Abstract
Background: Lower systolic blood pressure (SBP) is known to be associated with poor prognosis in heart failure (HF). We evaluated the efficacy and safety of sacubitril/valsartan according to baseline SBP tertiles in Japanese patients from the PARALLEL-HF study.
Methods and Results: In all, 223 patients were stratified into tertiles according to baseline SBP (≤114 mmHg: n=75; >114 and ≤130 mmHg: n=76; and >130 mmHg: n=72). Patients with lower SBP (≤114 mmHg) had the highest median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations at baseline (P=0.0184). No significant difference was observed between sacubitril/valsartan and enalapril for the composite outcome of cardiovascular death and HF hospitalization across SBP tertiles (P-interaction=0.2682). Although the P-interaction value was not significant (0.2106), a greater reduction in NT-proBNP with sacubitril/valsartan compared with enalapril was observed in patients with SBP >130 mmHg (P=0.0076). The incidence of hypotension-related events and reduction or discontinuation of treatment due to hypotension-related events was higher in the lower SBP subgroup, and these events were more frequent in the sacubitril/valsartan than enalapril group.
Conclusions: The efficacy of sacubitril/valsartan compared with enalapril was consistent across baseline SBP tertiles in Japanese patients from the PARALLEL-HF study. Hypotension-related events were more common in patients treated with sacubitril/valsartan with lower SBP.
Low systolic blood pressure (SBP) is common among patients with heart failure (HF) and those with HF with reduced ejection fraction (HFrEF), especially in those with advanced HF.1,2 Almost all treatment drugs for HF reduce blood pressure (BP). Although there is limited evidence regarding the possible relationship between hypotension and uptitration of drugs for HF treatment, studies have shown that patients with low SBP often receive suboptimal doses of guideline-recommended drugs for HF treatment.1,3,4
Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI) that simultaneously blocks the renin-angiotensin-aldosterone system and inhibits neprilysin, thus reducing BP considerably compared with an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB).5,6 The results from the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated the superiority of sacubitril/valsartan over enalapril in reducing the risk of cardiovascular (CV) death and HF hospitalizations in patients with HFrEF.6
A secondary analysis from the PARADIGM-HF trial that explored the impact of baseline SBP on the efficacy and safety of sacubitril/valsartan compared with enalapril showed that the benefits of sacubitril/valsartan were consistent and independent of SBP levels at baseline.7 However, patients with a low SBP (<110 mmHg) at baseline were at a higher risk of death and HF hospitalization. The occurrence of symptomatic hypotension and dose reduction or discontinuation of treatment was nominally higher in patients with a low SBP at baseline.7
The US and European Union (EU) guidelines for the pharmacological treatment of HF recommend replacing ACEi/ARB with sacubitril/valsartan for the treatment of chronic HFrEF to reduce morbidity and mortality.8,9 The 2021 Japanese HF treatment guideline also recommends switching from ACEi/ARB to ARNI in patients who remain symptomatic despite treatment with ACEi/ARB, β-blockers, and mineralocorticoid antagonists (MRA).10 However, the guidelines also highlight the increased risk of hypotension with sacubitril/valsartan in patients with HFrEF.8,9 Based on the existing evidence, treatment with sacubitril/valsartan is overall well tolerated; however, careful titration or dose adjustment of other vasoactive drugs, such as diuretics and nitrates, may be needed in patients experiencing hypotension.8,9
Results from a study conducted in Japanese patients indicated that a lower SBP in patients hospitalized for acute HF was associated with higher rates of all-cause mortality with increasing age.11 Hence, the baseline SBP in Japanese patients with HFrEF may affect the use of sacubitril/valsartan as a treatment.
The present subgroup analysis from the PARALLEL-HF (Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) trial evaluated the efficacy and safety of sacubitril/valsartan compared with enalapril according to baseline SBP tertiles (≤114, >114 to ≤130, and >130 mmHg) in Japanese patients with HFrEF and assessed whether baseline SBP affects the efficacy and safety of sacubitril/valsartan in these patients.
