Abstract
Background
Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP.
Methods
We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP.
Findings
All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74–1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65–1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP.
Interpretation
In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.
Keywords: Heart failure, Neprilysin, AT1-receptor, Angiotensin, Blood pressure
Introduction
Patients with heart failure often present with low systolic blood pressure (SBP) and because this is associated with poor outcomes, and because physicians are concerned about hypotension, they are often reluctant to prescribe medications likely to lower arterial pressure further, even if such treatments are known to improve prognosis.1–3 Recently, The Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin- converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) randomized 8399 patients in 47 countries to treatment with enalapril 10 mg twice daily or with sacubitril/valsartan (formerly known as LCZ696) 97/103 mg twice daily (equivalent to 200 mg LCZ696 twice daily).4,5 Compared with enalapril, sacubitril/valsartan reduced the primary composite endpoint of cardiovascular death or heart failure hospitalization by 20%.5 However, because sacubitril/valsartan not only blocks the renin angiotensin system, but also enhances the activity of vasoactive substances such as the natriuretic peptides and bradykinin, it reduces blood pressure more than an ACE inhibitor or ARB. Because this may cause concern among physicians treating patients with a low SBP, we analysed the efficacy and safety of sacubitril/valsartan, compared with enalapril, according to baseline SBP, and SBP after randomization, in PARADIGM-HF.
Methods
The design4 and the primary results5,6 have been published. Patients enrolled were in New York Heart Association (NYHA) class II–IV with an ejection fraction ≤40% (changed to ≤35% after amendment) and a plasma B-type natriuretic peptide (BNP) ≥150 pg/ml or N-terminal proBNP (NT-proBNP) ≥600 pg/ml (or for patients with a heart failure hospitalization within 12 months, BNP ≥100 pg/ml or NT-proBNP ≥400 pg/ml). Patients pre-exposed to an ACE-inhibitor or an angiotensin receptor blocker (ARB) at a dose equivalent to enalapril 10 mg daily for at least 4 weeks were screened and if eligible entered a run-in period during which they were required to tolerate first enalapril 10 mg twice daily and then sacubitril/valsartan 97/103 mg twice daily (see below). Furthermore, patients had to be on a stable dose of a beta-blocker (if tolerated) and a mineralocorticoid receptor antagonist (if indicated). Patients with intolerance to ACE-inhibitors or ARBs, with symptomatic hypotension or a systolic blood pressure <100 mmHg at screening/<95 mmHg at randomization, an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 or a decrease in eGFR of more than 25% (amended to 35%) between screening and randomization, a serum potassium >5.2 mmol/l at screening (or >5.4 mmol/l at randomization) and a history of angioedema were excluded.
Study procedures
On entering the run-in period, treatment with an ACE-inhibitor or ARB was stopped (other treatments were continued). Patients first received enalapril 10 mg twice daily for 2 weeks (single-blind) and then sacubitril/valsartan (single-blind) for an additional 3–6 weeks, initially at 49/51 mg twice daily (equivalent to 100 mg LCZ696 twice daily) and then 97/103 mg (200 mg) twice daily. Patients completing both phases of the active run-in period were assigned in a 1:1 ratio to double-blind treatment with either enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily. If symptomatic hypotension occurred, the protocol recommended reduction in the dose or discontinuation of concomitantly administered blood pressure lowering drugs (e.g. nitrates and diuretics), except guideline-recommended disease-modifying drugs for heart failure (e.g. beta-blockers and mineralocorticoid receptor antagonists). However, the study drug could also be reduced in dose or temporarily discontinued, if hypotension (or other adverse effects) occurred. BP was recorded at every visit using a standard sphygmomanometer with an appropriately sized cuff at the non-dominant arm in the sitting position after 5 min of rest. During the trial, the occurrence of hypotension was enquired about at each study visit by means of a question on the case report form.
Study outcomes
The main outcomes of interest were the primary endpoint (composite of cardiovascular death or heart failure hospitalization) of the trial and its components, as well as two of the secondary outcomes, all-cause death and the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ).
SBP analyses
We analysed change in SBP from baseline according to treatment assignment, relationship between SBP and clinical outcomes, and effect of study drug on outcomes according to SBP. Specifically, we analysed change in SBP from baseline to 4 months, and over the whole duration of follow-up, as well as time-updated SBP during follow-up. We analysed SBP at baseline by category (<110 mmHg, 110 to <120 mmHg, 120 to <130 mmHg, 130 to <140 mmHg and ≥140 mmHg) and as a continuous measure. We examined the association between baseline SBP, change in SBP and time-updated SBP and the primary endpoint and secondary endpoints described above. Finally, we explored the effect of sacubitril/valsartan, compared with enalapril, on these endpoints according to baseline SBP category and SBP analysed as a continuous measure. Adverse events according to baseline SBP category are also reported.
Statistical analysis
The effect of sacubitril/valsartan, compared with that of enalapril, on each outcome of interest, according to SBP category, was examined using Cox proportional hazards regression models. Restricted cubic spline analysis was used to examine the effect of treatment according to SBP modelled as a continuous variable. The interaction between continuous SBP and treatment group on the occurrence of the pre-specified safety outcomes was tested in a logistic regression model with a term for interaction between SBP and treatment. All analyses were conducted using R version 3.1.2. A P-value of <0.05 was considered statistically significant.
