Key Points
Question
What is the prognostic significance of elevated B-type natriuretic peptide levels after transcatheter aortic valve replacement (TAVR)?
Findings
In this cohort study including 3391 patients, among patients at intermediate, high, and prohibitive surgical risk treated with TAVR, elevated B-type natriuretic peptide levels after TAVR were associated with an increased hazard for subsequent mortality and rehospitalization. Decreases in B-type natriuretic peptide levels during follow-up were associated with lower risk of subsequent events.
Meaning
Further studies are warranted to evaluate whether strategies targeting the pathobiology underlying elevated natriuretic peptide levels after TAVR will improve patient outcomes.
This cohort study evaluates the associations of elevated B-type natriuretic peptide levels after transcatheter aortic valve replacement (TAVR) and change in B-type natriuretic peptide levels between follow-up time points with risk of subsequent clinical outcomes.
Abstract
Importance
Among those with aortic stenosis, natriuretic peptide levels can provide risk stratification, predict symptom onset, and aid decisions regarding the timing of valve replacement. Less is known about the prognostic significance and potential clinical utility of natriuretic peptide levels measured after valve replacement.
Objective
To determine the associations of elevated B-type natriuretic peptide (BNP) levels after transcatheter aortic valve replacement (TAVR) and change in BNP levels between follow-up time points with risk of subsequent clinical outcomes.
Design, Setting, and Participants
In this cohort study, patients with severe symptomatic aortic stenosis at intermediate, high, or prohibitive surgical risk for aortic valve replacement who underwent TAVR from the PARTNER IIA cohort, PARTNER IIB cohort, SAPIEN 3 intermediate-risk registry, and SAPIEN 3 high-risk registry were included. B-type natriuretic peptide levels were obtained at baseline and discharge as well as 30 days and 1 year after TAVR. For each measurement, a BNP ratio was calculated using measured BNP level divided by the upper limit of normal for the assay used. Outcomes were evaluated in landmark analyses out to 2 years. Data were collected from April 2011 to January 2019.
Main Outcomes and Measures
All-cause death, cardiovascular death, rehospitalization, and the combined end point of cardiovascular death or rehospitalization.
Results
Among 3391 included patients, 1969 (58.1%) were male, and the mean (SD) age was 82 (7.5) years. Most patients had a BNP ratio greater than 1 at each follow-up time point, including 2820 of 3256 (86.6%) at baseline, 2652 of 2995 (88.5%) at discharge, 1779 of 2209 (80.5%) at 30 days, and 1799 of 2391 (75.2%) at 1 year. After adjustment, every 1-point increase in BNP ratio at 30 days (approximately equivalent to an increase of 100 pg/mL in BNP) was associated with an increased hazard of all-cause death (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.07-1.15), cardiovascular death (aHR, 1.16; 95% CI, 1.11-1.21), and rehospitalization (aHR, 1.08; 95% CI, 1.03-1.14) between 30 days and 2 years. Among those with a BNP ratio of 2 or more at discharge, after adjustment, every 1-point decrease in BNP ratio between discharge and 30 days was associated with a decreased hazard of all-cause death (aHR, 0.92; 95% CI, 0.88-0.96) between 30 days and 2 years.
Conclusions and Relevance
Elevated BNP levels after TAVR was independently associated with increased subsequent mortality and rehospitalizations. Further studies to determine how best to mitigate this risk are warranted.
Introduction
Natriuretic peptide levels predict incident heart failure, aid in the diagnosis of heart failure in patients with dyspnea, and stratify prognosis among patients with heart failure.1,2,3 Both elevated B-type natriuretic peptide (BNP) and N-terminal pro–BNP (NT-proBNP) levels reflect hemodynamic loading and stretch and stress on the left ventricle (LV) that portend worse clinical outcomes.4,5 Among patients with aortic stenosis (AS), elevated natriuretic peptide levels predict symptom onset and clinical outcomes among asymptomatic patients, and preprocedure levels predict survival and rehospitalizations after valve replacement among symptomatic and asymptomatic patients.6,7,8,9 While the precise role of and cut points for natriuretic peptide levels prior to valve replacement are still being clarified, they are commonly measured as AS becomes severe and in preprocedure assessments of risk and treatment timing.10
The role for measuring and consequences of elevated natriuretic peptide levels after valve replacement for AS have not been carefully examined. In the treatment of patients with AS, emphasis is placed on relieving the mechanical obstruction with valve replacement. While unloading the heart in this manner is critical, less attention has been directed at what adjunctive therapies might improve clinical outcomes alongside valve replacement.
We hypothesized that elevated BNP levels after valve replacement would be associated with higher mortality and more frequent hospitalization. Alongside efforts to optimize procedural success and minimize complications, such a finding could direct attention to ways in which valve replacement timing or medical therapy after valve replacement may be optimized to mitigate the pathobiology that results in BNP release and thereby improve clinical outcomes.
Methods
Study Population
Patients with severe, symptomatic AS at intermediate, high, or prohibitive risk for surgery who were treated with transcatheter aortic valve replacement (TAVR) using the Edwards SAPIEN XT and SAPIEN 3 valve systems (Edwards Lifesciences) in the Placement of Aortic Transcatheter Valves (PARTNER) IIA cohort, PARTNER IIB cohort, SAPIEN 3 intermediate-risk registry, and SAPIEN 3 high-risk registry were included in this analysis if they had a BNP level recorded before TAVR or after TAVR at discharge, 30 days, or 1 year. Patients treated with a valve-in-valve procedure or surgical aortic valve replacement or from sites using an NT-proBNP assay were excluded. The design, inclusion and exclusion criteria, definitions for clinical variables, and primary results of these trial and registry cohorts have been previously reported.11,12,13,14 The study protocols were approved by the institutional review board at each enrolling site, and all patients provided written informed consent.
Clinical Data and Echocardiography
Clinical data and echocardiograms were obtained at baseline (prior to TAVR) and after TAVR at discharge (or 7 days), 30 days, and 1 year. Echocardiograms were analyzed by an independent core laboratory.15 Measurements of chamber dimensions and function as well as valve size and hemodynamics were calculated using methodology recommended by the American Society of Echocardiography.16 Left ventricular mass and measurements of chamber dimensions were indexed to body surface area. Postprocedure aortic regurgitation was assessed according to the Valve Academic Research Consortium–2 criteria.17
Clinical End Points
Our analysis focused on clinical end points of all-cause death, cardiovascular death, rehospitalization, and the combined end point of cardiovascular death or rehospitalization. End points including death, cause of death, rehospitalization, stroke, kidney failure, major bleeding, and vascular complications were adjudicated by a clinical events committee associated with the trials and registries. Rehospitalization was defined as hospitalization for symptoms of aortic valve disease (eg, heart failure, angina, syncope) or any complications related to the procedure.18 Health status was assessed using the Kansas City Cardiomyopathy Questionnaire and functional capacity by the 6-minute walk test.19,20
Measurement of BNP Levels and BNP Ratio
Since not all BNP measurements were made with a single assay, to allow for a more reliable comparison of BNP data across patients and sites, a BNP ratio was determined for each BNP measurement, as recommended previously.7,21 The BNP ratio was calculated as the measured circulating BNP level divided by the upper limit of normal for the BNP assay. Each site provided the upper limit of normal for the BNP assay used in their clinical laboratory, which in some cases was age-specific and/or sex-specific (eTable 1 in the Supplement). Across all patients included in our analysis, the mean (SD) upper limit of normal for BNP was 109.6 (46.3) pg/mL (to convert to nanograms per liter, multiply by 1). With an upper limit of normal of approximately 100 pg/mL, then a measured BNP value of 250 pg/mL would correspond to a BNP ratio of 2.5, and a 1-point increase in the BNP ratio would be analogous to an increase in BNP of 100 pg/mL.