Methods
Objectives
The objectives of this subgroup analysis were to: (1) analyze the potential risk factors associated with low SBP at baseline; (2) evaluate the efficacy of sacubitril/valsartan compared with enalapril in delaying the time to first occurrence of the composite endpoint (defined as CV death or HF hospitalization) in patients with HFrEF according to baseline SBP tertiles (≤114, >114 to ≤130, and >130 mmHg); and (3) assess whether baseline SBP could affect the efficacy of sacubitril/valsartan in delaying the time to first occurrence of the composite endpoint, as well as the safety and tolerability of sacubitril/valsartan compared with enalapril.
Study Design
PARALLEL-HF was a multicenter randomized double-blind study conducted across 53 sites in Japan that assessed the efficacy and safety of sacubitril/valsartan 200 mg, twice daily (b.i.d.), vs. enalapril 10 mg, b.i.d., in patients with HFrEF.
Briefly, patients with symptomatic chronic HFrEF (New York Heart Association [NYHA] Class II–IV; left ventricular ejection fraction [LVEF] ≤35%) and elevated N-terminal pro B-type natriuretic peptide (NT-proBNP; i.e., ≥600 pg/mL; or ≥400 pg/mL for those who had been hospitalized for HF within the past 12 months) were enrolled in the present study. Patients who met the eligibility criteria at screening entered a 2-week, single-blind, run-in period to receive sacubitril/valsartan 50 mg, b.i.d. If tolerated, patients entered the double-blind treatment period and were randomized (1 : 1) to receive sacubitril/valsartan 100 mg, b.i.d., or enalapril 5 mg, b.i.d., for 4 weeks. Patients who tolerated treatment during the double-blind period were then uptitrated to respective target doses of sacubitril/valsartan 200 mg, b.i.d., or enalapril 10 mg, b.i.d. In the event of hypotension, dose adjustments were made during the double-blind period. The detailed study design, rationale, and eligibility criteria for PARALLEL-HF have been published previously.10,12
Ethics Approval
PARALLEL-HF was conducted in accordance with the International Council for Harmonisation Good Clinical Practice regulations/guidelines (https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf [accessed November 7, 2023]) and the ethical principles set forth in the Declaration of Helsinki. The protocol was approved by an independent ethics committee or institutional review board at each participating center (for details, see the Supplementary Appendix). All patients provided written informed consent prior to participation. The executive committee designed and oversaw the conduct of the trial. The study was monitored by an independent data safety monitoring committee. The Consolidated Standards of Reporting Trials guidelines were followed.
Study Assessments
SBP was measured using an automated validated device or a standard sphygmomanometer with an appropriately sized cuff on the non-dominant arm at the run-in baseline and all subsequent visits. All BP measurements were performed in the sitting position after 5 min rest. In the event of symptomatic hypotension, investigators treated any treatable cause (e.g., hypovolemia). If hypotension persisted, any antihypertensive drug and any non-disease-modifying drugs, such as nitrates, calcium channel blockers, α-blockers, and diuretics, were downtitrated before downtitration or temporary withdrawal of the study drug was considered. In such cases, the study drug was reintroduced as soon as medically justified by the investigator. If tolerated, the dose was uptitrated to the target dose of the study drug every 1–4 weeks at the investigator’s discretion.
The efficacy assessments performed at each study visit have been published previously.12,13 Events of CV death and HF hospitalization were adjudicated by the Endpoint Adjudication Committee for classifying fatal events, CV and non-CV death. Plasma NT-proBNP concentrations were measured using kits from Roche Diagnostics before patients took their morning study drug dose. Safety and tolerability assessments included hypotension-related adverse events (AEs) and laboratory or vital sign abnormalities. Hypotension-related AEs were defined as investigator-reported AE terms potentially related to hypotension, including symptoms such as dizziness and change in BP such as “blood pressure decreased”, and were summarized based on Standardized MedDRA Queries, which are predetermined and grouped medical terms in the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary (Supplementary Table 1).