Results
Overall, 8399 patients were included in the analysis. Table 1 shows the baseline characteristics of patients in the different SBP categories. Compared to patients with higher SBP, those with lower SBP were younger, more often male and less likely to have an ischaemic aetiology or a history of diabetes or hypertension. Patients with a lower SBP also had a lower ejection fraction and slightly lower heart rate and body mass index. Notably, NTproBNP and eGFR did not differ substantially across SBP category. Patients with a lower SBP were more often treated with digoxin (not accounted for by differences in prevalence of atrial fibrillation), a MRA and devices.
Table 1.
Baseline characteristics according to baseline systolic blood pressure category
| Variable | Statistic | <110 (N = 1747) | 110 to < 120 (N = 1931) | 120 to < 130 (N = 2059) | 130 to < 140 (N = 1477) | ≥140 (N = 1185) | P value |
|---|---|---|---|---|---|---|---|
| SBP (mmHg) | Mean (SD) | 102.18 (3.77) | 112.66 (3.02) | 122.76 (3.01) | 132.45 (2.90) | 147.73 (9.16) | <0.0001 |
| DBP (mmHg) | Mean (SD) | 64.86 (7.31) | 70.31 (7.63) | 75.21 (7.93) | 78.48 (8.33) | 82.88 (10.00) | <0.0001 |
| Age | Mean (SD) | 61.30 (12.01) | 62.81 (11.58) | 64.34 (11.17) | 65.65 (10.36) | 65.83 (10.89) | <0.0001 |
| Sex Female | N (%) | 335 (19%) | 389 (20%) | 441 (21%) | 359 (24%) | 308 (26%) | <0.0001 |
| Race | |||||||
| White | N (%) | 941 (53.9%) | 1218 (63.1%) | 1441 (70.0%) | 1070 (72.4%) | 874 (73.8%) | <0.0001 |
| Black | N (%) | 111 (6.4%) | 101 (5.2%) | 92 (4.5%) | 54 (3.7%) | 70 (5.9%) | |
| Asian | N (%) | 453 (25.9%) | 392 (20.3%) | 320 (15.5%) | 205 (13.9%) | 139 (11.7%) | |
| Other | N (%) | 242 (13.9%) | 220 (11.4%) | 206 (10.0%) | 148 (10.0%) | 102 (8.6%) | |
| Region | |||||||
| North American | N (%) | 181 (10.4%) | 165 (8.5%) | 137 (6.7%) | 67 (4.5%) | 52 (4.4%) | <0.0001 |
| Latin America | N (%) | 357 (20.4%) | 381 (19.7%) | 331 (16.1%) | 212 (14.4%) | 152 (12.8%) | |
| Western Europe | N (%) | 510 (29.2%) | 467 (24.2%) | 442 (21.5%) | 321 (21.7%) | 311 (26.2%) | |
| Central Europe | N (%) | 258 (14.8%) | 526 (27.2%) | 832 (40.4%) | 672 (45.5%) | 538 (45.4%) | |
| Asia-Pacific | N (%) | 441 (25.2%) | 392 (20.3%) | 317 (15.4%) | 205 (13.9%) | 132 (11.1%) | |
| eGFR (ml/min/1.73m2) | Mean (SD) | 67.09 (20.86) | 67.96 (20.80) | 67.71 (20.28) | 67.95 (18.74) | 67.87 (19.21) | 0.6947 |
| BNP (pg/mL) | Median (IQR) | 263.9 [157.7, 520.8] | 251.0 [158.5, 482.9] | 243.3 [145.6, 455.2] | 243.9 [148.6, 442.2] | 262.6 [161.4, 447.4] | 0.0103 |
| NTproBNP (pg/mL) | Median (IQR) | 1765.0 [939.0, 3520.0] | 1606.0 [893.0, 3322.0] | 1597.5 [867.0, 3140.0] | 1578.5 [836.0, 3000.0] | 1600.0 [900.0, 3120.0] | 0.3009 |
| HR (bpm) | Mean (SD) | 71.26 (12.21) | 72.09 (11.69) | 72.70 (11.99) | 73.33 (12.07) | 72.57 (12.06) | <0.0001 |
| BMI (Kg/m2) | Mean (SD) | 27.24 (5.41) | 27.74 (5.46) | 28.28 (5.41) | 28.75 (5.52) | 29.28 (5.66) | <0.0001 |
| Creatinine (mg/dl) | Mean (SD) | 1.15 (0.30) | 1.13 (0.29) | 1.12 (0.30) | 1.10 (0.30) | 1.10 (0.30) | <0.0001 |
| Ischaemic etiology | N (%) | 949 (54.3%) | 1194 (61.8%) | 1231 (59.8%) | 923 (62.5%) | 739 (62.4%) | <0.0001 |
| HF duration | |||||||
| 0–1 years | N (%) | 514 (29.4%) | 562 (29.1%) | 636 (30.9%) | 468 (31.7%) | 343 (28.9%) | 0.0018 |
| >1–5 years | N (%) | 627 (35.9%) | 752 (38.9%) | 768 (37.3%) | 580 (39.3%) | 505 (42.6%) | |
| >5 years | N (%) | 606 (34.7%) | 617 (32.0%) | 655 (31.8%) | 429 (29.0%) | 337 (28.4%) | |
| Ejection fraction (%) | Mean (SD) | 27.58 (6.49) | 28.84 (6.27) | 30.01 (6.01) | 30.62 (5.89) | 31.03 (5.65) | <0.0001 |
| NYHA functional class | |||||||