Statistical Analysis
Continuous variables are presented as means and standard deviations and compared using analysis of variance. Categorical variables are shown as counts and frequencies and compared using the χ2 test. Time to first event curves are displayed using Kaplan-Meier estimates and compared using the log-rank test. Hazard ratios (HRs) and 95% CIs are estimated by study-stratified Cox proportional hazards regression models. The association of BNP ratio at several time points (baseline, discharge, 30 days, and 1 year) with clinical outcomes at 2 years was analyzed using a landmark approach, which only considered events between the biomarker time point and 2 years. Primary analyses treated BNP ratio as a continuous variable. Penalized splines (with 2 df) were used to test for nonlinear associations between BNP ratio and clinical outcomes.22 B-type natriuretic peptide ratio values of 20 or greater were excluded (238 of 3256 [7.3%] at baseline; 159 of 2995 [5.3%] at discharge; 81 of 2209 [3.7%] at 30 days; and 75 of 2391 [3.1%] at 1 year) from further analyses due to nonlinearities detected at high values. Adjustments were made for baseline clinical factors (age, estimated glomerular filtration rate, atrial fibrillation, mean gradient, Society of Thoracic Surgeons score, and access route) and postprocedural complications out to 30 days (stroke, acute kidney injury, and moderate to severe aortic regurgitation) as well as, where indicated, a prior BNP ratio value. The covariate set was determined by stepwise model selection (with entry and stay criteria of P < .10) on cardiovascular death or rehospitalization between 30 days and 2 years. A list of all variables considered, determined by an a priori selection, is included in the eMethods in the Supplement. Associations between 30-day BNP ratio and change in BNP ratio from discharge to 30 days, Kansas City Cardiomyopathy Questionnaire, and 6-minute walk distance were assessed by analysis of covariance regression models, adjusting for the baseline values of those variables. The linear association between changes in BNP ratio and echocardiographic parameters are measured by Pearson correlation coefficients with 95% CIs based on Fisher z transformation. We further explored the association of changes in BNP ratio with follow-up echocardiographic parameters using analysis of covariance models, adjusting the baseline values. For this analysis, we categorized changes in BNP ratio in an unbiased fashion using the observed quartiles. Overall P values are reported along with pairwise comparisons between the groups with greatest and least changes. Statistical significance was set at a P value less than .05, and all P values were 2-tailed. A linear regression model was also used to identify factors associated with 30-day BNP ratio. The factors considered were baseline clinical characteristics, procedural factors, postprocedural complications, 30-day echocardiographic parameters, and 30-day medications that differed (P < .10) across quartiles of 30-day BNP ratio; baseline BNP ratio was forced into the model. All statistical analyses were performed with SAS version 9.4 (SAS Institute).
Results
Patient Population
After excluding 354 patients missing a BNP measurement for all time points and 545 patients because they were from sites performing NT-proBNP assays, a total of 3391 patients were included in the analysis from the PARTNER trials and registries, including the PARTNER IIA cohort (n = 859), PARTNER IIB cohort (n = 1000), SAPIEN 3 intermediate-risk registry (n = 594), and SAPIEN 3 high-risk registry (n = 938). A total of 1969 patients (58.1%) were male, and the mean (SD) age was 82 (7.5) years. B-type natriuretic peptide levels were recorded for 3018 patients (89.0%) at baseline, 2836 patients (83.6%) at discharge, 2128 patients (62.8%) at 30 days, and 2316 patients (68.3%) at 1 year. Table 1 shows various baseline characteristics, procedure and postprocedure factors, and echocardiographic parameters by quartile of 30-day BNP ratio. As quartile of 30-day BNP ratio increased, patients had more comorbidities, higher Society of Thoracic Surgeons scores, worse LV function, and a lower rate of transfemoral TAVR. eTable 2 in the Supplement shows the proportion of patients taking various cardiovascular medications at baseline and 30 days.
Table 1. Baseline Characteristics by 30-Day B-Type Natriuretic Peptide Ratio Quartile After Transcatheter Aortic Valve Replacementa.