Statistical Analysis
Unless indicated otherwise, data are presented as percentages or as the median with interquartile range (IQR). Baseline characteristics were compared between baseline SBP tertile groups. Changes in SBP according to run-in baseline tertile were analyzed using the boxplot technique. The efficacy of sacubitril/valsartan relative to enalapril for the composite outcome (CV death or HF hospitalization) by SBP tertile was estimated using Cox regression models, with treatment and stratification of screening NT-proBNP as fixed factors.
Results
The PARALLEL-HF study screened 307 patients, of whom 225 were randomized to receive sacubitril/valsartan (n=112) or enalapril (n=113) during the double-blind treatment period of the core study. Detailed patient disposition and primary results have been published elsewhere.12 The present analysis included 223 patients (sacubitril/valsartan, n=111; enalapril, n=112) grouped into tertiles according to baseline SBP (≤114 mmHg: n=75, >114 to ≤130 mmHg: n=76, and >130 mmHg: n=72).
The baseline characteristics of patients according to SBP tertile are presented in Table 1. The mean SBP for tertiles ≤114, >114 to ≤130, and >130 mmHg was 110.7, 120.2, and 136.9 mmHg, respectively (P<0.0001). In patients with SBP ≤114 mmHg compared to patients with SBP >114 to ≤130 or >130 mmHg, LVEF tended to be lower (27.4% vs. 28.3% and 28.9%, respectively; P=0.2162) and median NT-proBNP concentrations at randomization were higher (880 [IQR 563–1,697] vs. 835 [IQR 534–1,602] and 770 [IQR 369–1,264] pg/mL, respectively; P=0.0184). In all SBP tertiles, >90% of patients belonged to NYHA Class II (Table 1).
Table 1.
Baseline Characteristics According to Baseline SBP Tertiles
| Characteristics |
SBP (mmHg) |
P valueA |
| ≤114 (n=75) |
>114 to ≤130 (n=76) |
>130 (n=72) |
| SBP (mmHg) |
110.7±9.6 |
120.2±11.3 |
136.9±15.2 |
<0.0001 |
| DBP (mmHg) |
67.0±10.0 |
72.0±10.8 |
79.7±13.6 |
<0.0001 |
| Age (years) |
67.6±10.8 |
68.0±11.0 |
68.0±9.4 |
0.9629 |
| Male sex |
63 (84.0) |
64 (84.2) |
65 (90.3) |
0.4600 |
| BMI (kg/m2) |
23.8±4.2 |
24.3±3.9 |
25.3±4.3 |
0.0876 |
| LVEF (%) |
27.4±5.2 |
28.3±5.2 |
28.9±5.4 |
0.2162 |
| Heart rate (beats/min) |
71.6±12.2 |
73.9±13.0 |
73.8±13.8 |
0.4620 |
| eGFR (mL/min/1.73 m2) |
56.7±16.8 |
58.6±16.3 |
58.7±15.6 |
0.6914 |
| NT-proBNP at randomization (pg/mL) |
880.0
[563.0–1,697.0] |
835.0
[534.0–1,602.0] |
770.5
[369.5–1,264.0] |
0.0184 |
| NT-proBNP ≥1,600 pg/mL at randomization |
23 (30.7) |
19 (25.0) |
10 (13.9) |
– |
| NYHA class at randomization |
|
|
|
0.3737 |
| I |
1 (1.3) |
2 (2.6) |
5 (6.9) |
|
| II |
70 (93.3) |
70 (92.1) |
65 (90.3) |
|
| III |
4 (5.3) |
4 (5.3) |
2 (2.8) |
|
| IV |
0 (0.0) |
0 (0.0) |
0 (0.0) |
|
| Medical history |
| Prior HF hospitalization |
55 (73.3) |
53 (69.7) |
54 (75.0) |
0.7625 |
| Hypertension |
39 (52.0) |
53 (69.7) |
61 (84.7) |
0.0004 |
| Diabetes |
30 (40.0) |
37 (48.7) |
37 (51.4) |
0.3484 |
| Prior angina pectoris |
13 (17.3) |
16 (21.0) |
28 (38.9) |
0.0061 |
| Prior MI |
35 (46.7) |
32 (42.1) |
30 (41.7) |
0.7927 |
| Prior stroke |
4 (5.3) |
10 (13.2) |
7 (9.7) |
0.2565 |
| Atrial fibrillation |
28 (37.3) |
23 (30.3) |
25 (34.7) |
0.6507 |
| Primary HF etiology |
|
|
|
0.3808 |
| Ischemic |
34 (45.3) |
33 (43.4) |
39 (54.2) |
|
| Non-ischemic |
41 (54.7) |
43 (56.6) |
33 (45.8) |
|
| Medications |
| ACEi |
55 (73.3) |
52 (68.4) |
33 (45.8) |
0.0012 |
| ARB |
