Patient selection
It may be unexpectedly challenging to identify patients most likely to derive survival and QOL benefits from sacubitril/valsartan. Considering the characteristics of patients in PARADIGM-HF is useful for predicting how real-world patients may respond to therapy. However, it may be difficult to accurately assess patients in clinical practice. For example, patients with chronic HF typically learn to avoid elective activities that may cause dyspnea or excessive fatigue, thereby redefining a new baseline QOL [
41,
42]. Thus, these patients may report that they are fine and never have dyspnea, leading them to appear completely or nearly asymptomatic. It is useful to take extra time during routine visits to identify patients who are nearly or completely asymptomatic because of reduced activity.
Ambulatory patients with HFrEF but improved EF of > 35% or those with no indicators of volume overload or symptoms may be less ill than the PARADIGM-HF cohort. Given the known AEs of sacubitril/valsartan, patients need to be screened for hypotension, dizziness, hyperkalemia, renal impairment, cough, and angioedema [
10]. Recalling the differences in side-effect profiles between sacubitril/valsartan and enalapril in PARADIGM-HF can help clinicians select patients most likely to tolerate the switch to sacubitril/valsartan.
Although most AEs occurred at a similar rate (Table
1), more patients taking sacubitril/valsartan developed symptomatic hypotension versus those taking enalapril. Thus, risk factors for hypotension should be carefully assessed and proactively managed before initiating therapy [
8,
10]. Careful assessment of hypotension is especially important in patients with marginal BP whose degree of decompensation differs from those in PARADIGM-HF.
In PARADIGM-HF, angioedema risk was similar for sacubitril/valsartan and enalapril; however, rates trended higher with sacubitril/valsartan (0.5% vs 0.2%;
P = 0.13) [
8]. The risk of angioedema with sacubitril/valsartan is less than that of previous neprilysin inhibitors (e.g., omapatrilat; 2.17%) [
8,
43]. However, patients with a history of angioedema should not be initiated on sacubitril/valsartan because of the complication risk; these patients were excluded from PARADIGM-HF [
8]. Because PARADIGM-HF suggests that black patients have a higher rate of angioedema with sacubitril/valsartan versus enalapril (2.4% vs 0.5%, respectively), they should be appropriately counseled about angioedema risk and maintaining vigilance regarding symptoms [
10]. Notably, black patients did receive similar benefits compared with the overall study population from sacubitril/valsartan therapy.
Another patient characteristic to consider is patient age. Because 1.4% of patients enrolled in PARADIGM-HF were ≥ 85 years old, the benefits observed from sacubitril/valsartan therapy were not statistically significant in this subpopulation [
28,
44]. Furthermore, elderly patients may have multiple comorbidities that could limit dose titration and reduce the benefits of sacubitril/valsartan therapy [
28]. However, it is important to note that there is very little trial data for the use of other HF medications in the elderly, and that the PARADIGM-HF trial did include elderly patients ≥ 75 years old, comprising 18.6% of the total trial population [
44]. Data from real-world registries will provide more insight into this potential issue [
28].
Practitioners should be aware of potential selection bias due to the run-in periods of PARADIGM-HF [
8]. Until additional real-world data are available, AEs with sacubitril/valsartan from the trial should be viewed conservatively as being potentially the minimum rate of AE occurrence. With proper preparation prior to initiating therapy and regular monitoring, side effects associated with sacubitril/valsartan can be successfully managed.
Initial dose selection and uptitration
Sacubitril/valsartan should be used as a replacement for existing ACEI/ARB medication, instead of as an additional therapy. This was typically viewed favorably by our patients. In our experience, the 36-h washout period required when switching therapies requires some logistical planning to ensure patients do not continue ACEI/ARB therapy. One approach is to instruct the patient to throw away the ACEI/ARB medication. If the patient is not comfortable with this approach, the patient can tape prescription bottles closed and safely store them.
When switching from ACEI/ARB to ARNI therapy, the initial dose of sacubitril/valsartan should be similar to the currently prescribed regimen [
8,
10,
45]. Patients on low-dose enalapril should be initiated on a low dose of sacubitril/valsartan (24/26 mg twice daily) [
10]. Subsequently, uptitration should occur every 2–4 weeks, as tolerated, to the target dose of sacubitril/valsartan (97/103 mg twice daily) [
8,
10].
A DB randomized trial observed that ACEI/ARB-naive patients and those who switched from lower-dose ACEI/ARB therapy achieved higher rates of treatment success from uptitration over 6 weeks versus for 3 weeks (84.9% vs 73.6%, respectively;
P = 0.030) [
45]. A more conservative uptitration approach may be considered if tolerance is a concern, particularly with renal impairment or hypotension.
Preparing for AEs
Clinicians should adequately inform patients of possible AEs when beginning a new medication. Common patient questions and concerns are listed in Table
2. Many patients have received an ACEI/ARB regimen, so they will be familiar with the risks for some AEs. All patients should be prepared for hypotension and orthostatic symptoms [
10], the most common symptomatic AEs in PARADIGM-HF [
8]. Clinicians must advise patients to take the risk of these potential AEs seriously [
10] and make an effort to prevent symptoms by avoiding dehydration, transitioning slowly from standing and sitting, and monitoring weight and BP daily. To prevent hypotension and potential consequent hospitalizations in patients taking diuretics, clinicians may need to reduce the dose or be proactive by discontinuing the medication. Notably, treatment with sacubitril/valsartan may reduce the need for loop diuretic therapy. In PARADIGM-HF, sacubitril/valsartan was associated with fewer loop diuretic dose increases and more dose decreases versus enalapril at 6, 12, and 24 months (net increase in diuretic use for sacubitril/valsartan vs enalapril, respectively; at 6 months, 0.8% vs 2.5%,
P = 0.05; at 12 months, 1.0% vs 4.6%,
P < 0.001; at 24 months, 1.9% vs 6.9%,
P < 0.001) [
46]. Correspondingly, hypotension may be prevented by discontinuation or down-titration of other potentially contributory medications (e.g., calcium channel blockers), because they are associated with less evidence-based morbidity and mortality benefits [
45,
47]. Although discontinuations due to AEs were significantly lower with sacubitril/valsartan versus enalapril (10.7% vs 12.3%, respectively;
P = 0.03) [
8], taking these precautions will help prevent serious AEs and subsequent therapy discontinuation.
