- Email: [email protected]
Effect of B-type Natriuretic Peptides on Long-Term Outcomes After Transcatheter Aortic Valve Implantation
Effect of B-type Natriuretic Peptides on Long-Term Outcomes After Transcatheter Aortic Valve Implantation Konstantinos C. Koskinas, MDa, Crochan J. O’Sullivan, MDa, Dik Heg, PhDb, Fabien Praz, MDa, Stefan Stortecky, MDa, Thomas Pilgrim, MDa, Lutz Buellesfeld, MDa, Peter Jüni, MDc, Stephan Windecker, MDa,*, and Peter Wenaweser, MDa B-type natriuretic peptide (BNP) levels are elevated in patients with aortic stenosis (AS) and decrease acutely after replacement of the stenotic valve. The long-term prognostic value of BNP after transcatheter aortic valve implantation (TAVI) and the relative prognostic utility of single versus serial peri-interventional measurements of BNP and N-terminal prohormone BNP (NT-pro-BNP) are unknown. This study sought to determine the impact of BNP levels on long-term outcomes after TAVI and to compare the utility of BNP versus NT-pro-BNP measured before and after intervention. We analyzed 340 patients with severe AS and baseline pre-TAVI assessment of BNP. In 219 patients, BNP and NT-pro-BNP were measured serially before and after intervention. Clinical outcomes over 2 years were recorded. Patients with high baseline BNP (higher tertile ‡591 pg/ml) had increased risk of all-cause mortality (adjusted hazard ratio 3.16, 95% confidence interval 1.84 to 5.42; p <0.001) and cardiovascular death at 2 years (adjusted hazard ratio 3.37, 95% confidence interval 1.78 to 6.39; p <0.001). Outcomes were most unfavorable in patients with persistently high BNP before and after intervention. Comparing the 2 biomarkers, NT-pro-BNP levels measured after TAVI showed the highest prognostic discrimination for 2-year mortality (area under the curve 0.75; p <0.01). Baseline-to-discharge reduction, but not baseline levels of BNP, was related to New York Heart Association functional improvement. In conclusion, high preintervention BNP independently predicts 2-year outcomes after TAVI, particularly when elevated levels persist after the intervention. BNP and NT-pro-BNP and their serial periprocedural changes provide complementary prognostic information for symptomatic improvement and survival. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;116:1560e1565) Transcatheter aortic valve implantation (TAVI) has evolved into a reliable treatment method in high-risk or inoperable patients with severe, symptomatic aortic stenosis (AS).1e3 B-type natriuretic peptide (BNP) and N-terminal prohormone BNP (NT-pro-BNP) increase in response to pressure or volume overload of the myocardium and are established as powerful predictors of adverse outcomes across the spectrum of cardiovascular disease.4 The possible predictive value of natriuretic peptides (NPs) has been previously examined in patients treated with TAVI,5e13 but important unaddressed issues were raised. First, previous findings were discordant with some studies reporting no independent impact of NP elevation on outcomes after TAVI.6,12 Second, previous studies were limited by relatively small patient numbers and shorter duration of follow-up. Third, although NPs undergo substantial changes immediately after replacement of the stenotic valve,10,14 previous reports focused on the prognostic a Department of Cardiology, Bern University Hospital, Bern, Switzerland; bInstitute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; and cInstitute of Primary Health Care, University of Bern, Bern, Switzerland. Manuscript received May 2, 2015; revised manuscript received and accepted August 4, 2015. See page 1564 for disclosure information. *Corresponding author: Tel: (þ41) 31 632 4497; fax: (þ41) 31 632 4771. E-mail address: [email protected] (S. Windecker).
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.016
impact of preintervention measurements or measurements obtained later during patient follow-up. Although serial reductions of NPs after therapeutic interventions provide incremental prognostic information in patients with heart failure15e17 and acute coronary syndromes,18,19 the relative predictive utility of BNP measured before versus early after TAVI has not been defined. Against this background, the purpose of this study was to determine the long-term prognostic impact of BNP and to compare the predictive value of pre and postintervention levels and of early periprocedural changes of BNP versus NT-pro-BNP in patients with severe AS who underwent TAVI. Methods This is a retrospective analysis of prospectively collected data. All patients with severe native-valve AS (defined as indexed aortic valve area [AVA] 0.6 cm2/m2 or mean gradient >40 mm Hg) who underwent TAVI at our institution from August 2007 to August 2012 were entered into a dedicated database. Of 500 consecutive patients treated with TAVI, 340 patients with measurement of BNP within 7 days before the intervention were included in the present analysis. The study conforms to the guiding principles of the Declaration of Helsinki and was approved by the local Ethics Committee. All patients provided written informed consent for prospective follow-up. www.ajconline.org
Valvular Heart Disease/Natriuretic Peptides and Prognosis After TAVI
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Table 1 Baseline characteristics of the study population All patients (n¼340)
Variable
Age (years) Female Body mass index (kg/m2) Cardiovascular risk factors Diabetes mellitus Hypercholesterolemia Arterial hypertension Medical history Previous myocardial infarction Previous PCI Renal failure (GFR<60ml/min/1.73m2) Chronic obstructive pulmonary disease Atrial fibrillation Functional class NYHA III/IV Risk assessment Logistic EuroScore STS Score Hemodynamic variables Aortic valve area (cm2) Indexed aortic valve area (cm2 /m2) Mean aortic valve gradient (mmHg) Peak aortic valve gradient (mmHg) Echocardiographic variables LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV ejection fraction (%) Natriuretic peptides BNP, pg/ml NT-pro-BNP, pg/ml
Baseline BNP
P value
Low (n¼227)
High (n¼113)
83.2 4.8 195 (57%) 26.7 5.1
82.9 4.8 143 (63%) 27.7 4.9
83.6 4.7 54 (48%) 24.5 4.3
0.10 0.05 <0.001
91 (27%) 207 (61%) 278 (82%)
62 (28%) 142 (62%) 188 (83%)
29 (26%) 65 (58%) 90 (80%)
0.48 0.32 0.71
53 (16%) 81 (24%) 227 (67%) 56 (16%) 94/310 (30%)
28 (12%) 51 (22%) 136 (60%) 44 (19%) 54/205 (26%)
25 (22%) 30 (27%) 91 (81%) 12 (11%) 40/105 (38%)
0.004 0.91 <0.001 0.023 0.037
224 (66%)
138 (61%)
86 (77%)
<0.001
23.0 13.5 6.3 4.1
19.3 11.2 5.8 4.0
30.2 14.8 7.4 4.1
<0.001 <0.001
0.13 0.13 0.28 0.32
0.60 0.33 44.2 69.3
0.22 0.12 17.4 25.7
0.61 0.34 44.9 70.7
0.21 0.12 16.6 24.3
48.9 9.9 34.6 12.4 53.0 15.3
45.4 7.9 28.2 7.5 60.2 10.3
605.7 787.6 5453.2 8059.6
214.9 145.6 1833.3 1830
0.57 0.31 42.7 66.9
0.22 0.12 18.9 27.9
50.9 10.4 38.0 13.2 45.9 16.2 1390.7 950.5 12908.3 10481
0.007 <0.001 <0.001 <0.001 <0.001
BNP ¼ B-type natriuretic peptide; GFR ¼ glomerular filtration rate; LV ¼ left ventricular; NT-pro-BNP ¼ amino-terminal pro-BNP; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; STS ¼ Society of Thoracic Surgeons.
