg twice daily (but taking the same precautions in ensuring tolerability at each dose-titration step).
It is important to reiterate the absolute necessity of omitting existing ACE inhibitor treatment for 36 hours before starting sacubitril/valsartan.
In summary, the ARNI sacubitril/valsartan is the first new class of drug in 15 years to reduce the risk of premature death in heart failure patients and is clearly superior to one of our most effective existing treatments, namely an ACE inhibitor. Not only does sacubitril/valsartan reduce the risk of death but it also decreased the risk of hospital admission for worsening heart failure and even deterioration in quality of life. Eligible patients with HFREF should be offered this new breakthrough treatment.
- Sacubitril/valsartan reduces the risk of each of death from cardiovascular causes and hospital admission for worsening heart failure by 20% (4.7% absolute risk reduction) compared with an ACE inhibitor
- Even heart failure patients with mild symptoms have a poor prognosis and the first manifestation of worsening is death, which is often sudden i.e. the physician is not alerted to progression of heart failure until it is too late
- As the benefits of sacubitril/valsartan over an ACE inhibitor occur early after initiation of treatment, there is a clear indication to switch patients to an ARNI as soon as possible
1. McMurray JJ, Packer M, Desai AS et al.; for the PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF). N Engl J Med 2014;371:993–1004. http://dx.doi.org/10.1056/NEJMoa1409077
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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