Table 2
Common patient questions and concerns regarding sacubitril/valsartan
Questions regarding the benefits of sacubitril/valsartan • I have been stable on my current medications. Why would I change? • How will this medication help my heart? What is the purpose of increasing the dose if I am feeling good on this dose and my blood pressure is good? • Why do I have to be on this medication if my blood pressure is not high? Is this medication for blood pressure? • How long will I live if I take all my medications and monitor what I eat and drink? • Will my heart function recover on medications? • Can I come off some medications if my heart function improves? Do I need to take these medications for the rest of my life? • I am trying to avoid an implantable cardioverter–defibrillator. Will this help? Will this medication improve my ejection fraction? Questions regarding possible negative effects of sacubitril/valsartan • I take so many medications. Will they interact with each other and cause harm? • What are the side effects of medications? • If I do not tolerate the medications, what options do I have? Questions regarding the cost of sacubitril/valsartan • Will my insurance pay for the new medications? • How much more does it cost? Other questions/concerns regarding sacubitril/valsartan • Why have my other doctors not mentioned it? • I am afraid to switch to a medication that is not commonly used. |
Laboratory testing should be performed periodically to monitor for significant clinical changes, including serum potassium and estimated glomerular filtration rate (eGFR) [
10]. Because the steady state of sacubitril/valsartan is reached 3 days after initiating therapy [
4,
10], we suggest performing laboratory tests then. Although sacubitril/valsartan is associated with electrolyte abnormalities, the incidence of hyperkalemia was lower with sacubitril/valsartan versus enalapril (11.6% vs 14.0%, respectively) during the DB treatment period in PARADIGM-HF [
8]. Correspondingly, higher rates of severe hyperkalemia were observed with enalapril versus sacubitril/valsartan among patients treated with mineralocorticoid receptor antagonist (MRA) therapy at baseline (3.1 vs 2.2 per 100 patient-years; HR 1.37; 95% CI 1.06–1.76;
P = 0.02) and those who were initiated on MRA therapy during the trial (3.3 vs 2.3 per 100 patient-years; HR 1.43; 95% CI 1.13–1.81;
P = 0.003) [
48]. These results suggest that sacubitril/valsartan may attenuate hyperkalemia risk associated with MRA [
48].
Occurrence of serious AEs, including angioedema or shock, should prompt permanent discontinuation of therapy. Overall, discontinuations due to AEs were significantly lower with sacubitril/valsartan versus enalapril (10.7% vs 12.3%, respectively;
P = 0.03), including discontinuations due to renal impairment (0.7% vs 1.4%, respectively;
P = 0.002) [
8]. Conversely, with less serious side effects, it is important to attempt to manage therapy before adjusting sacubitril/valsartan dose. In a subgroup analysis of PARADIGM-HF, dose reductions with sacubitril/valsartan and enalapril were associated with increased risk of cardiovascular death or hospitalizations for HF (HR 2.5; 95% CI 2.2–2.7) [
32]. Furthermore, in our clinical experience, patients often feel well despite hypotension identified on assessment of vital signs; therefore, in the setting of clinical improvement, dose adjustment of other therapies should be considered first. Hypotension may also be managed by counseling patients to take medications at bedtime or by staggering medications if they are taken twice daily. Generally, we found that side effects of sacubitril/valsartan usually resolve within 14 days; therefore, it is important to follow up with patients every 2 weeks during uptitration. It can also be useful to have patients keep a BP diary, checking their BP measurements at the same time each day and when experiencing symptoms consistent with hypotension, and to educate them to call if their systolic BP (SBP) drops to < 90 mmHg or if they are experiencing dizziness, lightheadedness, or syncope.
If side effects persist, dose reduction of sacubitril/valsartan should be considered. Dose reductions are preferable to discontinuation of sacubitril/valsartan, because patients treated with lower-dose sacubitril/valsartan experienced reduced risk of cardiovascular death or hospitalization compared with patients treated with lower-dose enalapril (HR 0.80; 95% CI 0.70–0.93) that was similar to those who did not receive dose reductions (HR 0.79, 95% CI 0.71–0.88;
P < 0.001) [
32]. Re-uptitration should be attempted 1–2 weeks following resolution of side effects. Many patients treated with sacubitril/valsartan in PARADIGM-HF were successfully re-uptitrated following dose reduction. Regarding hypotension, a significantly higher proportion of patients treated with sacubitril/valsartan were successfully re-uptitrated versus enalapril (36% vs 27%;
P = 0.026) [
32].
In May 2016, Novartis established the FortiHFy global clinical program, which includes more than 40 active and planned studies to collect additional data on symptom reduction, efficacy, safety, QOL, and real-world evidence with sacubitril/valsartan [
49]. Data collected from these studies may address some concerns associated with clinical use of sacubitril/valsartan.