20 (26.7) |
24 (31.6) |
39 (54.2) |
0.0012 |
| MRA |
58 (77.3) |
37 (48.7) |
38 (52.8) |
0.0006 |
| Diuretics |
68 (90.7) |
63 (82.9) |
55 (76.4) |
0.0661 |
| β-blockers |
74 (98.7) |
75 (98.7) |
64 (88.9) |
0.0043 |
| CRT/ICD |
16 (21.3) |
14 (18.4) |
12 (16.7) |
0.7648 |
| ACEi/ARB dose at screening (enalapril 10 mg/day) |
|
|
|
0.0861 |
| Low |
54 (72.0) |
43 (56.6) |
41 (56.9) |
|
| High |
21 (28.0) |
33 (43.4) |
31 (43.1) |
|
| ACEi/ARB dose at screening (highest dosage/day) |
|
|
|
0.8155 |
| Low |
67 (89.3) |
70 (92.1) |
66 (91.7) |
|
| High |
8 (10.7) |
6 (7.9) |
6 (8.3) |
|
Safety set. Unless indicated otherwise, data are given as the mean±SD, median [interquartile range], or n (%). AP values compare differences among SBP categories and were obtained from Chi-squared tests for categorical variables or analysis of variance (ANOVA) for continuous variables. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CRT/ICD, cardiac resynchronization therapy/implantable cardioverter-defibrillator; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure.
A medical history of HF hospitalization was also similar across SBP tertiles (73.3% vs. 69.7% vs. 75.0%; P=0.7625). Patients with higher baseline SBP were more likely to have a history of hypertension (52.0% vs. 69.7% vs. 84.7%; P=0.0004), angina pectoris (17.3 vs. 21.1% vs. 38.9%; P=0.0061), and diabetes (40.0% vs. 48.7% vs. 51.4%; P=0.3484). No significant differences among SBP tertiles were observed for other parameters (Table 1).
More patients in the lowest SBP tertiles were receiving an ACEi (P=0.0012), MRA (P=0.0006), β-blocker (P=0.0043), or diuretics (P=0.0661), and fewer were receiving an ARB (P=0.0012; Table 1). A similar trend was observed among patients in the lowest SBP tertiles in both treatment arms (Supplementary Table 2). Patients in the highest SBP tertile tended to have numerically higher mean daily doses of sacubitril/valsartan and enalapril than those in the lower SBP tertiles (≤114 mmHg: 319.6 and 16.5 mg/day, >114 to ≤130 mmHg: 322.0 and 17.4 mg/day, and >130 mmHg: 343.0 and 17.6 mg/day). However, the mean daily dose of sacubitril/valsartan and enalapril achieved during the double-blind treatment period was comparable across SBP tertiles.
Figure 1 summarizes changes in SBP from baseline to 6 months in each treatment group according to SBP tertile. In both the sacubitril/valsartan and enalapril groups, a decrease in SBP was observed in baseline SBP tertiles 114 to ≤130 and >130 mmHg. Overall, the change in SBP over time during the study was similar between the sacubitril/valsartan and enalapril groups for each SBP tertile (Supplementary Figure).
Consistent with the overall study population, there was no significant difference in the composite outcome of CV death and HF hospitalization between the sacubitril/valsartan-treated group stratified by baseline SBP tertile compared with the enalapril group (P-interaction=0.2682). The beneficial effect of sacubitril/valsartan on CV death or HF hospitalization compared with enalapril was numerically higher in SBP ≤114 mmHg tertile (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.3–1.7), whereas the effects of sacubitril/valsartan and enalapril were similar in SBP tertile >114 to ≤130 mmHg (HR 1.0; 95% CI 0.4–2.5). Patients in SBP tertile >130 mmHg had lesser benefit with sacubitril/valsartan than enalapril (HR 2.0; 95% CI 0.8–5.5; Figure 2).