| Characteristic | Mean (SD) | P value | |||
|---|---|---|---|---|---|
| Quartile 1 (lowest) (n = 534) | Quartile 2 (n = 529) | Quartile 3 (n = 533) | Quartile 4 (highest) (n = 532) | ||
| Baseline clinical characteristics | |||||
| Age, y | 80.7 (7.5) | 81.9 (6.9) | 82.1 (6.7) | 82.7 (7.0) | <.001 |
| Female, No. (%) | 256 (47.9) | 241 (45.6) | 225 (42.2) | 225 (42.3) | .17 |
| BMIb | 30.1 (6.6) | 28.4 (6.3) | 28.2 (6.1) | 27.7 (5.8) | <.001 |
| White, No./total No. (%) | 480/521 (92.1) | 490/519 (94.4) | 494/523 (94.5) | 480/514 (93.4) | .37 |
| Systolic blood pressure | 134.8 (19.5) | 136.3 (21.2) | 136.0 (20.7) | 131.8 (21.9) | .001 |
| eGFR | 70.9 (24.3) | 66.0 (22.8) | 62.8 (22.3) | 58.6 (19.7) | <.001 |
| Diabetes, No. (%) | 214 (40.1) | 180 (34.0) | 172 (32.3) | 186 (35.0) | .05 |
| Pulmonary disease, No. (%) | 221 (41.4) | 194 (36.7) | 194 (36.4) | 189 (35.5) | .19 |
| Oxygen dependence, No. (%) | 41 (7.7) | 27 (5.1) | 25 (4.7) | 28 (5.3) | .14 |
| Coronary artery disease, No. (%) | 401 (75.1) | 398 (75.2) | 433 (81.2) | 424 (79.7) | .03 |
| Prior MI, No. (%) | 69 (12.9) | 73 (13.8) | 84 (15.8) | 128 (24.1) | <.001 |
| Prior CABG, No. (%) | 125 (23.4) | 145 (27.4) | 168 (31.5) | 155 (29.1) | .03 |
| Prior PCI, No. (%) | 139 (26.0) | 140 (26.5) | 176 (33.0) | 176 (33.1) | .008 |
| Prior atrial fibrillation or flutter, No. (%) | 127 (23.8) | 178 (33.6) | 217 (40.7) | 245 (46.1) | <.001 |
| Prior TIA or stroke, No. (%) | 75 (14.0) | 91 (17.2) | 109 (20.5) | 109 (20.5) | .02 |
| STS PROM score | 5.7 (2.3) | 6.0 (2.4) | 6.4 (2.8) | 6.9 (3.2) | <.001 |
| NYHA class III or IV, No. (%) | 439 (82.2) | 417 (78.8) | 411 (77.1) | 413 (77.6) | .17 |
| Katz ADLs | 5.6 (0.9) | 5.7 (0.7) | 5.7 (0.7) | 5.7 (0.8) | .18 |
| 5-m walk, s | 7.8 (3.8) | 7.8 (4.0) | 7.6 (3.1) | 7.7 (3.2) | .63 |
| SAPIEN 3 valve, No. (%) | 337 (63.1) | 329 (62.2) | 340 (63.8) | 356 (66.9) | .41 |
| Transfemoral approach, No. (%) | 472 (88.4) | 463 (87.5) | 436 (81.8) | 444 (83.5) | .005 |
| Postprocedure complications | |||||
| Major vascular complication, No. (%) | 31 (5.8) | 37 (7.0) | 31 (5.8) | 24 (4.5) | .39 |
| Major bleeding, No. (%) | 91 (17.0) | 114 (21.6) | 119 (22.3) | 132 (24.8) | .02 |
| Stroke, No. (%) | 17 (3.2) | 14 (2.7) | 13 (2.4) | 15 (2.8) | .90 |
| Acute kidney injury, No. (%) | 40 (7.5) | 28 (5.3) | 51 (9.6) | 74 (13.9) | <.001 |
| Moderate or severe AR, No. (%) | 12 (2.3) | 20 (3.8) | 528 (6.4) | 36 (6.8) | .001 |
| Baseline echocardiographic parameters | |||||
| AVA, cm2 | 0.71 (0.18) | 0.69 (0.17) | 0.69 (0.16) | 0.67 (0.17) | <.001 |
| Mean gradient, mm Hg | 47.5 (13.7) | 46.6 (13.3) | 44.7 (13.1) | 44.0 (13.0) | <.001 |
| Peak velocity, m/s | 4.42 (0.60) | 4.38 (0.59) | 4.31 (0.60) | 4.27 (0.60) | <.001 |
| LV ejection fraction, % | 61.8 (9.5) | 60.0 (11.3) | 57.8 (12.1) | 52.5 (15.2) | <.001 |
| LV mass index, g/m2 | 112.0 (31.4) | 112.8 (32.7) | 117.8 (30.2) | 126.2 (35.1) | <.001 |
| LVESDi | 1.59 (0.33) | 1.67 (0.41) | 1.76 (0.41) | 1.91 (0.51) | <.001 |
| LVEDDi | 2.44 (0.33) | 2.50 (0.37) | 2.56 (0.37) | 2.67 (0.43) | <.001 |
| LAVi | 38.5 (13.5) | 41.5 (13.7) | 45.3 (14.4) | 47.2 (16.4) | <.001 |
| Normal RV function, No. (%) | 154/171 (90.1) | 151/178 (84.8) | 142/174 (81.6) | 115/153 (75.2) | .004 |
| Moderate or severe MR, No. (%) | 27 (5.5) | 49 (10.0) | 56 (11.2) | 73 (15.0) | <.001 |
| Moderate or severe AR, No. (%) | 40/517 (7.7) | 31/506 (6.1) | 42/520 (8.1) | 39/506 (7.7) | .64 |
| 30-d Echocardiographic parameters | |||||
| AVA, cm2 | 1.67 (0.40) | 1.64 (0.41) | 1.68 (0.41) | 1.63 (0.42) | .17 |
| Mean gradient, mm Hg | 11.5 (4.5) | 11.2 (4.9) | 10.6 (4.7) | 10.3 (4.1) | <.001 |
| Peak velocity, m/s | 2.30 (0.42) | 2.27 (0.43) | 2.22 (0.42) | 2.19 (0.41) | <.001 |
| LV ejection fraction, % | 62.0 (9.2) | 59.8 (10.3) | 57.7 (11.5) | 52.8 (14.4) | <.001 |
| LV mass index, g/m2 | 104.6 (29.4) | 108.8 (29.5) | 112.6 (28.5) | 123.5 (32.1) | <.001 |
| LVESDi | 1.57 (0.31) | 1.66 (0.36) | 1.73 (0.37) | 1.91 (0.48) | <.001 |
| LVEDDi | 2.44 (0.33) | 2.52 (0.34) | 2.57 (0.35) | 2.69 (0.41) | <.001 |
| LAVi | 37.3 (13.4) | 41.0 (13.5) | 45.1 (15.0) | 47.7 (16.4) | <.001 |
| Normal RV function, No. (%) | 148/170 (87.1) | 152/185 (82.2) | 132/167 (79.0) | 112/157 (71.3) | .004 |
| Moderate or severe MR, No. (%) | 17 (3.4) | 29 (5.7) | 51 (10.0) | 79 (16.5) | <.001 |
| Moderate or severe paravalvular AR, No. (%) | 15 (2.9) | 22 (4.3) | 39 (7.7) | 32 (6.3) | .004 |
Abbreviations: ADL, activities of daily living; AR, aortic regurgitation; AVA, aortic valve area; BMI, body mass index; CABG, coronary artery bypass surgery; eGFR, estimated glomerular filtration rate; LAVi, left atrial volume index; LV, left ventricle; LVEDDi, left ventricular end-diastolic dimension index; LVESDi, left ventricular end-systolic dimension index; MI, myocardial infarction; MR, mitral regurgitation; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; RV, right ventricular; STS PROM, Society of Thoracic Surgeons Predicted Risk of Mortality; TIA, transient ischemic attack.
Quartile 1 ranged from a B-type natriuretic peptide ratio of 0.07 to 1.17; quartile 2, 1.18 to 2.09; quartile 3, 2.10 to 4.05; and quartile 4, 4.06 to 19.99.
Calculated as weight in kilograms divided by height in meters squared.
