We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP ≤120 mm Hg. Propensity scores for SBP ≤120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP ≤120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP ≤120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP ≤120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs ≤120 and >120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP ≤120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP ≤120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics.
Hypertension is a known risk factor for incident heart failure (HF). However, several studies have demonstrated that in patients with acute decompensated HF, a low systolic blood pressure (SBP) is associated with poor outcomes. We recently demonstrated similar associations between low SBP and poor outcomes in a propensity-matched cohort of patients with advanced chronic systolic HF. However, the role of baseline SBP in outcomes in patients with mild to moderate chronic systolic and diastolic HF is relatively less known and has not been investigated using propensity-matched design. The purpose of the present study was to examine the association between baseline SBP and outcomes in a propensity-matched cohort of patients with mild to moderate chronic systolic and diastolic HF.
Methods
A public-use copy of the Digitalis Investigation Group (DIG) dataset was used for the present analysis. The DIG was a multicenter randomized placebo-controlled clinical trial of digoxin in patients with HF. Briefly, 7,788 patients with advanced chronic systolic HF were enrolled from 302 different sites across the United States and Canada from February 1991 through August 1993. At baseline patients had a mean duration of 17 months of HF and had a mean left ventricular ejection fraction (LVEF) of 29%. Most patients had New York Heart Association class I to III symptoms and >80% of patients were receiving angiotensin-converting enzyme inhibitors and diuretics.
Data on baseline SBP were available from 7,785 patients and were documented by study investigators. Of these, 3,538 (45%) had SBP ≤120 mm Hg (median 110, interquartile range 8), and 4,247 (54%) had SBP >120 mm Hg (median 140, interquartile range 20). We chose an SBP of 120 mm Hg as our cutoff because it is often considered the upper limit of normal range. Taking into account the significant imbalances in baseline characteristics between the 2 groups ( Table 1 ), we used propensity scores to assemble a matched cohort who were well-balanced baseline characteristics. We began by estimating propensity scores for SBP ≤120 mm Hg for each of the 7,785 patients using a nonparsimonious multivariable logistic regression model and then assembled a cohort of 1,869 pairs (n = 3,838) of propensity-matched patients with SBPs ≤120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. Absolute standardized differences were estimated to evaluate the prematch imbalance and postmatch balance and presented as a Love plot. An absolute standardized difference of 0% indicates no residual bias and differences <10% are considered inconsequential.
| Prematch SBP (mm Hg) | Postmatch SBP (mm Hg) | |||||
|---|---|---|---|---|---|---|
| >120 (n = 4,247) | ≤120 (n = 3,538) | p Value | >120 (n = 1,869) | ≤120 (n = 1,869) | p Value | |
| Age (years) | 65 ± 10 | 62 ± 11 | <0.001 | 64 ± 10 | 64 ± 11 | 0.511 |
| Women | 1,163 (27%) | 762 (22%) | <0.001 | 438 (23%) | 444 (24%) | 0.847 |
| Nonwhite | 657 (16%) | 470 (13%) | 0.006 | 254 (14%) | 242 (13%) | 0.595 |
| Body mass index (kg/m 2 ) | 28 ± 6 | 27 ± 5 | <0.001 | 27 ± 5 | 27 ± 6 | 0.410 |
| Duration of heart failure (months) | 30 ± 37 | 29 ± 35 | 0.434 | 30 ± 37 | 30 ± 36 | 0.565 |
| Primary cause of heart failure | <0.001 | 0.223 | ||||
| Ischemic | 2,811 (66%) | 2,548 (72%) | 1,330 (71%) | 1,330 (71%) | ||