Compared with enalapril, treatment with sacubitril/valsartan led to a numerically greater reduction in NT-proBNP concentrations in patients across all SBP tertiles (Figure 3). Although the P-interaction value was not significant (0.2106), the magnitude of the reduction in NT-proBNP concentrations tended to be greater in patients with the highest baseline SBP (>130 mmHg) than in patients in SBP tertile ≤114 mmHg or SBP >114 to ≤130 mmHg following treatment with sacubitril/valsartan compared with enalapril (least square mean ratio of change from baseline sacubitril/valsartan vs. enalapril in SBP tertile ≤114 mmHg: 0.8; 95% CI 0.6–1.1, P=0.1449; >114 to ≤130 mmHg: 1.0; 95% CI 0.7–1.2, P=0.7296; >130 mmHg: 0.7; 95% CI 0.5–0.9, P=0.0076; P-interaction=0.2106, respectively). The trend in the reduction in NT-proBNP concentrations among patients across all SBP tertiles was similar to that in the overall study population (Figure 3).
Hypotension (as per the investigators’ discretion) with SBP <90 mmHg, was experienced by a significantly higher proportion of patients treated with sacubitril/valsartan than enalapril in SBP tertile ≤114 mmHg (27.8% vs. 7.7%; P=0.0318), but not in >130 mmHg (5.3% vs. 0.0%; P=0.4945) or >114 to ≤130 mmHg (2.7% vs. 5.1%; P=1.0); however the difference between the 2 treatments was not statistically significant (P-interaction=0.7727; Table 2). A similar trend was also observed for SBP <90 mmHg (P-interaction=0.4572; Table 2).
Table 2.
Differences in Adverse Events of Interest Between Treatment Groups According to SBP Tertile
| Adverse event |
SBP ≤114 mmHg |
SBP >114 to ≤130 mmHg |
SBP >130 mmHg |
P-interactionA |
Sacubitril/valsartan
(n=36) |
Enalapril
(n=39) |
P value |
Sacubitril/valsartan
(n=37) |
Enalapril
(n=39) |
P value |
Sacubitril/valsartan
(n=38) |
Enalapril
(n=34) |
P value |
| HypotensionB |
| SBP <90 mmHg |
17 (47.2) |
17 (43.6) |
0.8186 |
4 (10.8) |
6 (15.4) |
0.7371 |
4 (10.5) |
1 (2.9) |
0.3611 |
0.4572 |
| Hypotension with SBP <90 mmHg |
10 (27.8) |
3 (7.7) |
0.0318 |
1 (2.7) |
2 (5.1) |
1.000 |
2 (5.3) |
0 (0.0) |
0.4945 |
0.7727 |
| Elevated serum creatinine |
| ≥2.0 mg/dL |
2 (5.6) |
2 (5.1) |
1.000 |
4 (10.8) |
3 (7.7) |
0.7077 |
1 (2.6) |
6 (17.6) |
0.0469 |
0.1317 |
| ≥2.5 mg/dL |
1 (2.8) |
1 (2.6) |
1.000 |
0 (0.0) |
1 (2.6) |
1.000 |
1 (2.6) |
2 (5.9) |
0.5992 |
0.5544 |
| ≥3.0 mg/dL |
0 (0.0) |
0 (0.0) |
– |
0 (0.0) |
0 (0.0) |
– |
0 (0.0) |
1 (2.9) |
0.4722 |
0.9926 |
| Elevated serum potassium |
| ≥5.5 mmol/L |
3 (8.3) |
1 (2.6) |
0.3452 |
3 (8.1) |
3 (7.7) |
1.000 |
2 (5.3) |
2 (5.9) |
1.000 |
0.8157 |
| ≥6.0 mmol/L |
0 (0.0) |
0 (0.0) |
– |
0 (0.0) |
0 (0.0) |
– |
0 (0.0) |
1 (2.9) |
0.4722 |
0.9867 |
Safety set. Unless indicated otherwise, data are given as n (%). AP-interaction values were calculated using a logistic regression model with treatment, systolic blood pressure (SBP) at run-in baseline and treatment-by-SBP at run-in baseline. BReported term as per investigators’ decision.