BNP Values Before and After TAVR
Histograms of BNP ratio values at each time point are shown in eFigure 1 in the Supplement. For those alive at 1 year after TAVR, BNP ratio is reported over time according to quartile of baseline BNP ratio (eFigure 2 in the Supplement). Among these patients, while there was an overall decrease in mean (SD) BNP ratio from pre-TAVR measurement (4.09 [3.73]) to values at 30 days (3.16 [3.22]) and 1 year (2.88 [3.42]) after TAVR (P < .001 for trend), most patients had an elevated BNP ratio (greater than 1) at each time point, including 2820 of 3256 (86.6%) at baseline, 2652 of 2995 (88.5%) at discharge, 1779 of 2209 (80.5%) at 30 days, and 1799 of 2391 (75.2%) at 1 year.
Post-TAVR BNP Ratio and Clinical Outcomes
After multivariable adjustment including baseline BNP ratio, penalized spline curves show the association between a higher 30-day BNP ratio and an increased hazard for clinical events between 30 days and 2 years after TAVR (Figure 1). Similar associations were observed between a higher BNP ratio and an increased hazard of subsequent clinical events for BNP ratios measured at discharge and 1 year (eFigures 3 and 4 in the Supplement). In Cox proportional hazards models, a higher BNP ratio at 30 days after TAVR was associated with a higher adjusted hazard per 1-point increase of BNP ratio of all-cause death (adjusted hazard ratio [aHR], 1.11; 95% CI, 1.07-1.15; P < .001) between 30 days and 2 years, whereas baseline BNP ratio was not (Table 2). Similar adverse associations were observed between higher BNP ratio at 30 days and higher adjusted hazards of cardiovascular death (aHR, 1.16; 95% CI, 1.11-1.21) or rehospitalization (aHR, 1.08; 95% CI, 1.03-1.14) between 30 days and 2 years (Table 2). When these models were additionally adjusted for 30-day LV mass index and 30-day LV ejection fraction, the results were unchanged. Data for discharge and 1-year BNP ratio are also reported in Table 2. Kaplan-Meier event-free survival curves and aHRs for clinical events for each group based on quartile of BNP ratio at 30 days are shown in Figure 2. For each outcome, there was a progressive increase in the 30-day to 2-year event rate for increasing quartile of 30-day BNP ratio (Figure 2). After adjustment, compared with the first quartile, those in the highest quartile of 30-day BNP ratio had an increased hazard of 30-day to 2-year all-cause death (aHR, 3.34; 95% CI, 1.67-6.67; P < .001). Similar associations were observed for the other end points.
Figure 1. Adjusted Hazards of Clinical Events 2 Years After Transcatheter Aortic Valve Replacement by 30-Day B-Type Natriuretic Peptide (BNP) Ratio.
Cox proportional hazard models were performed using restricted cubic splines technique. The associations between 30-day post–transcatheter aortic valve replacement BNP ratio and clinical events from 30 days to 2 years are shown for all-cause death (A), cardiovascular death or rehospitalization (B), cardiovascular death (C), and rehospitalization (D). Multivariable models adjusted for age, estimated glomerular filtration rate, atrial fibrillation, mean aortic gradient, Society of Thoracic Surgeons score, access approach (transfemoral vs alternative), postprocedure stroke, acute kidney injury, and moderate to severe aortic regurgitation as well as baseline BNP level. Spline curves were truncated at a BNP ratio of 20. The dotted line indicates a BNP ratio of 1 at 30 days, which was assigned an adjusted hazard ratio of 1.0. Shaded areas indicate 95% CIs.
Table 2. Adjusted Hazard Ratios (aHRs) of Outcomes 2 Years After Transcatheter Aortic Valve Replacement by B-Type Natriuretic Peptide (BNP) Ratio at Various Time Pointsa.
| Time point | All-cause death | Cardiovascular death or rehospitalization | Cardiovascular death | Rehospitalization | ||||
|---|---|---|---|---|---|---|---|---|
| aHR (95% CI)b | P value | aHR (95% CI)b | P value | aHR (95% CI)b | P value | aHR (95% CI)b | P value | |
| Association of BNP ratio with outcome between discharge and 2 y | ||||||||
| BNP ratio at baseline per 1-point increase | 1.01 (0.98-1.04) | .48 | 1.00 (0.97-1.03) | .98 | 1.00 (0.96-1.04) | .99 | 0.99 (0.96-1.02) | .70 |
| BNP ratio at discharge per 1-point increase | 1.06 (1.02-1.09) | .003 | 1.06 (1.03-1.10) | <.001 | 1.10 (1.05-1.15) | <.001 | 1.07 (1.03-1.10) | <.001 |
| Association of BNP ratio with outcome between 30 d and 2 y | ||||||||
| BNP ratio at baseline per 1-point increase | 0.99 (0.96-1.02) | .59 | 1.01 (0.98-1.04) | .66 | 0.96 (0.92-1.01) | .13 | 1.03 (0.99-1.06) | .17 |
| BNP ratio at 30 d per 1-point increase | 1.11 (1.07-1.15) | <.001 | 1.10 (1.06-1.15) | <.001 | 1.16 (1.11-1.21) | <.001 | 1.08 (1.03-1.14) | .001 |
| Association of BNP ratio with outcome between 1 y and 2 y | ||||||||
| BNP ratio at baseline per 1-point increase | 1.01 (0.96-1.05) | .82 | 0.99 (0.94-1.03) | .58 | 0.99 (0.92-1.05) | .67 | 0.98 (0.93-1.04) | .52 |
| BNP ratio at 1 y per 1-point increase | 1.13 (1.08-1.19) | <.001 | 1.12 (1.07-1.18) | <.001 | 1.13 (1.06-1.21) | <.001 | 1.11 (1.05-1.19) | <.001 |
| Association of change in BNP ratio from discharge to 30 d with outcome between 30 d and 2 yc | ||||||||
| Change in BNP ratio at 30 d per 1-point decrease | 0.92 (0.88-0.96) | <.001 | 0.92 (0.89-0.97) | <.001 | 0.91 (0.86-0.96) | .001 | 0.92 (0.88-0.97) | .003 |
| Association of change in BNP ratio from 30 d to 1 y with outcome between 1 y and 2 yd | ||||||||
| Change in BNP ratio at 1 y per 1-point decrease | 0.93 (0.86-1.00) | .04 | 0.91 (0.83-0.98) | .02 | 0.94 (0.85-1.03) | .19 | 0.87 (0.78-0.96) | .005 |
| Association of BNP ratio at baseline with outcome within 2 ye | ||||||||
| BNP ratio at baseline per 1-point increase | 1.05 (1.02-1.07) | <.001 | 1.04 (1.03-1.06) | <.001 | 1.06 (1.04-1.09) | <.001 | 1.04 (1.02-1.06) | <.001 |
All multivariable models adjusted for age, estimated glomerular filtration rate, atrial fibrillation, mean aortic gradient, Society of Thoracic Surgeons score, access approach (transfemoral vs alternative), postprocedure stroke, acute kidney injury, and moderate to severe aortic regurgitation as well as baseline BNP level.
Adjusted hazard ratios were calculated per 1-point changes in BNP ratio.