| Hypertensive | 622 (15%) | 182 (5%) | 150 (8%) | 133 (7%) | ||
| Idiopathic | 545 (13%) | 565 (16%) | 261 (14%) | 293 (15%) | ||
| Others | 269 (6%) | 243 (7%) | 128 (7%) | 113 (6%) | ||
| Previous myocardial infarction | 2,546 (60%) | 2,361 (67%) | <0.001 | 1,237 (66%) | 1,217 (65%) | 0.507 |
| Current angina pectoris | 1,170 (28%) | 944 (27%) | 0.392 | 520 (28%) | 524 (28%) | 0.913 |
| Hypertension | 1,159 (59%) | 2,514 (33%) | <0.001 | 792 (42%) | 794 (43%) | 0.972 |
| Diabetes mellitus | 1,366 (32%) | 852 (24%) | <0.001 | 519 (28%) | 524 (28%) | 0.883 |
| Chronic kidney disease | 2,017 (48%) | 1,508 (43%) | <0.001 | 854 (46%) | 840 (45%) | 0.646 |
| Medications | ||||||
| Pretrial digoxin use | 1,780 (42%) | 1,584 (45%) | 0.011 | 811 (43%) | 831 (45%) | 0.529 |
| Trial use of digoxin | 2,131 (50%) | 1,757 (50%) | 0.650 | 938 (50%) | 919 (50%) | 0.554 |
| Angiotensin-converting enzyme inhibitors | 3,929 (93%) | 3,343 (95%) | <0.001 | 1,740 (93%) | 1,745 (93%) | 0.793 |
| Nitroglycerin and hydralazine | 80 (2%) | 31 (1%) | <0.001 | 20 (1%) | 23 (1%) | 0.761 |
| Diuretics | 3,311 (78%) | 2,762 (78%) | 0.911 | 1,464 (78%) | 1,438 (77%) | 0.338 |
| Potassium-sparing diuretics | 284 (7%) | 312 (9%) | <0.001 | 146 (8%) | 156 (8%) | 0.581 |
| Potassium supplement | 1,185 (28%) | 1,013 (29%) | 0.476 | 545 (29%) | 529 (28%) | 0.595 |
| Symptoms and signs of heart failure | ||||||
| Dyspnea at rest | 922 (22%) | 782 (22%) | 0.676 | 395 (21%) | 381 (20%) | 0.602 |
| Dyspnea on exertion | 3,155 (74%) | 2,705 (77%) | 0.027 | 1,422 (76%) | 1,410 (75%) | 0.673 |
| Jugular venous distension | 519 (12%) | 501 (14%) | 0.012 | 251 (13%) | 227 (12%) | 0.249 |
| Third heart sound | 864 (20%) | 981 (28%) | <0.001 | 455 (24%) | 435 (23%) | 0.471 |
| Pulmonary rales | 657 (16%) | 644 (18%) | <0.001 | 314 (17%) | 289 (16%) | 0.272 |
| Lower extremity edema | 961 (23%) | 672 (19%) | <0.001 | 393 (21%) | 375 (20%) | 0.489 |
| Number of symptom/signs | 5.4 ± 2.0 | 5.5 ± 2.0 | 0.021 | 5.5 ± 2.0 | 5.5 ± 2.0 | 0.251 |
| New York Heart Association class | <0.001 | 0.269 | ||||
| I | 650 (15%) | 453 (13%) | 254 (14%) | 267 (14%) | ||
| II | 2,404 (57%) | 1,838 (52%) | 1,026 (55%) | 1,038 (56%) | ||
| III | 1,127 (27%) | 1,159 (33%) | 557 (30%) | 538 (29%) | ||
| IV | 66 (2%) | 88 (3%) | 32 (2%) | 26 (1%) | ||
| Heart rate (beats/min) | 78 ± 12 | 79 ± 13 | 0.393 | 78 ± 12 | 78 ± 13 | 0.819 |
| Diastolic blood pressure (mm Hg) | 80 ± 11 | 69 ± 9 | <0.001 | 74 ± 9 | 74 ± 8 | 0.578 |
| Chest x-ray findings | ||||||
| Pulmonary congestion | 550 (13%) | 559 (16%) | <0.001 | 276 (15%) | 256 (14%) | 0.365 |
| Cardiothoracic ratio >0.5 | 2,541 (60%) | 2,148 (61%) | 0.429 | 1,115 (60%) | 1,086 (58%) | 0.349 |
| Serum creatinine (mg/dL) | 1.29 ± 0.38 | 1.27 ± 0.36 | 0.004 | 1.29 ± 0.38 | 1.27 ± 0.36 | 0.208 |
| Serum potassium (mEq/L) | 4.33 ± 0.44 | 4.34 ± 0.44 | 0.078 | 4.35 ± 0.44 | 4.35 ± 0.45 | 0.923 |
| Left ventricular ejection fraction (%) | 35 ± 13 | 29 ± 11 | <0.001 | 31 ± 11 | 31 ± 12 | 0.834 |
| Left ventricular ejection fraction >45% | 725 (17%) | 263 (7%) | <0.001 | 177 (10%) | 211 (11%) | 0.068 |
The primary outcome for the present analysis was all-cause mortality during 5 years of follow-up. The secondary outcomes included various cause-specific mortalities and hospitalizations. Kaplan–Meier and Cox regression analyses were used to determine associations between SBP ≤120 mm Hg and outcomes during 5 years of follow-up. Subgroup analyses were conducted to determine the homogeneity of association between SBP ≤120 mm Hg and all-cause mortality. Formal sensitivity analyses were conducted to determine the impact of an unmeasured confounder. All statistical tests were 2-tailed with a p value <0.05 considered statistically significant. All data analyses were performed using SPSS 18 for Windows (SPSS, Inc., Chicago, Illinois).