| I | N (%) | 111 (6.4%) | 96 (5.0%) | 80 (3.9%) | 43 (2.9%) | 59 (5.0%) | <0.0001 |
| II | N (%) | 1315 (75.4%) | 1396 (72.4%) | 1402 (68.2%) | 992 (67.2%) | 814 (68.8%) | <0.0001 |
| III | N (%) | 310 (17.8%) | 431 (22.4%) | 556 (27.1%) | 428 (29.0%) | 293 (24.8%) | <0.0001 |
| IV | N (%) | 7 (0.4%) | 5 (0.3%) | 17 (0.8%) | 14 (0.9%) | 17 (1.4%) | 0.0011 |
| KCCQ-CSS | Median (IQR) | 82.3 [66.7, 93.8] | 82.3 [65.6, 92.7] | 79.2 [62.5, 91.7] | 77.9 [60.4, 90.6] | 78.1 [60.4, 91.1] | <0.0001 |
| Hypertension | N (%) | 892 (51.1%) | 1219 (63.1%) | 1526 (74.1%) | 1244 (84.2%) | 1059 (89.4%) | <0.0001 |
| Diabetes | N (%) | 503 (28.8%) | 671 (34.7%) | 709 (34.4%) | 546 (37.0%) | 478 (40.3%) | <0.0001 |
| Atrial Fibrillation | N (%) | 605 (34.6%) | 672 (34.8%) | 795 (38.6%) | 589 (39.9%) | 430 (36.3%) | 0.0031 |
| Prior HF Hospitalization | N (%) | 1081 (61.9%) | 1223 (63.3%) | 1333 (64.7%) | 921 (62.4%) | 716 (60.4%) | 0.1265 |
| MI | N (%) | 725 (41.5%) | 915 (47.4%) | 877 (42.6%) | 632 (42.8%) | 485 (40.9%) | 0.0009 |
| Stroke | N (%) | 151 (8.6%) | 143 (7.4%) | 194 (9.4%) | 132 (8.9%) | 105 (8.9%) | 0.2340 |
| Sacubitril/valsartan | N (%) | 834 (47.7%) | 990 (51.3%) | 1041 (50.6%) | 731 (49.5%) | 591 (49.9%) | 0.2714 |
| CABG | N (%) | 263 (15.1%) | 343 (17.8%) | 304 (14.8%) | 217 (14.7%) | 176 (14.9%) | 0.0444 |
| PCI | N (%) | 385 (22.0%) | 490 (25.4%) | 430 (20.9%) | 272 (18.4%) | 224 (18.9%) | <0.0001 |
| Diuretic | N (%) | 1403 (80.3%) | 1538 (79.6%) | 1656 (80.4%) | 1202 (81.4%) | 939 (79.2%) | 0.6564 |
| Digoxin | N (%) | 601 (34.4%) | 596 (30.9%) | 640 (31.1%) | 403 (27.3%) | 299 (25.2%) | <0.0001 |
| Beta-Blocker | N (%) | 1609 (92.1%) | 1805 (93.5%) | 1918 (93.2%) | 1373 (93.0%) | 1106 (93.3%) | 0.5383 |
| MRA | N (%) | 1082 (61.9%) | 1140 (59.0%) | 1154 (56.0%) | 745 (50.4%) | 550 (46.4%) | <0.0001 |
| Anticoagulant | N (%) | 545 (31.2%) | 603 (31.2%) | 723 (35.1%) | 471 (31.9%) | 343 (28.9%) | 0.0041 |
| Antiplatelet agent | N (%) | 999 (57.2%) | 1122 (58.1%) | 1116 (54.2%) | 828 (56.1%) | 671 (56.6%) | 0.1435 |
| Lipid lowering agent | N (%) | 988 (56.6%) | 1117 (57.8%) | 1134 (55.1%) | 840 (56.9%) | 650 (54.9%) | 0.3568 |
| ICD | N (%) | 349 (20.0%) | 343 (17.8%) | 279 (13.6%) | 160 (10.8%) | 112 (9.5%) | <0.0001 |
| CRT | N (%) | 181 (10.4%) | 151 (7.8%) | 134 (6.5%) | 58 (3.9%) | 50 (4.2%) | <0.0001 |
SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated GFR; BNP, brain natriuretic peptide; IQR, interquartile range; NT-proBNP, N-terminal-pro brain natriuretic peptide; HR, heart rate; bpm, beats per minute
BMI, body mass index; HF, heart failure; NYHA, New York Heart Association; KCCQ-CSS, Kansan City cardiomyopathy questionnaire- clinical summary score; MI, myocardial infarction; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy.
Effects of enalapril and sacubitril/valsartan on blood pressure
Figure 1 summarizes the change in SBP at 4 months in each treatment group. In both groups, SBP increased in patients with the lowest baseline SBP and decreased in those starting with a higher SBP (Figure 1), a finding that was similar over the whole follow-up period (Supplementary material online, Figure S1). However, the increase in SBP with sacubitril/valsartan was less than in the enalapril group and the decrease in SBP with sacubitril/valsartan greater than with enalapril (Supplementary material online, Figure S2A), meaning that post-randomization SBP was lower in the sacubitril/valsartan than in the enalapril group across the SBP range (Supplementary material online, Figure S2B). At 4 months, SBP was approximately 4–6 mmHg lower in the sacubitril/valsartan group across the SBP categories (Supplementary material online, Figure 2B).
Figure 1.