Adjusted for discharge BNP ratio instead of baseline BNP ratio.
Adjusted for 30-day BNP ratio instead of baseline BNP ratio.
Did not adjust for any postprocedure factors.
Figure 2. Kaplan-Meier Event-Free Survival Curves by 30-Day B-Type Natriuretic Peptide Ratio Quartile After Transcatheter Aortic Valve Replacement.
Kaplan-Meier curves were constructed for all-cause death (A), cardiovascular (CV) death or rehospitalization (B), CV death (C), and rehospitalization (D) between 30 days and 2 years after transcatheter aortic valve replacement by 30-day B-type natriuretic peptide ratio quartile. Quartile 1 ranged from a B-type natriuretic peptide ratio of 0.07 to 1.17; quartile 2, 1.18 to 2.09; quartile 3, 2.10 to 4.05; and quartile 4, 4.06 to 19.99. Adjusted hazard ratios (aHRs) were adjusted for age, estimated glomerular filtration rate, atrial fibrillation, mean aortic gradient, Society of Thoracic Surgeons score, access approach (transfemoral vs alternative), postprocedure stroke, acute kidney injury, moderate to severe aortic regurgitation, and baseline B-type natriuretic peptide level.
Change in Post-TAVR BNP Ratio Between Time Points and Clinical Outcomes
Among patients with a BNP ratio of 2 or greater at discharge and 30 days, we evaluated the associations of change in BNP ratio from discharge to 30 days and from 30 days to 1 year, respectively, with subsequent clinical events. After adjustment for baseline and postprocedure factors and discharge BNP ratio, penalized spline curves show the association of change in BNP ratio between discharge and 30 days with clinical outcomes from 30 days to 2 years (eFigure 5 in the Supplement). For each outcome, an increase in BNP ratio between discharge and 30 days was associated with an increased adjusted hazard for clinical events, and a decrease in BNP ratio was associated with a decreased adjusted hazard for clinical events. Similar findings were observed when evaluating change in BNP ratio from 30 days to 1 year (eFigure 6 in the Supplement). In Cox proportional hazards models, a decrease in BNP ratio from discharge to 30 days was associated with a lower adjusted hazard per 1-point decrease of BNP ratio of all-cause death (aHR, 0.92; 95% CI, 0.88-0.96; P < .001) between 30 days and 2 years (Table 2). Similar associations were observed between a greater decrease in BNP ratio from discharge to 30 days and lower adjusted hazards of cardiovascular death or rehospitalization (as a composite outcome and individually) between 30 days and 2 years (Table 2). Kaplan-Meier event-free survival curves and aHRs for clinical events for groups based on quartile of change in BNP ratio between discharge and 30 days are shown in eFigure 7 in the Supplement.
Pre-TAVR BNP Ratio and Clinical Outcomes
An elevated pre-TAVR BNP ratio was associated with an increased adjusted hazard for clinical events out to 2 years after TAVR, but these associations were more modest than those observed for elevated post-TAVR values (Table 2) (eFigure 8 in the Supplement). When pre-TAVR and post-TAVR BNP ratios were both included in multivariable models, the hazard associated with increasing pre-TAVR BNP ratio usually became nonsignificant (Table 2).
Changes in BNP Ratio and Changes in Cardiac Structure and Function
Correlations between changes in BNP ratio and changes in indices of cardiac structure and function and valvular afterload are shown in Table 3 at both earlier (30 days) and later (1 year) time points after TAVR. A decrease in BNP ratio over time was significantly associated with improvement in LVEF and decrease in LV mass index and chamber dimensions. While these correlations were slightly stronger when evaluating changes between baseline and 1 year than when comparing baseline and 30 days, all the correlations were quite modest. While there was no significant correlation between change in BNP ratio and effective orifice area index (as an index of valvular afterload), there was a significant correlation between a decrease in BNP ratio and a decrease in transvalvular mean gradient (as an index that integrates valvular and vascular afterload and ventricular function). There was no significant correlation between change in BNP ratio and change in estimated glomerular filtration rate over time. To complement data in Table 3, indices of cardiac structure and function and valvular afterload are reported in eTable 3 in the Supplement according to quartile of change in BNP ratio between baseline and 30 days and between baseline and 1 year. eTable 4 in the Supplement shows the univariable and multivariable associations between clinical and echocardiographic factors and 30-day BNP ratio.
Table 3. Correlation Between Changes in B-Type Natriuretic Peptide (BNP) Ratio From Baseline and Left Ventricular Structure and Function and Valvular Afterload Over Time.
| Characteristic | Change in BNP ratio from baseline to 30 d | Change in BNP ratio from baseline to 1 y | ||||
|---|---|---|---|---|---|---|
| No. | r (95% CI) | P value | No. | r (95% CI) | P value | |
| LVEF | 1915 | −0.16 (−0.20 to −0.12) | <.001 | 1967 | −0.31 (−0.35 to −0.27) | <.001 |
| LVMi | 1664 | 0.10 (0.05 to 0.14) | <.001 | 1684 | 0.13 (0.08 to 0.18) | <.001 |
| LVESDi | 1699 | 0.10 (0.05 to 0.15) | <.001 | 1712 | 0.24 (0.20 to 0.29) | <.001 |
| LVEDDi | 1752 | 0.08 (0.03 to 0.12) | .001 | 1745 | 0.17 (0.12 to 0.21) | <.001 |
| LAVi | 1608 | 0.04 (−0.004 to 0.09) | .07 | 1535 | 0.13 (0.08 to 0.18) | <.001 |
| AV mean gradient | 1915 | 0.14 (0.10 to 0.19) | <.001 | 1969 | 0.12 (0.08 to 0.16) | <.001 |
| EOAi | 1754 | −0.04 (−0.09 to 0.01) | .08 | 1777 | −0.04 (−0.09 to 0.01) | .08 |
Abbreviations: AV, aortic valve; EOAi; effective orifice area index; LAVi, left atrial volume index; LVEDDi, left ventricular end-diastolic dimension index; LVEF, left ventricular ejection fraction; LVESDi, left ventricular end-systolic dimension index; LVMi, left ventricular mass index.
Quality of Life and 6-Minute Walk Test
Higher BNP ratio at 30 days and 1 year were associated with worse quality of life at 30 days and 1 year, respectively (eTable 5 in the Supplement). Further, greater decreases in BNP ratio between discharge and 30 days and between 30 days and 1 year were associated with better quality of life at 30 days and 1 year, respectively (eTable 5 in the Supplement). Similar associations were observed between BNP ratio and 6-minute walk distance (eTable 6 in the Supplement).