Table 2 Procedural characteristics Variable
Access route Femoral Apical Subclavian Valve type Medtronic CoreValve Edwards Sapien XT Valve Revascularization Concomitant PCI Procedural complications Access vessel complication Moderate/severe (grade 2) post-procedure AR Severe (grade 3) post-procedure AR
Baseline BNP
P value
Low (n¼227)
High (n¼113)
210 (93%) 16 (7%) 1 (0%)
99 (88%) 11 (10%) 3 (3%)
0.16 0.40 0.11
135 (59%) 92 (41%)
78 (69%) 35 (31%)
0.096 0.096
40 (18%)
24 (21%)
0.46
21 (9%) 27 (12%)
9 (8%) 17 (15%)
0.84 0.80
1 (0%)
0 (0%)
1.00
AR ¼ aortic regurgitation; PCI ¼ percutaneous coronary intervention.
Patients underwent right and left heart catheterization for hemodynamic assessment before TAVI. Aortic valve gradients were measured by pullback technique from the left ventricle to the ascending aorta. Calculation of the AVA was derived from the Gorlin equation and was indexed by body surface area.20,21 Standardized transthoracic echocardiographic examination was performed before TAVI, and left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson method. Severity of aortic valve regurgitation was evaluated using spectral and color Doppler images and semiquantitatively graded as mild, moderate, and severe according to guidelines.20,22 TAVI was performed using standard techniques.20,21 Vascular access was transfemoral using the Medtronic CoreValve Revalving System (Medtronic, Inc., Minneapolis, Minnesota) or the Edwards SAPIEN XT valve (Edwards Lifesciences, Irvine, California), transapical for Edwards SAPIEN XT, or trans-subclavian using the Medtronic CoreValve prosthesis. BNP was measured in 340 patients before intervention on hospital admission (1.5 1.3 days before TAVI) using a chemiluminescent microparticle immunoassay (ARCHITECT BNP assay; Abbott Laboratories Diagnostics Division, Abbott
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Table 3 Clinical outcomes at 2 years in patients with low or high baseline levels of BNP Outcome
Baseline BNP Low (n¼227)
High (n¼113)
Death 40 (18.9%) 41 (37.4%) Cardiovascular 22 (10.7%) 33 (31.2%) death Myocardial 5 (2.3%) 3 (3.3%) infarction Stroke 5 (2.5%) 11 (10.8%) Death, myocardial 46 (21.5%) 46 (41.7%) infarction or stroke
Adjusted Hazard Ratio (95% CI)
P value
3.16 (1.84-5.42) 3.37 (1.78-6.39)
<0.001 <0.001
0.61 (0.11-3.42)
0.57
8.44 (2.67-26.67) <0.001 2.61 (1.50-4.55) 0.001
Presented are counts with % incidence rates from life-table estimates.
Figure 1. KaplaneMeier graphs of the cumulative incidence of all-cause mortality (A) and cardiovascular death at 2 years (B) in patients with low versus high baseline (pre-TAVI) BNP.