Boxplot showing the change in systolic blood pressure at 4 months according to systolic blood pressure at baseline. Enalapril (left) and sacubitril/valsartan (right) treated patients. Patients with extreme increases or decreases in these groups are depicted separately.
Relationship between baseline SBP and cardiovascular outcomes
Figure 2 summarizes the relationship between baseline SBP category and clinical outcome (SBP <110 mmHg used as the reference group, hazard ratio = 1). Risk was lower for all outcomes in the higher SBP categories although less clearly in patients with a baseline SBP ≥140 mmHg. In order to investigate this potentially non-linear relationship further, we carried out restricted cubic spline analyses of the association between SBP and the outcomes of interest. Examination of these confirmed that the risk of death (all-cause and cardiovascular) and the risk of heart failure hospitalization was higher in patients with a lower SBP (Figure 3). However, above a SBP of approximately 120 mmHg the relationship between SBP and both types of death was flat, whereas the risk of heart failure hospitalization was greater in patients with a higher SBP (< 140 mmHg approximately) i.e. there was a U-shaped relationship between SBP and heart failure hospitalization. The shape of the relationship between SBP and outcomes was similar in the time-updated covariate analyses (using the last SBP measurement at the time point closest to an event or at the end of the study) (Supplementary material online, Figure S3).
Figure 2.
Adjusted hazard ratios for the (A) primary endpoint, (B) cardiovascular death, (C) heart failure hospitalization and (D) all-cause death according to systolic blood pressure at baseline in all patients. The group with systolic blood pressure < 110 mmHg is given as a reference (=1).
Figure 3.
Hazard ratio for (A) primary endpoint, (B) cardiovascular death, (C) heart failure hospitalization and (D) all-cause death in (left) all patients, (middle) on sacubitril/valsartan and (right) on enalapril according to systolic blood pressure at baseline. The reference point for the spline is at 140 mmHg. The shaded areas are 95% confidence limits.
Beneficial effects of sacubitril/valsartan compared with enalapril according to baseline SBP
Figure 4 shows the primary endpoint rates by baseline SBP category, according to treatment assignment. Compared with enalapril, sacubitril/valsartan reduced the risk of the primary endpoint across all SBP categories (P-value for SBP-treatment interaction = 0.55). Similar findings were observed for cardiovascular death, heart failure hospitalization and all-cause death (Table 2 and Supplementary material online, Figures S4–S6).
Figure 4.
Kaplan-Meier event curves for the primary endpoint (A) < 110 mmHg, (B) 110 to < 120 mmHg, (C) 120 to < 130 mmHg, (D) 130 to < 140 mmHg and (E) ≥ 140 mmHg on (blue) enalapril and (red) sacubitril/valsartan. The shaded areas represent the 95% confidence limits. P-value for interaction shows that baseline systolic blood pressure category did not modify the benefit of sacubitril/valsartan over enalapril.
Table 2.
Event rates and hazard ratios for the outcomes in sacubitril/valsartan- versus enalapril- treated patients across SBP categories
| Primary Endpoint |
CV Death |
|||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SBP-Group | Treat | Events | Event Rate / 100 patient years (CI) | HR (CI) | P-value | P for interaction | Events | Event Rate / 100 patient years (CI) | HR (CI) | P-value | P for interaction | |
| All | Enalapril | 1117 | 13.2 (12.4, 13.9) | 0.80 (0.73–0.87) | <0.0001 | 693 | 7.5 (7.0, 8.1) | 0.80 (0.71–0.89) | 0.0001 | |||
| Sac/val | 914 | 10.5 (9.8, 11.2) | 558 | 6.0 (5.5, 6.5) | ||||||||
| <110 | Enalapril | 249 | 14.0 (12.3, 15.8) | 0.88 (0.74–1.06) | 0.19 | 164 | 8.6 (7.3, 10.0) | 0.84 (0.66–1.05) | 0.13 | |||
| Sac/val | 208 | 12.3 (10.7, 14.1) | 130 | 7.1 (6.0, 8.5) | ||||||||
| 110 to <120 | Enalapril | 249 | 13.3 (11.7, 15.1) | 0.84 (0.70–1.01) | 0.06 | 148 | 7.2 (6.1, 8.5) | 0.88 (0.70–1.11) | 0.27 | |||
| Sac/val | 223 | 11.2 (9.7, 12.7) | 136 | 6.3 (5.3, 7.5) | ||||||||