The proportion of patients with elevated serum creatinine concentrations was comparable between the sacubitril/valsartan- and enalapril-treated groups in all SBP tertiles (Table 2). Overall, the incidence of hypotension-related events and the reduction or discontinuation of treatment dose due to hypotension-related events were lower in patients with the highest baseline SBP tertile. In the lowest SBP tertile, patients treated with sacubitril/valsartan were more likely to experience hypotension-related events than those treated with enalapril (47.2% vs. 18.0%; P=0.0124), as well as reductions in treatment dose due to hypotension-related events (22.2% vs. 2.6%; P=0.0118) and reduction/discontinuation of treatment dose due to hypotension-related events (22.2% vs. 7.7%; P=0.1051). A similar trend was observed among patients in SBP tertile >114 to ≤130 mmHg, with a numerically higher proportion of patients in the sacubitril/valsartan vs. enalapril group experiencing hypotension-related events (35.1% vs. 15.4%; P=0.0643), reductions in treatment dose due to hypotension-related events (10.8% vs. 5.1%; P=0.4246), and reduction/discontinuation of treatment dose due to hypotension-related events (13.5% vs. 5.1%; P=0.2562), although the difference did not reach statistical significance. In the highest SBP tertile, a numerically higher proportion of patients treated with sacubitril/valsartan compared with enalapril experienced hypotension-related events (31.6% vs. 23.5%; P=0.5991); however, comparable proportion of patients in the 2 treatment arms required reductions in treatment dose due to hypotension-related events (5.3% vs. 5.9%; P=1.0) and reduction/discontinuation in treatment dose due to hypotension-related events (5.3% vs. 5.9%; P=1.0; Figure 4).
Discussion
The present subanalysis of the PARALLEL-HF trial explored the efficacy and safety of sacubitril/valsartan across SBP tertiles. The PARADIGM-HF trial demonstrated that patients in the group with lower (<110 mmHg) SBP were more likely to experience all-cause and CV death than those with higher (≥140 mmHg) SBP; however, a U-shaped association between SBP and the HF hospitalization rate was observed.7 A similar trend has been observed in several real-world studies with a J-shaped association between SBP and HF outcomes.14–16 In PARADIGM-HF, the benefits of sacubitril/valsartan over enalapril on the composite endpoint of CV death and HF hospitalization, individual events of CV death, HF hospitalization, and all-cause death were consistent across all baseline SBP categories.7 The association between the treatment effect of sacubitril/valsartan compared with enalapril on the composite outcome of CV death and HF hospitalization by baseline SBP tertile was not significant (P-interaction=0.2682), and it was thus inferred that the treatment effect of sacubitril/valsartan over enalapril was not modified by baseline SBP (Figure 2). Interestingly, in the present study, the risk of CV death and HF hospitalization associated with treatment with sacubitril/valsartan was numerically lowest in the lowest SBP tertile (HR 0.7; 95% CI 0.3–1.7; Figure 2). However, most of the patients in this SBP tertile, compared with patients in the other SBP tertiles, were receiving MRA and diuretics, which may have contributed to their overall better clinical outcomes (Supplementary Table 2).