Park, Illinois). In addition, BNP levels were measured in 253 patients, and both BNP and NT-pro-BNP were measured in 219 patients, after the intervention (on the days of discharge, 6.3 2.8 days after TAVI). Patients were followed throughout 2 years, and no patient was lost to follow-up. Adverse cardiac and cerebrovascular events were assessed in hospital, and regular follow-up was performed at 1 month, 1 year, and 2 years by means of
a clinical visit or a standardized telephone interview. All events were adjudicated by a clinical event committee. An academic clinical trials unit (CTU Bern, Bern University Hospital, Switzerland) was responsible for central data audits and maintenance of the dedicated database. Clinical end points were defined according to the Valve Academic Research Consortium (VARC)-2 criteria.23 Primary end points were all-cause and cardiovascular death at 2 years. Secondary end points included the VARC-2edefined clinical efficacy end point (composite of all-cause death, stroke, hospitalizations for valve-related symptoms or worsening congestive heart failure, New York Heart Association [NYHA] class III or IV, and valve-related dysfunction defined as mean aortic valve gradient >20 mm Hg, effective orifice area <0.9 to 1.1 cm2, Doppler velocity index <0.35 m/sec, and/or moderate or severe prosthetic valve regurgitation). Because repeat hospitalizations were consistently recorded during 1 year after intervention in this cohort, the VARC-2edefined clinical efficacy end point is reported at 1 year. In addition, NYHA class at follow-up and change of NYHA functional class status from baseline to 2 years were recorded.20 Baseline BNP was categorized as low, defined as the lower 2 tertiles (<591 pg/ml), or high, defined by the higher tertile of all measurements (591 pg/ml).5 Our primary assessment was the impact of baseline BNP levels on outcomes. A secondary goal compared the prognostic performance of single (before TAVI) versus serial measurements of BNP and the performance of BNP versus NT-pro-BNP in the subset of patients with serial assessment of both peptides. On the basis of previous reports examining serial changes of NPs in patients with heart failure15 and acute coronary syndromes,17,18 we explored outcomes in relation to (1) any decrease compared to any increase or no change of BNP and (2) presence of persistently high BNP 591 pg/ml both before and after TAVI (high / high) versus high baseline BNP but subsequently low post-TAVI BNP (high / low) versus low baseline BNP.16,18,19 Continuous variables are summarized as mean standard deviation and categorical variables as actual numbers and percentages. Event rates at 2 years are reported using time-to-first-event data and graphically presented using KaplaneMeier curves with incidence rates calculated from life tables, censoring patients at death, at the last follow-up performed, or at withdrawal of consent (whichever occurred first). Event rates at 2 years were compared using Cox’s regressions. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p values were derived from the Wald chi-square test. Adjusted HRs are based on inverse probability of treatment weighing in 100 multiple imputation data sets using chained equations, using baseline variables with a univariate and/or multivariate effect (p <0.2) on all-cause mortality at 2 years. These included age, gender, renal failure, LVEF, body mass index, chronic obstructive pulmonary disease, atrial fibrillation, previous myocardial infarction, NYHA class III or IV, logistic EuroScore, and Society of Thoracic Surgeons score. The prognostic discrimination of before and after TAVI levels of BNP and NT-pro-BNP was assessed by receiver operating characteristics (ROC) curves; the chi-square test was used to determine the equality of the ROC-estimated
Valvular Heart Disease/Natriuretic Peptides and Prognosis After TAVI
Figure 2. Rates of all-cause (A) and cardiovascular death at 2 years (B) in patients with persistently high BNP 591 pg/ml before and after intervention (high / high) versus high before intervention but low postintervention BNP (high / low) versus low baseline BNP. Note that a very small proportion of patients with baseline low BNP had high BNP after TAVI (n ¼ 10 of 177) to allow for a meaningful subclassification into a “low / low” and a “low / high” BNP group.
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frequently men with NYHA class III or IV symptoms and had lower body mass index, lower LVEF, and increased Society of Thoracic Surgeons scores and EuroScores. Procedural characteristics of TAVI interventions did not differ between groups (Table 2). Interventions were performed by means of the femoral route in 91% of patients. Overall mortality was 15.3% at 1 year and 23.8% at 2 years. After multivariate adjustments, high baseline BNP was associated with a higher risk of all-cause death (p <0.001) and cardiovascular death at 2 years (p <0.001; Table 3, Figure 1). The VARC-2 clinical efficacy end point at 1 year occurred more frequently in patients with high compared to those with low baseline BNP (Odds ratio [OR] 2.41, 95% CI 1.50 to 3.88; p <0.001). There was no difference with regard to hospitalization for valve-related symptoms or worsening heart failure (OR 0.83, 95% CI 0.28 to 2.41; p ¼ 0.73) or NYHA class III or IV (OR 0.94, 95% CI 0.38 to 2.33; p ¼ 0.89) in relation to baseline BNP. BNP levels increased or remained unchanged between before and after TAVI in 35% of patients, and they decreased in 65% of patients. A mean aortic valve gradient 20 mm Hg after intervention tended to be more frequent in patients with any increase or no serial change versus any decrease of BNP (4.4% vs 0%; p ¼ 0.08), with no difference in moderate or severe prosthetic valve regurgitation (9.4% vs 8.6%; p ¼ 0.84). Patients with nondecreasing versus those with decreasing BNP levels had similar all-cause death (p ¼ 0.13) and cardiovascular mortality (p ¼ 0.24) but more frequently showed worsening or no improvement of NYHA functional status at 2 years (40% vs 21%, p ¼ 0.015). Moreover, patients with persistently high BNP 591 pg/ml before and after intervention (high / high) compared to those with high preintervention but low postintervention BNP (high / low) and those with low baseline BNP had increased rates of death (p ¼ 0.003) and of cardiovascular death at 2 years (p <0.001; Figure 2). In the subgroup of patients with serial measurements of both peptides (n ¼ 219), the prognostic discrimination of baseline BNP versus NT-pro-BNP for 2-year mortality rate did not differ according to ROC analysis; in contrast, postprocedural NT-pro-BNP outperformed all other single measurements as a predictor of all-cause mortality at 2 years (AUC 0.75; p ¼ 0.019 vs baseline BNP; Figure 3). Discussion
Figure 3. Comparison of ROC curves of preintervention and postintervention levels of BNP and NT-pro-BNP for all-cause death at 2 years in 219 patients who were alive at discharge and had serial (before and after TAVI) measurements of both peptides.