| 120 to <130 | Enalapril | 264 | 12.6 (11.1, 14.2) | 0.73 (0.61–0.87) | 0.0006 | 173 | 7.7 (6.6, 8.9) | 0.65 (0.52–0.82) | 0.0003 | |||
| Sac/val | 202 | 9.2 (8.0, 10.5) | 118 | 5.0 (4.2, 6.0) | ||||||||
| 130 to <140 | Enalapril | 190 | 12.3 (10.7, 14.2) | 0.74 (0.59–0.92) | 0.0058 | 116 | 6.9 (5.7, 8.3) | 0.79 (0.60–1.04) | 0.10 | |||
| Sac/val | 141 | 9.1 (7.6, 10.7) | 90 | 5.5 (4.4, 6.7) | ||||||||
| ≥140 | Enalapril | 165 | 13.6 (11.6, 15.9) | 0.81 (0.65–1.02) | 0.07 | 0.55 | 92 | 6.8 (5.5, 8.4) | 0.91 (0.68–1.22) | 0.54 | 0.36 | |
| Sac/val | 140 | 11.0 (9.2, 13.0) | 84 | 6.2 (4.9, 7.7) | ||||||||
|
HF-Hospitalization |
All Cause Death |
|||||||||||
| SBP-Group | Treat | Events | Event Rate / 100 patient years (CI) | HR (CI) | P-value | P for interaction | Events | Event Rate / 100 patient years (CI) | HR (CI) | P-value | P for interaction | |
| All | Enalapril | 658 | 7.7 (7.2, 8.4) | 0.80 (0.71–0.89) | 0.0001 | 835 | 9.0 (8.4, 9.7) | 0.84 (0.76–0.93) | 0.0009 | |||
| Sac/val | 537 | 6.2 (5.6, 6.7) | 711 | 7.6 (7.1, 8.2) | ||||||||
| <110 | Enalapril | 152 | 8.5 (7.2, 10.0) | 0.91 (0.72–1.15) | 0.45 | 195 | 10.2 (8.8, 11.7) | 0.85 (0.69–1.05) | 0.14 | |||
| Sac/val | 131 | 7.7 (6.5, 9.2) | 158 | 8.7 (7.4, 10.2) | ||||||||
| 110 to <120 | Enalapril | 147 | 7.9 (6.7, 9.3) | 0.85 (0.67–1.07) | 0.17 | 186 | 9.1 (7.8, 10.5) | 0.84 (0.68–1.04) | 0.11 | |||
| Sac/val | 133 | 6.7 (5.6, 7.9) | 164 | 7.6 (6.5, 8.9) | ||||||||
| 120 to <130 | Enalapril | 153 | 7.3 (6.2, 8.6) | 0.75 (0.59–0.95) | 0.02 | 203 | 9.0 (7.8, 10.4) | 0.75 (0.61–0.92) | 0.0062 | |||
| Sac/val | 121 | 5.5 (4.6, 6.6) | 159 | 6.8 (5.8, 7.9) | ||||||||
| 130 to <140 | Enalapril | 108 | 7.0 (5.8, 8.5) | 0.69 (0.51–0.93) | 0.01 | 142 | 8.4 (7.1, 9.9) | 0.83 (0.65–1.06) | 0.13 | |||
| Sac/val | 75 | 4.8 (3.8, 6.0) | 115 | 7.0 (5.8, 8.4) | ||||||||
| ≥140 | Enalapril | 98 | 8.1 (6.6, 9.9) | 0.75 (0.56–1.01) | 0.06 | 0.58 | 109 | 8.1 (6.6, 9.7) | 1.05 (0.81–1.37) | 0.70 | 0.41 | |
| Sac/val | 77 | 6.0 (4.8, 7.6) | 115 | 8.5 (7.0, 10.2) | ||||||||
Sac/val: Sacubitril/Valsartan; SBP: Systolic Blood Pressure; CV: Cardiovascular; HF: Heart Failure; HR: Hazard Ratio; CI: 95% Confidence interval
The effects of sacubitril/valsartan, compared with enalapril, on the primary and other outcomes, adjusting for SBP, are summarized in Supplementary material online, Figure S7. The effect of treatment was adjusted in a variety of models all of which included age and sex. The models took account of baseline SBP (as a continuous measure), baseline SBP category, average SBP including baseline and all follow-up visits, baseline and post-randomization SBP updated to the time of an event and time-updated SBP group. These adjustments did not change the benefit of sacubitril/valsartan over enalapril. Furthermore, we analysed patients with low blood pressure at baseline ( < = 100 mm Hg vs. >100 mmHg), who further dropped or increased SBP on treatment. Supplementary material online, Figure S8 shows all-cause death (A, sacubitril/valsartan; B, enalapril) and the primary endpoint (C, sacubitril/valsartan; D, enalapril) for low ( < = 100 mmHg) or high (> 100 mmHg) SBP. Low SBP was clearly associated with high all-cause death on enalapril, with lower rates on sacubitril/valsartan. Similar results were obtained for the primary end point (Supplementary material online, Figure S8C and D). Furthermore, we pooled patients and explored high or lower SBP (> or ≤ 100 mmHg) at 4 months after randomization to enalapril or sacubitril/valsartan (Supplementary material online, Figure S9). The event rates were higher on sacubitril/valsartan and on enalapril when SBP was low. There were lower event rates on sacubitril/valsartan than on enalapril in either SBP group.
Change in Kansas City cardiomyopathy questionnaire (KCCQ) score
At each visit in each SBP group, the proportion of patients having a fall of five or more units in the KCCQ clinical summary score (i.e. clinically significant worsening) was smaller in the sacubitril/valsartan group than in the enalapril group (Table 3). The benefit of sacubitril/valsartan over enalapril in preventing worsening of KCCQ was consistent across SBP groups when adjusted for baseline variables (P for interaction 0.47).
Table 3.