Results
Matched patients had a mean age of 64 ± 10 years with 23% women and 14% nonwhites. Matched patients with SBP ≤120 mm Hg had a median SBP of 114 mm Hg (interquartile range 10) and those with SBP >120 mm Hg had a median SBP of 134 mm Hg (interquartile range 10). More than 90% of matched patients with SBP ≤120 mm Hg had their SBP from 110 to 120 mm Hg. Before matching, patients with SBP ≤120 mm Hg were younger (by a mean age of 3 years) and had a lower prevalence of hypertension, diabetes, and chronic kidney disease ( Table 1 ). They were also more likely to be men, have a higher prevalence of ischemic cardiomyopathy, a greater symptom burden, and a lower mean LVEF. These and other prematch imbalances in baseline covariates were balanced after matching ( Table 1 ). Postmatch standardized differences for all measured covariates were <10% (most were <5%), suggesting substantial covariate balance across groups ( Figure 1 ).
All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤120 and >120 mm Hg, respectively, during 5 years of follow-up (SBP ≤120 compared to >120 mm Hg, hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088; Figure 2 and Table 2 ). This association was homogenous across various subgroups of patients except that it was observed only in those receiving diuretics ( Figure 3 ). In the absence of a hidden bias, a sign-score test for matched data with censoring provided evidence (p = 0.0147) that patients with SBP ≤120 mm Hg clearly had higher mortality than those with SBP >120 mm Hg. A hidden covariate that is a near-perfect predictor of mortality could explain away this association if it also increased the odds of having SBP ≤120 mm Hg by only 3.13%. Associations of SBP ≤120 mm Hg with other cause-specific mortalities before and after matching are presented in Table 2 .
| Events, n (%) | SBP (mm Hg) | Absolute Risk Increase ⁎ | HR (95% CI) † | p Value | |
|---|---|---|---|---|---|
| >120 | ≤120 | ||||
| Before match | |||||
| Subjects | 4,247 | 3,538 | |||
| All causes | 1,289 (30%) | 1,316 (37%) | 7% | 1.31 (1.21–1.41) | <0.001 |
| Cardiovascular | 987 (23%) | 1,064 (30%) | 7% | 1.38 (1.27–1.51) | <0.001 |
| Heart failure | 396 (9%) | 511 (14%) | 5% | 1.66 (1.45–1.89) | <0.001 |
| Other cardiovascular | 591 (14%) | 553 (16%) | 2% | 1.20 (1.06–1.34) | 0.003 |
| Noncardiovascular | 232 (6%) | 178 (5%) | −1% | 0.99 (0.81–1.20) | 0.894 |
| Unknown | 70 (2%) | 74 (2%) | 0% | 1.36 (0.98–1.88) | 0.068 |
| After match | |||||
| Subjects | 1,869 | 1,869 | |||
| All causes | 606 (32%) | 650 (35%) | 3% | 1.10 (0.99–1.23) | 0.088 |
| Cardiovascular | 459 (25%) | 514 (28%) | 3% | 1.15 (1.01–1.30) | 0.031 |
| Heart failure | 194 (10%) | 246 (13%) | 3% | 1.30 (1.08–1.57) | 0.006 |
| Other cardiovascular | 265 (14%) | 268 (14%) | 0% | 1.04 (0.87–1.23) | 0.682 |
| Noncardiovascular | 110 (6%) | 99 (5%) | −1% | 0.93 (0.71–1.22) | 0.581 |
| Unknown | 37 (2%) | 37 (2%) | 0% | 1.03 (0.65–1.62) | 0.907 |
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