area under the curve (AUC). Two-sided p values <0.05 were considered statistically significant. All analyses were performed with Stata version 13.1 (StataCorp, College Station, Texas). Results Baseline characteristics are summarized in Table 1. Patients with high versus low baseline BNP were more
The main findings of the present analysis can be summarized as follows: (1) high preintervention levels of BNP are independently associated with long-term mortality after TAVI; (2) BNP levels decrease in most patients early after the intervention; persistence of significantly elevated BNP levels before and after TAVI identifies a subgroup of patients with worse clinical outcomes; (3) of single measurements of BNP and NT-pro-BNP obtained before and after TAVI, NT-pro-BNP measured early after intervention shows relatively better prognostic discrimination for 2-year mortality rate; and (4) periprocedural reduction of BNP, but not baseline BNP, correlates with functional class improvement within 2 years. Together, these findings indicate an additive predictive value of serial assessment of periinterventional BNP changes and point to a complementary
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role of BNP and NT-pro-BNP for risk stratification of patients undergoing TAVI. The predictive value of NPs has been established across a wide spectrum of cardiovascular disease.4 Previous reports in patients undergoing TAVI were limited by shorter duration of follow-up,5e10,12,13 relatively small sample sizes, and heterogeneity of treatment modes including transapical interventions only12 or transcatheter and surgical management within the same study population,8 and they showed discordant findings regarding the prognostic impact of preintervention neurohormonal activation in this setting.6,12,13 This study advances the findings of previous investigations by uniquely demonstrating that elevated BNP represents an independent predictor of mortality and VARC–2edefined clinical outcomes within an extended 2-year period. Importantly, these findings persisted after multivariate adjustments for patient characteristics known to affect NPs including age, renal failure, LVEF, and body mass index. The incremental prognostic value of serial NP measurements has been documented in different clinical settings of congestive heart failure15e17 and acute coronary syndromes.18,19 Levels of NPs increase substantially and dose dependently in the presence of AS,24 and they decrease early after replacement of the stenotic valve10,14 likely reflecting a rapid response to acute, profound reductions of the intraventricular wall stress.24 The impact of early periprocedural changes of NPs on patient prognosis has not been previously addressed. In this study, persistence of elevated BNP levels identified a small subset of patients with worst long-term outcomes. Our findings thereby indicate that serial BNP measurement for assessment of early peri-interventional changes provides additive prognostic information for monitoring the longitudinal clinical course after TAVI compared with a single preprocedural measurement alone. This is corroborated further by the observed association of serial reductions, but not of baseline levels of BNP, with long-term changes of NYHA functional status. Although a marginally greater frequency of residual valve gradients >20 mm Hg (indicative of prosthetic valve dysfunction according to VARC-2 criteria23) may provide in part a plausible mechanistic link between nondecreasing BNP levels and worse clinical outcomes, it is likely that other mechanisms not addressed in this observational study are also involved. Overall, our observations focusing on immediate, peri-interventional alterations of BNP levels complement a recent analysis from the PARTNER trial13 and a study by Gotzman et al25 showing that BNP levels measured at 30 days after TAVI correlate with higher mid- and long-term mortality rate, respectively. BNP and NT-pro-BNP have previously shown comparable but not identical predictive performance in different clinical settings.26,27 This study shows that preintervention levels of the 2 peptides are equivalent prognostic markers for a priori identification of TAVI candidates more likely to experience unfavorable outcomes. Notably, NT-pro-BNP measured early after intervention outperformed the prognostic discrimination of all other measurements for prediction of long-term mortality. It is important to note that, similar to all previous reports that assessed NPs and other biomarkers in a serial fashion before and after an intervention,16e19 post-TAVI measurements in this study were
by necessity limited to subjects who were discharged alive. This fact relates to overall lower 2-year event rates in the subset of inhospital survivors with serial peptide assessment compared with the entire population with baseline peptide measurement, and it inherently limits direct comparison of the predictive value of preintervention versus postintervention measurement. The differential predictive efficacy of the 2 biomarkers, which is in line with the somewhat superior prognostic performance of NT-pro-BNP over BNP in patients with heart failure,26,27 might relate in part to differing clearance characteristics4 despite the fact that BNP and its N-terminal equivalent are released in a 1:1 fashion. Along these lines, serial changes of the 2 biomarkers were substantially but not completely concordant in our cohort, in that BNP increased in a quarter of patients with a decrease of NT-pro-BNP between before and after intervention (Supplementary Figure 1). This study adds to the cumulative evidence supporting the value of NPs as risk predictors after TAVI by demonstrating an independent association of BNP levels with longterm outcomes; by showing an additive value of serial, early peri-interventional measurements of BNP for refining risk stratification; and by comparing the prognostic discrimination of BNP and NT-pro-BNP in this setting. Although the information conferred by increased NP levels cannot be used currently to guide selection or exclusion of patients suitable for TAVI, it may be useful for identification of higher-risk patients who might benefit from continued, closer vigilance after TAVI. Direct evidence from prospective studies would be required to explore the therapeutic implications of detecting most pronounced neurohormonal activation for guiding and monitoring therapy in patients with severe AS. This study has limitations. Although all data were prospectively collected, this is a retrospective, single-center analysis with all inherent limitations of such analyses. Because only two-thirds of all patients treated with TAVI had baseline BNP measurement, this is not a consecutive patient series; no significant differences, however, were observed in baseline characteristics or clinical outcomes between patients with and those without BNP assessment, suggesting minimal selection bias. Although the primary end points were recorded at 2 years, data regarding repeat hospitalization and thereby regarding the composite VARC-2 clinical efficacy end point were available only for 1 year of follow-up. Finally, although the measured NPs were independently associated with long-term outcomes, their predictive performance was moderate and thus needs to be considered in conjunction with established risk predictors in patients undergoing TAVI. Disclosures Dr. Windecker has received research grants to the institution from Abbott, Biotronik, Boston Scientific, Edwards Lifesciences, Medtronic, Medicines Company, and St Jude and speaker fees from Astra Zeneca, Eli Lilly, Abbott, Biotronik, Boston Scientific, Bayer, and Biosensors. Dr. Wenaweser has received honoraria and lecture fees from Medtronic and Edwards Lifesciences. The other authors have no conflicts of interest to report.