Five unit fall from baseline in KCCQ clinical summary score at each in trial visit
| Variable | Statistic | <110 E* (N = 913) | <110 S/V** (N = 834) | 110 to <120 E* (N = 941) | 110 to <120 S/V** (N = 990) | 120 to <130 E* (N = 1018) | 120 to <130 S/V** (N = 1041) | 130 to <140 E* (N = 746) | 130 to <140 S/V** (N = 731) | ≥140 E* (N = 594) | ≥140 S/V** (N = 591) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Month 4 | Nobs (Nmiss) | 743 (170) | 692 (142) | 793 (148) | 836 (154) | 880 (138) | 912 (129) | 648 (98) | 633 (98) | 507 (87) | 510 (81) |
| N (%) | 210 (28.3%) | 176 (25.4%) | 212 (26.7%) | 241 (28.8%) | 233 (26.5%) | 214 (23.5%) | 172 (26.5%) | 154 (24.3%) | 138 (27.2%) | 124 (24.3%) | |
| Month 8 | Nobs (Nmiss) | 717 (196) | 678 (156) | 761 (180) | 811 (179) | 838 (180) | 868 (173) | 618 (128) | 614 (117) | 488 (106) | 489 (102) |
| N (%) | 229 (31.9%) | 183 (27.0%) | 246 (32.3%) | 226 (27.9%) | 262 (31.3%) | 231 (26.6%) | 181 (29.3%) | 157 (25.6%) | 149 (30.5%) | 144 (29.4%) | |
| Month 12 | Nobs (Nmiss) | 668 (245) | 647 (187) | 731 (210) | 774 (216) | 804 (214) | 848 (193) | 599 (147) | 591 (140) | 463 (131) | 469 (122) |
| N (%) | 220 (32.9%) | 170 (26.3%) | 227 (31.1%) | 234 (30.2%) | 248 (30.8%) | 243 (28.7%) | 181 (30.2%) | 179 (30.3%) | 139 (30.0%) | 147 (31.3%) | |
| Month 24 | Nobs (Nmiss) | 359 (554) | 377 (457) | 401 (540) | 440 (550) | 502 (516) | 494 (547) | 365 (381) | 366 (365) | 287 (307) | 300 (291 |
| N (%) | 123 (34.3%) | 119 (31.6%) | 154 (38.4%) | 133 (30.2%) | 152 (30.3%) | 152 (30.8%) | 137 (37.5%) | 108 (29.5%) | 104 (36.2%) | 90 (30.0%) | |
| Month 36 | Nobs (Nmiss) | 114 (799) | 125 (709) | 152 (789) | 158 (832) | 210 (808) | 188 (853) | 138 (608) | 138 (593) | 126 (468) | 114 (477) |
| N (%) | 46 (40.4%) | 42 (33.6%) | 71 (46.7%) | 47 (29.7%) | 71 (33.8%) | 60 (31.9%) | 55 (39.9%) | 60 (43.5%) | 46 (36.5%) | 45 (39.5%) | |
| End of study | Nobs (Nmiss) | 680 (233) | 637 (197) | 715 (226) | 752 (238) | 809 (209) | 834 (207) | 574 (172) | 579 (152) | 451 (143) | 450 (141) |
| N (%) | 319 (46.9%) | 215 (39.4%) | 315 (44.1%) | 282 (37.5%) | 357 (44.1%) | 317 (38.0%) | 253 (44.1%) | 229 (39.6%) | 198 (43.9%) | 211 (46.9%) |
Nobs (Nmiss), number of available observations (number of missing observations); N (%), percentage of five unit fall from baseline in available observations.
E=enalapril.
S/V=sacubitril/valsartan.
Pre-specified safety assessments according to baseline SBP and treatment assignment
Table 4 summarizes the occurrence of the pre-specified safety outcomes according to SBP at baseline. Symptomatic hypotension and hypotensive symptoms with a SBP <90 mmHg were more frequent in the group starting with a SBP <110 mmHg, irrespective of treatment allocation, although these adverse effects occurred more often in the sacubitril/valsartan group than in the enalapril group. The other adverse effects of interest, including elevation in serum creatinine concentration, did not have an obvious relationship with baseline SBP. Study-drug dose reduction and discontinuation for hypotension was more frequent in patients with a low SBP at baseline (Figure 5). These rates were also nominally higher for sacubitril/valsartan than for enalapril. However, only 13 patients (1.3%) discontinued sacubitril/valsartan compared with 9 (1.0%) discontinuing enalapril in those with SBP <110 mmHg. The number was ≤ 1% in all other baseline SBP groups for both drugs.
Table 4.
Adverse events during the randomized treatment.
