Sacubitril/valsartan instead of renin‐angiotensin system inhibition alone: A step forward in resistant hypertension

LCZ696 (sacubitril/valsartan) is the first-in-class agent of dual angiotensin receptor neprilysin inhibitors for the management of heart failure (HF).1 Initially, it was hypothesized that neprilysin inhibition could lead to beneficial effects on HF, as this zinc-dependent metalloprotease degrades natriuretic peptides. However, the use of neprilysin inhibitors failed to consistently improve HF-related hard end points in clinical studies, probably because of the loss of neprilysin-induced degradation of angiotensin II (as well as endothelin, vasopressin, and bradykinin). Further scientific efforts focused on the dual inhibition of neprilysin and angiotensin-converting enzyme, but they were prematurely interrupted because of the increased risk of life-threatening angioedema. Finally, in the PARADIGM-HF (Determine Impact on Global Mortality and Morbidity in Heart Failure) trial,2 it was found that the use of an angiotensin receptor neprilysin inhibitor led to a statistically significant reduction in cardiovascular death or hospitalization for HF (relative risk, 0.80) and all-cause mortality (relative risk, 0.84) among participants with HF with reduced ejection fraction, compared with enalapril. Currently, LCZ696 is recommended in the treatment of HF with reduced ejection fraction in combination with other pharmacological agents and devices.3, 4 The neurohumoral therapeutic approach of HF that LCZ696 offers may be a beneficial option for the management of arterial hypertension.5, 6 Thus, the antihypertensive effects of LCZ696 were evaluated and confirmed in several clinical trials of this agent. Accumulating data suggest that LCZ696 administration effectively reduces blood pressure (BP) levels in patients with mild, moderate, and severe hypertension.7-9 Ruilope and colleagues conducted the first randomized, controlled, clinical trial that primarily evaluated the effects of LCZ696 on BP levels.10 In 1215 participants with mild to moderate hypertension, LCZ696 resulted in a greater mean reduction in sitting diastolic BP by –2.17 mm Hg compared with valsartan (95% confidence interval, −3.28 to −1.06 mm Hg. Moreover, LCZ696 200 and 400 mg were associated with a greater decrease in mean sitting systolic BP (SBP) by –2.97 (P = .0023) and −2.7 mm Hg (P = .0055) compared with valsartan 160 and 320 mg, respectively. Several clinical trials confirmed that LCZ696 is associated with a more pronounced reduction in office (or sitting) BP and ambulatory BP monitoring (ABPM) vs angiotensin receptor blockers per se.10-13 Since the publication of the first scientific statement by the American Heart Association a decade ago, resistant hypertension has emerged at the epicenter of scientific interest.14 Currently, it is well established that patients with resistant hypertension (defined as the presence of uncontrolled hypertension despite the use of three different classes of antihypertensive drugs including a diuretic, in the maximum tolerable dosages) have a greater risk of cardiovascular morbidity and all-cause mortality, as well as extended target organ damage compared with individuals with hypertension with more easily controlled BP.14, 15 Resistant hypertension becomes more prevalent in the settings of nondipping status and obstructive sleep apnea syndrome, chronic kidney disease, diabetes mellitus, and obesity, and all are associated with a greater cardiovascular and target organ damage.16 Currently, two novel interventional strategies (renal nerve denervation and baroreflex activation therapy) were introduced for the treatment of resistant hypertension, aiming to reduce sympathetic nervous tone (an effect that is observed with LCZ696 administration), but long-term, clinically meaningful benefits have not been consistently proved.14, 17-20 Nondipping status and increased nighttime BP are commonly found in patients with resistant hypertension and are associated with increased risk of cardiorenal disease and extended target organ damage.16, 21 Of note, nighttime BP levels have a greater prognostic value than daytime BP values.22 Even after the exclusion of secondary causes of hypertension, such as obstructive sleep apnea and primary aldosteronism, control rates of nocturnal hypertension remain restricted.23 Data from controlled, randomized, clinical trials that evaluated the antihypertensive effects of LCZ696 via 24-hour ABPM revealed interesting findings related to the nighttime BP effect of this agent (Table). Kario and colleagues11 conducted a randomized, double-blind, placebo-controlled trial to evaluate the effect of LCZ696 on 24-hour ABPM.11 Study participants were randomized to receive LCZ696 100, 200, or 400 mg or placebo for 8 weeks. At the end of the study, a significant least square mean reduction in nighttime BP by −12.27/−7.96, −16.14/−10.36, and −14.65/−9.47 mm Hg was observed in the LCZ696 100-, 200-, and 