Discussion
Among patients with severe symptomatic AS at intermediate, high, or prohibitive risk for surgery who were treated with TAVR, we showed that higher BNP levels at discharge, 30 days, and 1 year were each independently associated with higher subsequent mortality and rehospitalization rates. After adjustment, every 1-point increase in BNP ratio at 30 days (approximately equivalent to an increase of 100 pg/mL in BNP level) was associated with 11% higher risk of all-cause death, 16% higher risk of cardiovascular death, and 8% higher risk of rehospitalization at 2 years. At discharge and 30 days, 2044 of 2995 patients (68.2%) and 1185 of 2209 patients (53.6%), respectively, had an elevated BNP ratio of 2 or greater. Among those with an elevated BNP ratio at discharge and 30 days, greater decreases in BNP levels at 30 days and 1 year, respectively, were associated with lower subsequent mortality and rehospitalization rates. Analogous to the associations with clinical events, higher BNP ratio values at 30 days and 1 year were associated with worse quality of life and shorter 6-minute walk distance at 30 days and 1 year, respectively, and greater decreases in BNP ratio during follow-up were associated with better quality of life and longer 6-minute walk distances. Collectively, these findings demonstrate that most patients have residual BNP elevation after TAVR despite mechanical unloading of the heart and that this is associated with more clinical events and worse quality of life and functional capacity. Further investigation is warranted to understand these findings and determine whether steps taken to mitigate the pathobiology resulting in elevated BNP levels after TAVR may improve patient outcomes.
While much attention has been paid to natriuretic peptide levels as a predictor of outcomes before an intervention, less emphasis has been placed on their utility following an intervention. We demonstrate that elevated natriuretic peptide levels early after TAVR are common and independently associated with subsequent clinical events and that a decrease in BNP between follow-up time periods portends a better clinical outcome. These findings highlight that although valve replacement is necessary for patients with AS, even after unloading the heart with valve replacement, many patients have ongoing elevations in BNP level, which has untoward consequences. Our findings are consistent with non-AS trials in patients with chronic heart failure in which the amount of natriuretic peptide decrease was associated with subsequent clinical outcomes.23,24,25
While the mechanisms underlying an elevated BNP level in patients with AS recently treated with TAVR are likely similar to and shared with other patients with heart failure, there is undoubtedly some distinctive pathophysiology stemming from the presence of longstanding marked pressure overload from valve obstruction that is suddenly relieved by valve replacement. The maladaptive hypertrophic remodeling and impaired systolic and diastolic function that develop in the setting of chronic pressure overload from AS often do not reverse and normalize after valve replacement alone, leaving many patients who previously had heart failure due to valve disease now with a more common, albeit heterogeneous, form of heart failure with preserved or reduced ejection fraction.18,26,27,28 An elevated BNP level after TAVR is likely the result of many factors, including residual cardiac hypertrophy and fibrosis, impaired cardiac function, volume overload, increased vascular load, hypertension, and sympathetic system activation, among others.18,26,27,28,29 Prior studies in patients with heart failure with reduced ejection fraction have linked changes in natriuretic peptide levels with changes in cardiac structure and function.30,31 There were modest but significant correlations between decrease in BNP ratio and improvement in LV function as well as decrease in LV mass index and chamber dimensions over time. Notably, though, the adverse associations between higher BNP ratio at 30 days and higher hazards of clinical events between 30 days and 2 years persisted after adjustment for LV ejection fraction and mass at 30 days. It is likely that there are drivers of elevated BNP levels that are not fully captured by echocardiographic indices.
Our data provide a biomarker lens through which to see the residual risk associated with heart failure after TAVR. Although unloading the heart with valve replacement can reverse the pathophysiology and manifestations of heart failure for patients with AS, this reversal is often incomplete, yielding substantial residual risk related to ongoing heart failure. A large minority of patients treated with TAVR have residual heart failure symptoms and poor quality of life after the procedure.32,33 Heart failure is the most common admitting diagnosis during the first year after TAVR, with rates only slightly lower compared with the year before TAVR.34,35
Given the adverse association of an elevated BNP level after TAVR with worse clinical outcomes, 2 questions arise: How might elevations in BNP level after TAVR be mitigated? Will efforts to target pathobiology driving BNP elevations after TAVR improve clinical outcomes? To be clear, the objective is not to target and reduce BNP levels per se; rather, the potential therapeutic target(s) is the abnormal and deleterious underlying pathobiology—maladaptive hypertrophy, abnormal LV function, increased wall stress, and volume overload—that results in BNP release. Mitigation of post-TAVR elevations in BNP could potentially be influenced by more optimal timing of valve replacement (perhaps before more advanced maladaptive hypertrophic remodeling has occurred) and by medical therapy. Studies examining reverse LV hypertrophic remodeling after valve replacement demonstrate that while, for example, LV hypertrophy regresses, it does not return to normal in a large percentage of patients.18,36 Perhaps earlier valve replacement in hearts that have greater plasticity could yield more complete reversal of LV hypertrophy and, alongside, less residual elevation in BNP. This hypothesis can be evaluated in ongoing strategy trials testing the optimal timing of valve replacement in patients with severe asymptomatic AS. With respect to medical therapy, there are now several retrospective analyses pointing to a potential benefit of renin-angiotensin system inhibition after TAVR, which may serve to decrease BNP levels.37,38 The ongoing Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation (RASTAVI) randomized clinical trial39 is testing this hypothesis. Whether renin-angiotensin system inhibition or some other medical therapy would benefit all patients after valve replacement or only those with evidence of residual heart failure—perhaps indicated, in part, by persistent elevation in BNP levels—should also be studied.
Limitations
Our study has several limitations that must be considered. Site clinical laboratories were used for BNP measurements, and assays used to measure BNP varied across sites. However, most sites used an assay with a consistent upper limit of normal (100 pg/mL). To minimize the impact of assay variability, we used BNP ratio as our primary analytic variable, which normalized the absolute BNP measurement for the upper limit of normal value for the assay used at the site. Patients without a BNP measurement at any time point were excluded from our analysis. While patients without a BNP measurement may have been doing better clinically perhaps with less cause to measure BNP, the trial and registry protocols required measurement of BNP at all the time points we examined, thus reducing the likelihood that this would influence our findings. Further, to minimize confounding from treating NT-proBNP values as BNP values, we excluded patients from sites where NT-proBNP data were submitted for some patients. However, these exclusions only removed approximately one-fifth of patients otherwise eligible for this analysis. We lack information on how the BNP values were interpreted and acted on. Data on medication changes were not systematically and consistently obtained at all time points across all the PARTNER trials and registries. To minimize heterogeneity in our study cohort, we did not include those treated with surgical aortic valve replacement or valve-in-valve TAVR, limiting the generalizability to those patients. As expected, the baseline characteristics indicated that patients in higher BNP quartiles were sicker; despite multivariable adjustment, unmeasured confounders could have influenced our results. However, the strength of the associations observed make it less likely that they were spurious. Our findings may not be generalizable to lower-risk, less symptomatic patients. Additionally, survival bias could have influenced our landmark analyses, particularly those examining the association between BNP levels at 30 days or 1 year and subsequent outcomes.