| Variable | <110 E* (N = 913) | <110 S/V** (N = 834) | 110 to <120 E* (N = 941) | 110 to <120 S/V** (N = 990) | 120 to <130 E* (N = 1018) | 120 to <130 S/V** (N = 1041) | 130 to <140 E* (N = 746) | 130 to <140 S/V** (N = 731) | ≥140 E* (N = 594) | ≥140 S/V** (N = 591) | P value | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Symptomatic Hypotension | 125 (13.7%) | 213 (25.5%) | 101 (10.7%) | 143 (14.4%) | 87 (8.5%) | 119 (11.4%) | 50 (6.7%) | 66 (9.0%) | 25 (4.2%) | 47 (8.0%) | 0.21 | ||
| Symptomatic Hypotension SBP <90mmHg | 26 (2.8%) | 59 (7.1%) | 18 (1.9%) | 25 (2.5%) | 10 (1.0%) | 15 (1.4%) | 5 (0.7%) | 9 (1.2%) | 0 (0.0%) | 4 (0.7%) | 0.59 | ||
| Creatinine ≥ 2.5 mg/dL | 42 (4.6%) | 32 (3.8%) | 47 (5.0%) | 25 (2.5%) | 46 (4.5%) | 42 (4.0%) | 26 (3.5%) | 17 (2.3%) | 27 (4.5%) | 23 (3.9%) | 0.74 | ||
| Creatinine ≥ 3.0 mg/dL | 15 (1.6%) | 13 (1.6%) | 22 (2.3%) | 11 (1.1%) | 17 (1.7%) | 18 (1.7%) | 15 (2.0%) | 10 (1.4%) | 14 (2.4%) | 11 (1.9%) | 0.98 | ||
| Potassium > 5.5 mmol/L | 149 (16.3%) | 114 (13.7%) | 146 (15.5%) | 152 (15.4%) | 201 (19.7%) | 203 (19.5%) | 136 (18.2%) | 118 (16.1%) | 102 (17.2%) | 94 (15.9%) | 1.00 | ||
| Potassium > 6.0 mmol/L | 39 (4.3%) | 28 (3.4%) | 53 (5.6%) | 40 (4.0%) | 64 (6.3%) | 51 (4.9%) | 51 (6.8%) | 31 (4.2%) | 29 (4.9%) | 31 (5.2%) | 0.14 | ||
| Cough | 164 (18.0%) | 133 (15.9%) | 145 (15.4%) | 118 (11.9%) | 127 (12.5%) | 100 (9.6%) | 99 (13.3%) | 69 (9.4%) | 66 (11.1%) | 54 (9.1%) | 0.44 | ||
| Angioedema | |||||||||||||
| No treatment/antihistamines only | 3 (0.3%) | 1 (0.1%) | 1 (0.1%) | 2 (0.2%) | 0 (0.0%) | 4 (0.4%) | 0 (0.0%) | 2 (0.3%) | 0 (0.0%) | 2 (0.3%) | 0.02 | ||
| Catecholamines/corticosteroids without hospitalization | 1 (0.1%) | 0 (0.0%) | 1 (0.1%) | 1 (0.1%) | 1(0.1%) | 2 (0.2%) | 1 (0.1%) | 0 (0.0%) | 0 (0.0%) | 3 (0.5%) | 0.35 | ||
| Hospitalized/no airway compromise | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 2 (0.2%) | 0 (0.0%) | 1 (0.1%) | 0 (0.0%) | 0 (0.0%) | 1 (0.2%) | 0 (0.0%) | 0.03 | ||
| Airway compromise | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1.00 | ||
The data is presented as n (%);
E=enalapril;
S/V=sacubitril/valsartan
Figure 5.
(A) Any report of hypotension, (B), dose reduction and (C) dose reduction or discontinuation of study drug for enalapril (left) or sacubitril/valsartan (right). SBP, systolic blood pressure.
Discussion
In this study, we have confirmed and extended prior findings about the relationship between blood pressure and outcomes in patients with heart failure and reduced ejection fraction (HF-REF), albeit in a selected group which had tolerated full-dose enalapril and sacubitril/valsartan during an active run-in period before randomization. We have also described the safety and efficacy of sacubitril/valsartan, compared with enalapril, across the range of blood pressure in PARADIGM-HF.
Several studies have shown that patients with low SBP have a worse prognosis than those with higher SBP.1–3
Because patients with low SBP were often undertreated with disease-modifying therapy, previous studies left open the possibility that sub-optimal treatment, rather than SBP per se, accounted for, or at least contributed to, the poor outcomes in these patients. By design, all patients randomized in PARADIGM-HF5,6 were treated with an evidence-based dose of renin–angiotensin system blocker and more than 90% also received a beta-blocker. Despite this, and greater use of mineralocorticoid receptor antagonists and digoxin, patients with a low BP still had worse outcomes than those with a higher SBP. It is not clear why this was, as patients with low baseline SBP in PARADIGM-HF did not have evidence suggesting more advanced disease. Specifically, patients with lower SBP at baseline were younger and did not have worse NYHA class and KCCQ scores or notably higher natriuretic peptide or lower eGFR levels. LVEF was only slightly lower in patients with lower SBP. Therefore, in this study, low SBP was not clearly a marker of more advanced disease or greater comorbidity, suggesting that below a certain threshold low SBP may itself be harmful.
Interpretation of the relationship between SBP and outcomes in previous studies has also been hampered by the statistical phenomenon of ‘regression to the mean’ whereby SBP was consistently noted to decrease after randomization in patients with a higher starting SBP and to increase in those with a lower baseline SBP (CHARM,7 Val-HeFT,8 A-HeFT9 and COPERNICUS10). Potentially, this may have diluted the relationship between baseline SBP and outcomes. For this reason, we also conducted a time-updated covariate analyses, using the last SBP measurement at the time point closest to an event or at the end of the study. Finally, patients with a low SBP on treatment (≤ 100 mmHg) had worse outcomes compared to those with a higher SBP (>100 mmHg), but the event rate was lower on sacubitril/valsartan compared to enalapril. Whether or to what extent low SBP at baseline, spontaneous decline or drug-induced effects are associated with, if not involved in, poor outcomes cannot be established in analyses of this type. However, our findings strengthen what is already known about the relationship between SBP and outcome, reinforcing the importance of SBP as a predictor of outcome.
The third extension of prior findings is our demonstration of a U-shaped relationship between SBP and heart failure hospitalization (and therefore the composite of cardiovascular death or heart failure hospitalization) whereby higher hospitalization rates were observed at both ends of the SBP range included in PARADIGM-HF.5 This was quite different than for mortality (cardiovascular or all-cause) where the relationship between SBP and the risk of death was flat above a SBP of approximately 120 mmHg. Indeed, it was notable that 14% of patients in PARADIGM-HF had a SBP above the threshold for treatment of hypertension (i.e. those in the ≥140 mmHg category, with a mean SBP of 148 mmHg), despite their treatment with multiple hypotensive medications. Why the rate of hospitalization of heart failure was higher in patients with a SBP ≥140 mmHg, but mortality was not, is unclear.