The treatment benefits with sacubitril/valsartan vs. enalapril were indicated by the reduction in NT-proBNP concentrations in patients across all SBP tertiles, with greater reductions observed in patients with the highest baseline SBP, although P-interaction was not significant (0.2106; Figure 3). The trend in the reduction in NT-proBNP concentrations in the SBP tertiles was similar to that in the overall study population. These findings are in accordance with the analysis from PARADIGM-HF, which indicated better responsiveness to treatment with sacubitril/valsartan over enalapril among patients with higher SBP.7 Although a numerically greater reduction in concentrations of NT-proBNP, a prognostic cardiac wall stress biomarker for HF, was observed among patients with highest SBP tertile, it did not result in a difference in the reduction in the risk of CV death or HF hospitalization. The reduction in NT-proBNP concentrations with sacubitril/valsartan compared with enalapril was not modified by SBP tertile (P-interaction=0.2106), which indicates the consistent treatment benefits of sacubitril/valsartan among patients across SBP ranging from ≤114 to >130 mmHg. Moreover, it was observed that patients with lower SBP were more likely to have higher baseline NT-proBNP concentrations (880.0 vs. 835.0 vs. 770.5 pg/mL; Table 1). Therefore, the lowering effect of sacubitril/valsartan on NT-proBNP was considered to be consistent regardless of baseline NT-proBNP concentration before the initiation of treatment.
Overall, HF patients with low SBP have a worse prognosis than those with higher SBP.7 Furthermore, low SBP among HF patients limits uptitration of HF therapy, which is why these patients are usually treated with suboptimal doses of guideline-recommended HF treatment drugs.1,4,17 In the present study, a higher proportion of patients in the lower SBP tertiles reduced or discontinued study drug (Figure 4). The proportion of patients experiencing hypotension with SBP <90 mmHg was higher among patients treated with sacubitril/valsartan than enalapril in the lowest SBP and the highest SBP tertiles, similar to the trend observed in the PARADIGM-HF trial.7 Physicians must monitor for hypotension when treating HF patients with low SBP with sacubitril/valsartan; however, these hypotensive events can often be managed with adjustment of non-life-saving medications (e.g., diuretics) and a gradual uptitration approach.18 There was no significant difference across baseline SBP tertiles in the proportion of patients with elevated serum creatinine or serum potassium between treatment arms (Table 2). These results are similar to those observed in PARADIGM-HF.7 Considering the benefits of sacubitril/valsartan on CV mortality and HF hospitalizations even in patients with low SBP in PARADIGM-HF, physicians should not be discouraged to initiate sacubitril/valsartan in HF patients with low SBP.
This study has several potential limitations that should be acknowledged. First, this is a post hoc analysis of the PARALLEL-HF study, and the small sample size of baseline SBP tertiles may be a limiting factor for statistical comparisons. Second, patients with SBP <100 mmHg at the screening visit or <95 mmHg at the end of the run-in period were not included in the study. Third, hypotension-related events were investigator reported and were not adjudicated.
Conclusions
In PARALLEL-HF, treatment effects of sacubitril/valsartan compared with enalapril on the risk of CV death and HF hospitalization were consistent across SBP tertiles. Similarly, consistent reductions in NT-proBNP concentrations were associated with sacubitril/valsartan among patients in all SBP tertiles. The incidence of hypotension-related events and reduction/discontinuation of treatment dose due to hypotension-related events was higher in patients with the lowest baseline SBP tertile ≤114 mmHg, which is consistent with the trend observed in PARADIGM-HF. The results indicate that patients in lowest SBP tertile benefit from sacubitril/valsartan as much as patients in the highest SBP tertile.
Acknowledgments
The authors thank all the patients, investigators, and staff who participated in this study. The authors also thank Tripti Sahu (Novartis Healthcare Pvt. Ltd., Hyderabad, India) for providing medical writing assistance and editorial support.
Sources of Funding
This study was funded by Novartis Pharmaceuticals Corporation.
Disclosures
H.T. was an Executive Committee Chair of PARALLEL-HF and has received consultation fees from Novartis Pharma K.K., Nippon Boehringer Ingelheim, Bayer Yakuhin, Ono Pharmaceutical; remuneration from MSD, Astellas Pharma, Pfizer, Bristol-Myers Squibb, Otsuka Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Bayer Yakuhin, Novartis Pharma K.K., Kowa Pharmaceutical, and Teijin Pharma; research funding from Actelion Pharmaceuticals, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Daiichi Sankyo, IQVIA Services, and Omron Healthcare; and scholarship funds from Astellas Pharma, Novartis Pharma K.K., Daiichi Sankyo, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, and MSD. H.T. is an Associate Editor of Circulation Journal, an official open-access scientific journal of the Japanese Circulation Society.