Conclusions
In this study, despite mechanical unloading of the heart with TAVR in patients with AS, most patients had a residual elevation in BNP, and this was associated with increased subsequent mortality and rehospitalizations. Among those with elevated natriuretic peptide levels early after TAVR, a decrease in BNP levels during follow-up was associated with improved clinical outcomes. Whether efforts to mitigate the pathobiology that results in elevated BNP levels after TAVR, either through earlier timing of valve replacement or intensification of medical therapy after TAVR, will yield better clinical outcomes requires further study.
eMethods.
eFigure 1. BNP ratio values at various time points.
eFigure 2. Change in mean BNP ratio with time by quartile.
eFigure 3. Discharge BNP ratio and outcomes from discharge to 2 years.
eFigure 4. 1-year BNP ratio and outcomes from 1 to 2 years.
eFigure 5. Change in BNP ratio from discharge to 30 days and outcomes from 30 days to 2 years.
eFigure 6. Change in BNP ratio from 30 days to 1 year and outcomes from 1 to 2 years.
eFigure 7. Event rates from 30 days to 2 years by quartile of change in BNP ratio from discharge to 30 days after TAVR.
eFigure 8. Baseline (pre-TAVR) BNP ratio and outcomes at 2 years.
eTable 1. Site information on BNP assay and upper limit of normal.
eTable 2. Medications at baseline and 30 days based on quartile of BNP ratio at 30 days.
eTable 3. Association between follow-up measures of cardiac structure and function and valvular afterload and changes in BNP from baseline over time.
eTable 4. Factors associated with 30-day BNP ratio.
eTable 5. BNP ratio and quality of life.
eTable 6. BNP ratio and 6-minute walk distance.
References
- 1.Smith JG, Newton-Cheh C, Almgren P, et al. Assessment of conventional cardiovascular risk factors and multiple biomarkers for the prediction of incident heart failure and atrial fibrillation. J Am Coll Cardiol. 2010;56(21):1712-1719. doi: 10.1016/j.jacc.2010.05.049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Januzzi JL Jr, Sakhuja R, O’donoghue M, et al. Utility of amino-terminal pro–brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Arch Intern Med. 2006;166(3):315-320. doi: 10.1001/archinte.166.3.315 [DOI] [PubMed] [Google Scholar]
- 3.Anand IS, Fisher LD, Chiang YT, et al. ; Val-HeFT Investigators . Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107(9):1278-1283. doi: 10.1161/01.CIR.0000054164.99881.00 [DOI] [PubMed] [Google Scholar]
- 4.Lerman A, Gibbons RJ, Rodeheffer RJ, et al. Circulating N-terminal atrial natriuretic peptide as a marker for symptomless left-ventricular dysfunction. Lancet. 1993;341(8853):1105-1109. doi: 10.1016/0140-6736(93)93125-K [DOI] [PubMed] [Google Scholar]
- 5.Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation. 1994;90(1):195-203. doi: 10.1161/01.CIR.90.1.195 [DOI] [PubMed] [Google Scholar]
- 6.Bergler-Klein J, Klaar U, Heger M, et al. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation. 2004;109(19):2302-2308. doi: 10.1161/01.CIR.0000126825.50903.18 [DOI] [PubMed] [Google Scholar]
- 7.Clavel MA, Malouf J, Michelena HI, et al. B-type natriuretic peptide clinical activation in aortic stenosis: impact on long-term survival. J Am Coll Cardiol. 2014;63(19):2016-2025. doi: 10.1016/j.jacc.2014.02.581 [DOI] [PubMed] [Google Scholar]
- 8.Lindman BR, Breyley JG, Schilling JD, et al. Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement. Heart. 2015;101(17):1382-1388. doi: 10.1136/heartjnl-2015-307742 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Monin JL, Lancellotti P, Monchi M, et al. Risk score for predicting outcome in patients with asymptomatic aortic stenosis. Circulation. 2009;120(1):69-75. doi: 10.1161/CIRCULATIONAHA.108.808857 [DOI] [PubMed] [Google Scholar]
- 10.Lindman BR, Dweck MR, Lancellotti P, et al. Management of asymptomatic severe aortic stenosis: evolving concepts in timing of valve replacement. JACC Cardiovasc Imaging. 2020;13(2, pt 1):481-493. doi: 10.1016/j.jcmg.2019.01.036 [DOI] [PubMed] [Google Scholar]
- 11.Leon MB, Smith CR, Mack MJ, et al. ; PARTNER 2 Investigators . Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374(17):1609-1620. doi: 10.1056/NEJMoa1514616 [DOI] [PubMed] [Google Scholar]
- 12.Webb JG, Doshi D, Mack MJ, et al. A randomized evaluation of the SAPIEN XT transcatheter heart valve system in patients with aortic stenosis who are not candidates for surgery. JACC Cardiovasc Interv. 2015;8(14):1797-1806. doi: 10.1016/j.jcin.2015.08.017 [DOI] [PubMed] [Google Scholar]
- 13.Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet. 2016;387(10034):2218-2225. doi: 10.1016/S0140-6736(16)30073-3 [DOI] [PubMed] [Google Scholar]
- 14.Herrmann HC, Thourani VH, Kodali SK, et al. ; PARTNER Investigators . One-year clinical outcomes with SAPIEN 3 transcatheter aortic valve replacement in high-risk and inoperable patients with severe aortic stenosis. Circulation. 2016;134(2):130-140. doi: 10.1161/CIRCULATIONAHA.116.022797 [DOI] [PubMed] [Google Scholar]
- 15.Douglas PS, Waugh RA, Bloomfield G, et al. Implementation of echocardiography core laboratory best practices: a case study of the PARTNER I trial. J Am Soc Echocardiogr. 2013;26(4):348-358.e3. doi: 10.1016/j.echo.2013.01.013 [DOI] [PubMed] [Google Scholar]
- 16.Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1-39.e14. doi: 10.1016/j.echo.2014.10.003 [DOI] [PubMed] [Google Scholar]
- 17.Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60(15):1438-1454. doi: 10.1016/j.jacc.2012.09.001 [DOI] [PubMed] [Google Scholar]
- 18.Lindman BR, Stewart WJ, Pibarot P, et al. Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations. JACC Cardiovasc Interv. 2014;7(6):662-673. doi: 10.1016/j.jcin.2014.02.011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Reynolds MR, Magnuson EA, Wang K, et al. ; PARTNER Trial Investigators . Health-related quality of life after transcatheter or surgical aortic valve replacement in high-risk patients with severe aortic stenosis: results from the PARTNER (Placement of Aortic Transcatheter Valve) trial (cohort A). J Am Coll Cardiol. 2012;60(6):548-558. doi: 10.1016/j.jacc.2012.03.075 [DOI] [PubMed] [Google Scholar]