400-mg groups, respectively, compared with the insignificant mild increase in the placebo group (0.61/0.97 mm Hg). In another multicenter, double-blind, clinical study, 266 Asian individuals with systolic hypertension (uncontrolled with amlodipine) were randomized to receive LCZ696 200 mg plus amlodipine 5 mg or amlodipine 5 mg for 8 weeks.24 At the end of follow-up, the LCZ696 plus amlodipine group showed a significantly greater decrease in nighttime ambulatory BP vs amlodipine monotherapy, featuring a least square mean between-treatment difference of approximately −14.5/−8.9 mm Hg (P < .001). The most significant data for the nighttime BP effect of LCZ696 are derived from the PARAMETER study.25 This trial was designed to assess the impact of LCZ696 on central hemodynamics and 24-hour ABPM vs olmesartan among elderly patients with isolated systolic hypertension and arterial stiffness. In total, 454 participants were randomly assigned to LCZ696 200 mg (n = 229) or olmesartan 20 mg (n = 225) (with doubling initial doses after 4 weeks) for 12 weeks. Then, a double-blind period of 40 weeks followed, during which add-on therapy with a calcium channel blocker and hydrochlorothiazide was permitted in participants of both groups with BP levels >140/90 mm Hg. At the 12th week of the study, it was noted that between-group differences in mean 24-hour SBP was predominantly attributed to more pronounced reduction in nocturnal SBP. In brief, from 10 pm to 6 am, LCZ696 was associated with a greater reduction in SBP by −5.9 mm Hg vs olmesartan (P < .001), and the difference reached maximum values (−6.9 mm Hg) at early morning (2 am–6 am). Of note, olmesartan is an angiotensin receptor blocker with 24-hour antihypertensive action. Furthermore, LCZ696 seems to ameliorate a wide cluster of pathogenetic deteriorations and comorbidities that are associated with difficult to treat and resistant hypertension, such as chronic kidney disease, salt sensitivity, aldosterone excess, endothelial dysfunction, arterial stiffness, fibrosis, and structural alternations in the vasculature and myocardium.1, 5, 14, 16, 26, 27 In a small, multicenter, open-label study with a placebo run-in period of 2 to 5 weeks, LCZ696 100 mg (with a possible titration to 200 and 400 mg) was administered in 32 Asians with arterial hypertension (mean baseline BP: 151.6/81.9 mm Hg) and chronic kidney disease stage 3 or 4 for 8 weeks.28 LCZ696 treatment was associated with a mean decrease in BP by −20.5/−8.3 mm Hg from baseline, featuring well-controlled BP levels at week 8 (mean BP: 131.1/73.6 mm Hg). Another small clinical trial suggests that LCZ696 could substantially reduce BP in salt-sensitive patients with hypertension. In this crossover, double-blind clinical study, the BP-lowering effect of LCZ696 (400 mg) was evaluated among 72 Asian individuals with salt-sensitive hypertension compared with valsartan (320 mg). Participants were previously identified to have salt-sensitive hypertension if an increase in the mean arterial pressure of ≥10% occurred when switching from a 1-week, low- to high-sodium diet.29 LCZ696 resulted in a greater reduction in office BP compared with valsartan (−13.3/−6.2 mm Hg vs −5.8/−4.2 mm Hg, respectively), with a statistically significant mean between-treatment difference in office SBP of −7.6 mm Hg (P = .002). Similar benefits of LCZ696 over valsartan were observed in 24-hour ABPM. Of interest, the largest adjusted between-treatment difference for ABPM was noted in nighttime BP (−4.7/−2.6 mm Hg, P = .008), confirming the above-mentioned potent antihypertensive effect of LCZ696 on nocturnal BP. Together, the aforementioned trials raise expectations about the use of LCZ696 in difficult to treat and resistance hypertension. It seems rational to assume that the replacement of a renin angiotensin system blocker with an angiotensin receptor neprilysin inhibitor in the triple-drug algorithm of resistant hypertension could provide significant benefits in the management of these patients with high cardiovascular risk. The impact of LCZ696 on resistant hypertension and other nondipping comorbidities and on uncontrolled hypertension with three drugs vs mineralocorticoid antagonists and renal nerve denervation are emerging as significant aspects that need to be addressed. The design and conduction of relevant randomized controlled studies is needed to evaluate this hypothesis, which, if confirmed, will offer a useful therapeutic option in the management of patients with resistant hypertension and comorbidities. Whether the antihypertensive properties of LCZ696 will be mentioned in the upcoming guidelines for the management of arterial hypertension by the American Heart Association and the American Cardiology College and later in the European Society of Cardiology and European Society of Hypertension guidelines will be interesting. The authors report no specific funding in relation to this research and no conflicts of interest to disclose.