Valvular Heart Disease/Natriuretic Peptides and Prognosis After TAVI
Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2015.08.016. 1. Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Buchbinder M, Hermiller J Jr, Kleiman NS, Chetcuti S, Heiser J, Merhi W, Zorn G, Tadros P, Robinson N, Petrossian G, Hughes GC, Harrison JK, Conte J, Maini B, Mumtaz M, Chenoweth S, Oh JK; U.S. CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790e1798. 2. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB; PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686e1695. 3. Gotzmann M, Czauderna A, Hehnen T, Aweimer A, Lind A, Kloppe A, Bösche L, Mügge A, Ewers A. Three-year outcomes after transcatheter aortic valve implantation with the CoreValve prosthesis. Am J Cardiol 2014;114:606e611. 4. Volpe M, Rubattu S, Burnett J Jr. Natriuretic peptides in cardiovascular diseases: current use and perspectives. Eur Heart J 2014;35:419e425. 5. O’Sullivan CJ, Stortecky S, Heg D, Jüni P, Windecker S, Wenaweser P. Impact of B-type natriuretic peptide on short-term clinical outcomes following transcatheter aortic valve implantation. EuroIntervention 2015;10:e1ee8. 6. Ben-Dor I, Minha S, Barbash IM, Aly O, Dvir D, Deksissa T, Okubagzi P, Torguson R, Lindsay J, Satler LF, Pichard AD, Waksman R. Correlation of brain natriuretic peptide levels in patients with severe aortic stenosis undergoing operative valve replacement or percutaneous transcatheter intervention with clinical, echocardiographic, and hemodynamic factors and prognosis. Am J Cardiol 2013;112:574e579. 7. López-Otero D, Trillo-Nouche R, Gude F, Cid-Álvarez B, OcaranzaSanchez R, Alvarez MS, Lear PV, Gonzalez-Juanatey JR. Pro B-type natriuretic peptide plasma value: a new criterion for the prediction of short- and long-term outcomes after transcatheter aortic valve implantation. Int J Cardiol 2013;168:1264e1268. 8. Elhmidi Y, Bleiziffer S, Piazza N, Ruge H, Krane M, Deutsch MA, Hettich I, Voss B, Mazzitelli D, Lange R. The evolution and prognostic value of N-terminal brain natriuretic peptide in predicting 1-year mortality in patients following transcatheter aortic valve implantation. J Invasive Cardiol 2013;25:38e44. 9. Kefer J, Beauloye C, Astarci P, Renkin J, Glineur D, Dekleermaeker A, Vanoverschelde JL. Usefulness of B-type natriuretic peptide to predict outcome of patients treated by transcatheter aortic valve implantation. Am J Cardiol 2010;106:1782e1786. 10. Spargias K, Polymeros S, Dimopoulos A, Manginas A, Pavlides G, Balanika M, Smirli A, Stavridis G, Dangas G, Cokkinos DV. The predictive value and evolution of N-terminal pro-B-type natriuretic peptide levels following transcutaneous aortic valve implantation. J Interv Cardiol 2011;24:462e469. 11. Ribeiro HB, Urena M, Le Ven F, Nombela-Franco L, Allende R, Clavel MA, Dahou A, Côté M, Laflamme J, Laflamme L, DeLarochellière H, DeLarochellière R, Doyle D, Dumont E, Bergeron S, Pibarot P, Rodés-Cabau J. Long-term prognostic value and serial changes of plasma N-terminal prohormone B-type natriuretic peptide in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014;113:851e859. 12. Pfister R, Wahlers T, Baer FM, Scherner M, Strauch J, Erdmann E. Utility of NT-pro-BNP in patients undergoing transapical aortic valve replacement. Clin Res Cardiol 2010;99:301e307. 13. O’Neill BP, Guerrero M, Thourani VH, Kodali S, Heldman A, Williams M, Xu K, Pichard A, Mack M, Babaliaros V, Herrmann HC,
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27.
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Webb J, Douglas PS, Leon MB, O’Neill WW. Prognostic value of serial B-type natriuretic peptide measurement in transcatheter aortic valve replacement (from the PARTNER Trial). Am J Cardiol 2015;115:1265e1272. Sherif MA, Abdel-Wahab M, Awad O, Geist V, El-Shahed G, Semmler R, Tawfik M, Khattab AA, Richardt D, Richardt G, Tölg R. Early hemodynamic and neurohormonal response after transcatheter aortic valve implantation. Am Heart J 2010;160:862e869. Latini R, Masson S, Wong M, Barlera S, Carretta E, Staszewsky L, Vago T, Maggioni AP, Anand IS, Tan LB, Tognoni G, Cohn JN; ValHeFT Investigators. Incremental prognostic value of changes in B-type natriuretic peptide in heart failure. Am J Med 2006;119:70.e23e70.e30. Masson S, Latini R, Anand IS, Barlera S, Angelici L, Vago T, Tognoni G, Cohn JN. Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial). J Am Coll Cardiol 2008;52:997e1003. Olsson LG, Swedberg K, Cleland JG, Spark PA, Komajda M, Metra M, Torp-Pedersen C, Remme WJ, Scherhag A, Poole-Wilson P. Prognostic importance of plasma NT-pro BNP in chronic heart failure in patients treated with a beta-blocker: results from the Carvedilol or Metoprolol European Trial (COMET) trial. Eur J Heart Fail 2007;9: 795e801. Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, White HD, Fox KA, Califf RM, Braunwald E. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294:2866e2871. Heeschen C, Hamm CW, Mitrovic V, Lantelme NH, White HD. Nterminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation 2004;110:3206e3212. O’Sullivan CJ, Stortecky S, Heg D, Pilgrim T, Hosek N, Buellesfeld L, Khattab AA, Nietlispach F, Moschovitis A, Zanchin T, Meier B, Windecker S, Wenaweser P. Clinical outcomes of patients with lowflow, low-gradient, severe aortic stenosis and either preserved or reduced ejection fraction undergoing transcatheter aortic valve implantation. Eur Heart J 2013;34:3437e3450. Wenaweser P, Pilgrim T, Kadner A, Huber C, Stortecky S, Buellesfeld L, Khattab AA, Meuli F, Roth N, Eberle B, Erdös G, Brinks H, Kalesan B, Meier B, Jüni P, Carrel T, Windecker S. Clinical outcomes of patients with severe aortic stenosis at increased surgical risk according to treatment modality. J Am Coll Cardiol 2011;58:2151e2162. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, Quiñones M. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:1e25. Kappetein AP, Head SJ, Généreux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, RodésCabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J 2012;33:2403e2418. Ray SG. Natriuretic peptides in heart valve disease. Heart 2006;92: 1194e1197. Gotzmann M, Czauderna A, Aweimer A, Hehnen T, Bösche L, Lind A, Kloppe A, Mügge A, Ewers A. B-type natriuretic peptide is a strong independent predictor of long-term outcome after transcatheter aortic valve implantation. J Heart Valve Dis 2014;23:537e544. Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, Missov ED, Clerico A, Tognoni G, Cohn JN. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data. Clin Chem 2006;52:1528e1538. Savarese G, Trimarco B, Dellegrottaglie S, Prastaro M, Gambardella F, Rengo G, Leosco D, Perrone-Filardi P. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PLoS One 2013;8: e58287.