- 20.Arnold SV, Spertus JA, Lei Y, et al. Use of the Kansas City Cardiomyopathy Questionnaire for monitoring health status in patients with aortic stenosis. Circ Heart Fail. 2013;6(1):61-67. doi: 10.1161/CIRCHEARTFAILURE.112.970053 [DOI] [PubMed] [Google Scholar]
- 21.Lindman BR, Clavel MA, Abu-Alhayja’a R, et al. Multimarker approach to identify patients with higher mortality and rehospitalization rate after surgical aortic valve replacement for aortic stenosis. JACC Cardiovasc Interv. 2018;11(21):2172-2181. doi: 10.1016/j.jcin.2018.07.039 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Eilers PHC, Marx BD. Flexible smoothing with B-splines and penalties. Stat Sci. 1996;11(2):89-102. doi: 10.1214/ss/1038425655 [DOI] [Google Scholar]
- 23.Januzzi JL Jr, Ahmad T, Mulder H, et al. Natriuretic peptide response and outcomes in chronic heart failure with reduced ejection fraction. J Am Coll Cardiol. 2019;74(9):1205-1217. doi: 10.1016/j.jacc.2019.06.055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Myhre PL, Vaduganathan M, Claggett B, et al. B-type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol. 2019;73(11):1264-1272. doi: 10.1016/j.jacc.2019.01.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Zile MR, Claggett BL, Prescott MF, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol. 2016;68(22):2425-2436. doi: 10.1016/j.jacc.2016.09.931 [DOI] [PubMed] [Google Scholar]
- 26.Kafa R, Kusunose K, Goodman AL, et al. Association of abnormal postoperative left ventricular global longitudinal strain with outcomes in severe aortic stenosis following aortic valve replacement. JAMA Cardiol. 2016;1(4):494-496. doi: 10.1001/jamacardio.2016.1132 [DOI] [PubMed] [Google Scholar]
- 27.Chin CWL, Everett RJ, Kwiecinski J, et al. Myocardial fibrosis and cardiac decompensation in aortic stenosis. JACC Cardiovasc Imaging. 2017;10(11):1320-1333. doi: 10.1016/j.jcmg.2016.10.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Weidemann F, Herrmann S, Störk S, et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation. 2009;120(7):577-584. doi: 10.1161/CIRCULATIONAHA.108.847772 [DOI] [PubMed] [Google Scholar]
- 29.Yotti R, Bermejo J, Gutiérrez-Ibañes E, et al. Systemic vascular load in calcific degenerative aortic valve stenosis: insight from percutaneous valve replacement. J Am Coll Cardiol. 2015;65(5):423-433. doi: 10.1016/j.jacc.2014.10.067 [DOI] [PubMed] [Google Scholar]
- 30.Daubert MA, Adams K, Yow E, et al. NT-proBNP goal achievement is associated with significant reverse remodeling and improved clinical outcomes in HFrEF. JACC Heart Fail. 2019;7(2):158-168. doi: 10.1016/j.jchf.2018.10.014 [DOI] [PubMed] [Google Scholar]
- 31.Januzzi JL Jr, Prescott MF, Butler J, et al. ; PROVE-HF Investigators . Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA. 2019;322(11):1085-1095. doi: 10.1001/jama.2019.12821 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Arnold SV, Afilalo J, Spertus JA, et al. ; U.S. CoreValve Investigators . Prediction of poor outcome after transcatheter aortic valve replacement. J Am Coll Cardiol. 2016;68(17):1868-1877. doi: 10.1016/j.jacc.2016.07.762 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Lindman BR, Alexander KP, O’Gara PT, Afilalo J. Futility, benefit, and transcatheter aortic valve replacement. JACC Cardiovasc Interv. 2014;7(7):707-716. doi: 10.1016/j.jcin.2014.01.167 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Vemulapalli S, Dai D, Hammill BG, et al. Hospital resource utilization before and after transcatheter aortic valve replacement: the STS/ACC TVT registry. J Am Coll Cardiol. 2019;73(10):1135-1146. doi: 10.1016/j.jacc.2018.12.049 [DOI] [PubMed] [Google Scholar]
- 35.Kolte D, Khera S, Sardar MR, et al. Thirty-day readmissions after transcatheter aortic valve replacement in the United States: insights from the Nationwide Readmissions Database. Circ Cardiovasc Interv. 2017;10(1):e004472. doi: 10.1161/CIRCINTERVENTIONS.116.004472 [DOI] [PubMed] [Google Scholar]
- 36.Rader F, Sachdev E, Arsanjani R, Siegel RJ. Left ventricular hypertrophy in valvular aortic stenosis: mechanisms and clinical implications. Am J Med. 2015;128(4):344-352. doi: 10.1016/j.amjmed.2014.10.054 [DOI] [PubMed] [Google Scholar]
- 37.Inohara T, Manandhar P, Kosinski AS, et al. Association of renin-angiotensin inhibitor treatment with mortality and heart failure readmission in patients with transcatheter aortic valve replacement. JAMA. 2018;320(21):2231-2241. doi: 10.1001/jama.2018.18077 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Ochiai T, Saito S, Yamanaka F, et al. Renin-angiotensin system blockade therapy after transcatheter aortic valve implantation. Heart. 2018;104(8):644-651. doi: 10.1136/heartjnl-2017-311738 [DOI] [PubMed] [Google Scholar]
- 39.Amat-Santos IJ, Catalá P, Diez Del Hoyo F, et al. Impact of renin-angiotensin system inhibitors on clinical outcomes and ventricular remodelling after transcatheter aortic valve implantation: rationale and design of the RASTAVI randomised multicentre study. BMJ Open. 2018;8(2):e020255. doi: 10.1136/bmjopen-2017-020255 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods.
eFigure 1. BNP ratio values at various time points.
eFigure 2. Change in mean BNP ratio with time by quartile.
eFigure 3. Discharge BNP ratio and outcomes from discharge to 2 years.
eFigure 4. 1-year BNP ratio and outcomes from 1 to 2 years.
eFigure 5. Change in BNP ratio from discharge to 30 days and outcomes from 30 days to 2 years.
eFigure 6. Change in BNP ratio from 30 days to 1 year and outcomes from 1 to 2 years.
eFigure 7. Event rates from 30 days to 2 years by quartile of change in BNP ratio from discharge to 30 days after TAVR.
eFigure 8. Baseline (pre-TAVR) BNP ratio and outcomes at 2 years.
eTable 1. Site information on BNP assay and upper limit of normal.
eTable 2. Medications at baseline and 30 days based on quartile of BNP ratio at 30 days.
eTable 3. Association between follow-up measures of cardiac structure and function and valvular afterload and changes in BNP from baseline over time.
eTable 4. Factors associated with 30-day BNP ratio.
eTable 5. BNP ratio and quality of life.
eTable 6. BNP ratio and 6-minute walk distance.