Sacubitril/valsartan improved clinical outcomes, compared with enalapril, across the range of SBP studied. This treatment benefit was robust, persisting after adjustment for SBP at baseline, average SBP during follow-up and time-updated SBP, the latter, as explained above, strengthening the relationship between low SBP and poor outcomes. Consequently, even in patients with a persistently low SBP after treatment, sacubitril/valsartan was superior to enalapril in reducing mortality and morbidity.
In our analyses, patients with a low baseline SBP are those of most interest given their greater risk of death and hospitalization and the concern physicians often have about using blood pressure lowering drugs in them. Indeed, because of this concern, patients with a low SBP have even been excluded from many key trials in heart failure (CIBIS-2, MERIT-HF).11,12 PARADIGM-HF enrolled a large number (n = 1747) of patients with a low SBP (1747 <110, 1173 <105 and 309 <100 mmHg), comparing favourably with other major trials that have examined the safety and tolerability of blood pressure reducing drugs in heart failure, including Val-HeFT (1156 patients ≤110 mmHg), COPERNICUS (396 <105 mmHg) and CHARM (385 ≤100 mmHg).7,8,10 Patients in the lowest SBP category in PARADIGM-HF attained the same relative magnitude of benefit from sacubitril/valsartan as patients in the trial overall. Consequently, because such patients are at higher risk of adverse clinical outcomes, the same relative risk reduction with sacubitril/valsartan is expected to give a greater absolute risk reduction—of the order of a 3–4 fewer fatal and non-fatal events per 1000 patient years of treatment. This principle is true for all disease modifying neurohumoural and vasodilating drugs studied to date yet, paradoxically, as mentioned earlier, these sicker patients with potentially more to gain are the least likely to be treated. Inevitably, however, this additional benefit comes at a cost. As in prior studies, patients with a low baseline SBP have more hypotension-related adverse effects reported, irrespective of treatment allocation (even if assigned to placebo). This was also observed in PARADIGM-HF, although the proportion of patients assigned to sacubitril/valsartan and experiencing symptoms of hypotension and a SBP <90 mmHg or discontinuing study drug for hypotension was not large. However, this finding must be interpreted in light of the study design (with sequential active run-in periods — enalapril followed by sacubitril/valsartan). Specifically, of 10513 patients treated with enalapril over a median duration of 15 [IQR 14–21] days, 1102 (10.5%) discontinued the study for any reason (including administrative reasons and withdrawal of consent). For sacubitril/valsartan, of 9419 patients treated over a median duration of 29 [IQR 26–35] days 977 (10.4%) discontinued the study. In the two periods, 146 and 164 patients respectively, discontinued for an adverse effect related to hypotension. A recent analysis, using inverse probability weighting to adjust for variables associated with discontinuation during the run-in, showed no significant diminution of the benefit of sacubitril/valsartan over enalapril with respect to the key outcomes cardiovascular death, heart failure hospitalization and all-cause death.13 Furthermore, in another study with only a 5-day active run-in period (TITRATION), up to 84% of patients tolerated the introduction of sacubitril/valsartan without dose-interruption or down-titration.14
Some limitations of our study need to be acknowledged. This was a post-hoc exploratory analysis and patients were not randomized according to SBP. All randomized patients had demonstrated toleration of both enalapril 10mg twice daily followed by sacubitril/valsartan 97/103 mg twice daily. Patients could not be randomized if their SBP was <95 mmHg or they had symptoms of hypotension.
In conclusion, we have confirmed that low SBP is associated with worse outcomes in HF-REF and have shown that, if an individual could tolerate sacubitril/valsartan, (notably after exposure to the maximal dose in a run-in phase) it was beneficial across the range of SBP included in PARADIGM-HF in patients taking other guideline recommended therapies.15 Compared to patients with a higher SBP, those with lower SBP may obtain greater absolute benefits from sacubitril/valsartan but at the expense of more hypotension-related adverse effects.
Supplementary material
Supplementary material is available at European Heart Journal online.
Conflict of interest: M Böhm reports personal fees from Servier, Medtronic, Bayer, Pfizer outside the submitted work. J Gong, M Lefkowitz, A Rizkala and V Shi are employees of Novartis. P Jhund consulted for Novartis. J McMurray reports other from Novartis, Cardiorentis, Amgen, Oxford University/Bayer, GlaxoSmithKline, Theracos, Abbvie, DalCor, Pfizer, and Merck, outside the submitted work. M Packer has consulted for Amgen, AstraZeneca, Bayer, BioControl, Boehringer Ingelheim, Cardio3, Cardiokinetix, Cardiorentis, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Novartis, Takeda and ZS Pharma during the conduct of the study. JL Rouleau consulted for Novartis. S Solomon reports grants and personal fees from Novartis, during the conduct of the study; grants and personal fees from Amgen, personal fees from Merck and Bayer, grants from Alnylam and Ionis outside the submitted work. K Swedberg reports personal fees from Novartis, AstraZeneca and received grants from Servier. R Young has nothing to disclose. M Zile consulted for and received research support from Novartis.
Supplementary Material
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