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.016
impact of preintervention measurements or measurements obtained later during patient follow-up. Although serial reductions of NPs after therapeutic interventions provide incremental prognostic information in patients with heart failure15e17 and acute coronary syndromes,18,19 the relative predictive utility of BNP measured before versus early after TAVI has not been defined. Against this background, the purpose of this study was to determine the long-term prognostic impact of BNP and to compare the predictive value of pre and postintervention levels and of early periprocedural changes of BNP versus NT-pro-BNP in patients with severe AS who underwent TAVI. Methods This is a retrospective analysis of prospectively collected data. All patients with severe native-valve AS (defined as indexed aortic valve area [AVA] 0.6 cm2/m2 or mean gradient >40 mm Hg) who underwent TAVI at our institution from August 2007 to August 2012 were entered into a dedicated database. Of 500 consecutive patients treated with TAVI, 340 patients with measurement of BNP within 7 days before the intervention were included in the present analysis. The study conforms to the guiding principles of the Declaration of Helsinki and was approved by the local Ethics Committee. All patients provided written informed consent for prospective follow-up. www.ajconline.org
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Table 1 Baseline characteristics of the study population All patients (n¼340)
Variable
Age (years) Female Body mass index (kg/m2) Cardiovascular risk factors Diabetes mellitus Hypercholesterolemia Arterial hypertension Medical history Previous myocardial infarction Previous PCI Renal failure (GFR<60ml/min/1.73m2) Chronic obstructive pulmonary disease Atrial fibrillation Functional class NYHA III/IV Risk assessment Logistic EuroScore STS Score Hemodynamic variables Aortic valve area (cm2) Indexed aortic valve area (cm2 /m2) Mean aortic valve gradient (mmHg) Peak aortic valve gradient (mmHg) Echocardiographic variables LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV ejection fraction (%) Natriuretic peptides BNP, pg/ml NT-pro-BNP, pg/ml
Baseline BNP
P value
Low (n¼227)
High (n¼113)
83.2 4.8 195 (57%) 26.7 5.1
82.9 4.8 143 (63%) 27.7 4.9
83.6 4.7 54 (48%) 24.5 4.3
0.10 0.05 <0.001
91 (27%) 207 (61%) 278 (82%)
62 (28%) 142 (62%) 188 (83%)
29 (26%) 65 (58%) 90 (80%)
0.48 0.32 0.71
53 (16%) 81 (24%) 227 (67%) 56 (16%) 94/310 (30%)
28 (12%) 51 (22%) 136 (60%) 44 (19%) 54/205 (26%)
25 (22%) 30 (27%) 91 (81%) 12 (11%) 40/105 (38%)
0.004 0.91 <0.001 0.023 0.037
224 (66%)
138 (61%)
86 (77%)
<0.001
23.0 13.5 6.3 4.1
19.3 11.2 5.8 4.0
30.2 14.8 7.4 4.1
<0.001 <0.001
0.13 0.13 0.28 0.32
0.60 0.33 44.2 69.3
0.22 0.12 17.4 25.7
0.61 0.34 44.9 70.7
0.21 0.12 16.6 24.3
48.9 9.9 34.6 12.4 53.0 15.3
45.4 7.9 28.2 7.5 60.2 10.3
605.7 787.6 5453.2 8059.6
214.9 145.6 1833.3 1830
0.57 0.31 42.7 66.9
0.22 0.12 18.9 27.9
50.9 10.4 38.0 13.2 45.9 16.2 1390.7 950.5 12908.3 10481
0.007 <0.001 <0.001 <0.001 <0.001
BNP ¼ B-type natriuretic peptide; GFR ¼ glomerular filtration rate; LV ¼ left ventricular; NT-pro-BNP ¼ amino-terminal pro-BNP; NYHA ¼ New York Heart Association; PCI ¼ percutaneous coronary intervention; STS ¼ Society of Thoracic Surgeons.
Table 2 Procedural characteristics Variable
Access route Femoral Apical Subclavian Valve type Medtronic CoreValve Edwards Sapien XT Valve Revascularization Concomitant PCI Procedural complications Access vessel complication Moderate/severe (grade 2) post-procedure AR Severe (grade 3) post-procedure AR
Baseline BNP
P value
Low (n¼227)
High (n¼113)
210 (93%) 16 (7%) 1 (0%)
99 (88%) 11 (10%) 3 (3%)
0.16 0.40 0.11
135 (59%) 92 (41%)
78 (69%) 35 (31%)
0.096 0.096
40 (18%)
24 (21%)
0.46
21 (9%) 27 (12%)
9 (8%) 17 (15%)
0.84 0.80
1 (0%)
0 (0%)
1.00
AR ¼ aortic regurgitation; PCI ¼ percutaneous coronary intervention.