S.M. was an Executive Committee member of PARALLEL-HF and has received speakers’ bureau fees/honoraria from Mitsubishi Tanabe Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Pfizer, Bayer Yakuhin, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Toa Eiyo, Actelion Pharmaceuticals Japan, Philips Respironics GK, Teijin Pharma, Medtronic Japan, St. Jude Medical, Boston Scientific Japan, and Torii Pharmaceutical; honoraria for writing promotional material for Medtronic Japan, Teijin Pharma, Kyowa Hakko Kirin; research funds from Mitsubishi Tanabe Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Toa Eiyo, Actelion Pharmaceuticals, Teijin Pharma, Medtronic, St. Jude Medical, Abbott, Nippon Boehringer Ingelheim, and Bayer Yakuhin; and consultation fees from Novartis Pharma K.K.
Y. Saito was an Executive Committee member of PARALLEL-HF and has received research funds from Otsuka Pharmaceutical, Ono Pharmaceutical, Takeda Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Actelion Pharmaceuticals, Kyowa Kirin, Kowa Pharmaceutical, Shionogi & Co., Dainippon Sumitomo Pharma, Teijin Pharma, Chugai Pharmaceutical, Eli Lilly, Nihon Medi-Physics, Novartis Pharma K.K., Pfizer, and Fuji Yakuhin; research expenses from Novartis Pharma K.K., Roche Diagnostics, Amgen, Bayer Yakuhin, Astellas Pharma, and Actelion Pharmaceuticals; speakers’ bureau fees/honoraria from Alnylam, AstraZeneca, Otsuka Pharmaceutical, Kowa Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Tsumura & Co., Teijin Pharma, Toa Eiyo, Nippon Shinyaku, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Bayer Yakuhin, Pfizer Japan, Bristol-Myers Squibb, and Mochida Pharmaceutical; and consultation fees from Ono Pharmaceutical and Novartis Pharma K.K.
H.I. was an Executive Committee member of PARALLEL-HF and has received speakers’ bureau fees/honoraria from Takeda Pharmaceutical, Daiichi Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, and Ono Pharmaceutical; research funds from Takeda Pharmaceutical, Daiichi Sankyo, MSD, Mochida Pharmaceutical, Mitsubishi Tanabe Pharma, Kowa Pharmaceutical, Toa Eiyo, Otsuka Pharmaceutical, Medtronic Japan, Astellas Pharma, Bayer Yakuhin, Shionogi, Sumitomo Dainippon Pharma, and Ono Pharmaceutical; honoraria for writing promotional material for Daiichi Sankyo; consultation fees from Novartis Pharma K.K.; and is affiliated with an endowed department sponsored by Medtronic Japan. H.I. is a member of Circulation Journal’s Editorial Board.
K.Y. was a Medical Advisor of PARALLEL-HF and has received speakers’ bureau fees/honoraria from Otsuka Pharmaceutical, Daiichi Sankyo, and Novartis Pharma K.K.; research funds from Abbott, Otsuka Pharmaceutical, Medtronic Japan, Daiichi Sankyo, Bayer Yakuhin, Ltd, Biotronik Japan, Japan Lifeline, Mitsubishi Tanabe Pharma, Fukuda Denshi, Takeda Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, and Boston Scientific; and consultation fees from Novartis Pharma K.K. K.Y. is an Associate Editor of Circulation Journal.
Y. Sakata was a Data Monitoring Committee member of PARALLEL-HF and reports no conflicts of interest. Y. Sakata is an Associate Editor of Circulation Journal.
T.O., T.I., and T.K. were employees of Novartis at the time of the study.
Author Contributions
All authors participated in the development and writing of the paper, reviewed and critically revised the manuscript for content, and approved the final version of the manuscript for submission.
IRB Information
The study protocol and all amendments were reviewed and approved by the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for each center (e.g., Nihon University Hospitals Joint IRB [Reference no. 5010005002382]). A list of IECs and IRBs is provided in the Supplementary Appendix.
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-23-0349
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