Patients underwent right and left heart catheterization for hemodynamic assessment before TAVI. Aortic valve gradients were measured by pullback technique from the left ventricle to the ascending aorta. Calculation of the AVA was derived from the Gorlin equation and was indexed by body surface area.20,21 Standardized transthoracic echocardiographic examination was performed before TAVI, and left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson method. Severity of aortic valve regurgitation was evaluated using spectral and color Doppler images and semiquantitatively graded as mild, moderate, and severe according to guidelines.20,22 TAVI was performed using standard techniques.20,21 Vascular access was transfemoral using the Medtronic CoreValve Revalving System (Medtronic, Inc., Minneapolis, Minnesota) or the Edwards SAPIEN XT valve (Edwards Lifesciences, Irvine, California), transapical for Edwards SAPIEN XT, or trans-subclavian using the Medtronic CoreValve prosthesis. BNP was measured in 340 patients before intervention on hospital admission (1.5 1.3 days before TAVI) using a chemiluminescent microparticle immunoassay (ARCHITECT BNP assay; Abbott Laboratories Diagnostics Division, Abbott
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Table 3 Clinical outcomes at 2 years in patients with low or high baseline levels of BNP Outcome
Baseline BNP Low (n¼227)
High (n¼113)
Death 40 (18.9%) 41 (37.4%) Cardiovascular 22 (10.7%) 33 (31.2%) death Myocardial 5 (2.3%) 3 (3.3%) infarction Stroke 5 (2.5%) 11 (10.8%) Death, myocardial 46 (21.5%) 46 (41.7%) infarction or stroke
Adjusted Hazard Ratio (95% CI)
P value
3.16 (1.84-5.42) 3.37 (1.78-6.39)
<0.001 <0.001
0.61 (0.11-3.42)
0.57
8.44 (2.67-26.67) <0.001 2.61 (1.50-4.55) 0.001
Presented are counts with % incidence rates from life-table estimates.
Figure 1. KaplaneMeier graphs of the cumulative incidence of all-cause mortality (A) and cardiovascular death at 2 years (B) in patients with low versus high baseline (pre-TAVI) BNP.
Park, Illinois). In addition, BNP levels were measured in 253 patients, and both BNP and NT-pro-BNP were measured in 219 patients, after the intervention (on the days of discharge, 6.3 2.8 days after TAVI). Patients were followed throughout 2 years, and no patient was lost to follow-up. Adverse cardiac and cerebrovascular events were assessed in hospital, and regular follow-up was performed at 1 month, 1 year, and 2 years by means of
a clinical visit or a standardized telephone interview. All events were adjudicated by a clinical event committee. An academic clinical trials unit (CTU Bern, Bern University Hospital, Switzerland) was responsible for central data audits and maintenance of the dedicated database. Clinical end points were defined according to the Valve Academic Research Consortium (VARC)-2 criteria.23 Primary end points were all-cause and cardiovascular death at 2 years. Secondary end points included the VARC-2edefined clinical efficacy end point (composite of all-cause death, stroke, hospitalizations for valve-related symptoms or worsening congestive heart failure, New York Heart Association [NYHA] class III or IV, and valve-related dysfunction defined as mean aortic valve gradient >20 mm Hg, effective orifice area <0.9 to 1.1 cm2, Doppler velocity index <0.35 m/sec, and/or moderate or severe prosthetic valve regurgitation). Because repeat hospitalizations were consistently recorded during 1 year after intervention in this cohort, the VARC-2edefined clinical efficacy end point is reported at 1 year. In addition, NYHA class at follow-up and change of NYHA functional class status from baseline to 2 years were recorded.20 Baseline BNP was categorized as low, defined as the lower 2 tertiles (<591 pg/ml), or high, defined by the higher tertile of all measurements (591 pg/ml).5 Our primary assessment was the impact of baseline BNP levels on outcomes. A secondary goal compared the prognostic performance of single (before TAVI) versus serial measurements of BNP and the performance of BNP versus NT-pro-BNP in the subset of patients with serial assessment of both peptides. On the basis of previous reports examining serial changes of NPs in patients with heart failure15 and acute coronary syndromes,17,18 we explored outcomes in relation to (1) any decrease compared to any increase or no change of BNP and (2) presence of persistently high BNP 591 pg/ml both before and after TAVI (high / high) versus high baseline BNP but subsequently low post-TAVI BNP (high / low) versus low baseline BNP.16,18,19 Continuous variables are summarized as mean standard deviation and categorical variables as actual numbers and percentages. Event rates at 2 years are reported using time-to-first-event data and graphically presented using KaplaneMeier curves with incidence rates calculated from life tables, censoring patients at death, at the last follow-up performed, or at withdrawal of consent (whichever occurred first). Event rates at 2 years were compared using Cox’s regressions. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p values were derived from the Wald chi-square test. Adjusted HRs are based on inverse probability of treatment weighing in 100 multiple imputation data sets using chained equations, using baseline variables with a univariate and/or multivariate effect (p <0.2) on all-cause mortality at 2 years. These included age, gender, renal failure, LVEF, body mass index, chronic obstructive pulmonary disease, atrial fibrillation, previous myocardial infarction, NYHA class III or IV, logistic EuroScore, and Society of Thoracic Surgeons score. The prognostic discrimination of before and after TAVI levels of BNP and NT-pro-BNP was assessed by receiver operating characteristics (ROC) curves; the chi-square test was used to determine the equality of the ROC-estimated
Valvular Heart Disease/Natriuretic Peptides and Prognosis After TAVI
Figure 2. Rates of all-cause (A) and cardiovascular death at 2 years (B) in patients with persistently high BNP 591 pg/ml before and after intervention (high / high) versus high before intervention but low postintervention BNP (high / low) versus low baseline BNP. Note that a very small proportion of patients with baseline low BNP had high BNP after TAVI (n ¼ 10 of 177) to allow for a meaningful subclassification into a “low / low” and a “low / high” BNP group.
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frequently men with NYHA class III or IV symptoms and had lower body mass index, lower LVEF, and increased Society of Thoracic Surgeons scores and EuroScores. Procedural characteristics of TAVI interventions did not differ between groups (Table 2). Interventions were performed by means of the femoral route in 91% of patients. Overall mortality was 15.3% at 1 year and 23.8% at 2 years. After multivariate adjustments, high baseline BNP was associated with a higher risk of all-cause death (p <0.001) and cardiovascular death at 2 years (p <0.001; Table 3, Figure 1). The VARC-2 clinical efficacy end point at 1 year occurred more frequently in patients with high compared to those with low baseline BNP (Odds ratio [OR] 2.41, 95% CI 1.50 to 3.88; p <0.001). There was no difference with regard to hospitalization for valve-related symptoms or worsening heart failure (OR 0.83, 95% CI 0.28 to 2.41; p ¼ 0.73) or NYHA class III or IV (OR 0.94, 95% CI 0.38 to 2.33; p ¼ 0.89) in relation to baseline BNP. BNP levels increased or remained unchanged between before and after TAVI in 35% of patients, and they decreased in 65% of patients. A mean aortic valve gradient 20 mm Hg after intervention tended to be more frequent in patients with any increase or no serial change versus any decrease of BNP (4.4% vs 0%; p ¼ 0.08), with no difference in moderate or severe prosthetic valve regurgitation (9.4% vs 8.6%; p ¼ 0.84). Patients with nondecreasing versus those with decreasing BNP levels had similar all-cause death (p ¼ 0.13) and cardiovascular mortality (p ¼ 0.24) but more frequently showed worsening or no improvement of NYHA functional status at 2 years (40% vs 21%, p ¼ 0.015). Moreover, patients with persistently high BNP 591 pg/ml before and after intervention (high / high) compared to those with high preintervention but low postintervention BNP (high / low) and those with low baseline BNP had increased rates of death (p ¼ 0.003) and of cardiovascular death at 2 years (p <0.001; Figure 2). In the subgroup of patients with serial measurements of both peptides (n ¼ 219), the prognostic discrimination of baseline BNP versus NT-pro-BNP for 2-year mortality rate did not differ according to ROC analysis; in contrast, postprocedural NT-pro-BNP outperformed all other single measurements as a predictor of all-cause mortality at 2 years (AUC 0.75; p ¼ 0.019 vs baseline BNP; Figure 3). Discussion
Figure 3. Comparison of ROC curves of preintervention and postintervention levels of BNP and NT-pro-BNP for all-cause death at 2 years in 219 patients who were alive at discharge and had serial (before and after TAVI) measurements of both peptides.
area under the curve (AUC). Two-sided p values <0.05 were considered statistically significant. All analyses were performed with Stata version 13.1 (StataCorp, College Station, Texas). Results Baseline characteristics are summarized in Table 1. Patients with high versus low baseline BNP were more
The main findings of the present analysis can be summarized as follows: (1) high preintervention levels of BNP are independently associated with long-term mortality after TAVI; (2) BNP levels decrease in most patients early after the intervention; persistence of significantly elevated BNP levels before and after TAVI identifies a subgroup of patients with worse clinical outcomes; (3) of single measurements of BNP and NT-pro-BNP obtained before and after TAVI, NT-pro-BNP measured early after intervention shows relatively better prognostic discrimination for 2-year mortality rate; and (4) periprocedural reduction of BNP, but not baseline BNP, correlates with functional class improvement within 2 years. Together, these findings indicate an additive predictive value of serial assessment of periinterventional BNP changes and point to a complementary
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role of BNP and NT-pro-BNP for risk stratification of patients undergoing TAVI. The predictive value of NPs has been established across a wide spectrum of cardiovascular disease.4 Previous reports in patients undergoing TAVI were limited by shorter duration of follow-up,5e10,12,13 relatively small sample sizes, and heterogeneity of treatment modes including transapical interventions only12 or transcatheter and surgical management within the same study population,8 and they showed discordant findings regarding the prognostic impact of preintervention neurohormonal activation in this setting.6,12,13 This study advances the findings of previous investigations by uniquely demonstrating that elevated BNP represents an independent predictor of mortality and VARC–2edefined clinical outcomes within an extended 2-year period. Importantly, these findings persisted after multivariate adjustments for patient characteristics known to affect NPs including age, renal failure, LVEF, and body mass index. The incremental prognostic value of serial NP measurements has been documented in different clinical settings of congestive heart failure15e17 and acute coronary syndromes.18,19 Levels of NPs increase substantially and dose dependently in the presence of AS,24 and they decrease early after replacement of the stenotic valve10,14 likely reflecting a rapid response to acute, profound reductions of the intraventricular wall stress.24 The impact of early periprocedural changes of NPs on patient prognosis has not been previously addressed. In this study, persistence of elevated BNP levels identified a small subset of patients with worst long-term outcomes. Our findings thereby indicate that serial BNP measurement for assessment of early peri-interventional changes provides additive prognostic information for monitoring the longitudinal clinical course after TAVI compared with a single preprocedural measurement alone. This is corroborated further by the observed association of serial reductions, but not of baseline levels of BNP, with long-term changes of NYHA functional status. Although a marginally greater frequency of residual valve gradients >20 mm Hg (indicative of prosthetic valve dysfunction according to VARC-2 criteria23) may provide in part a plausible mechanistic link between nondecreasing BNP levels and worse clinical outcomes, it is likely that other mechanisms not addressed in this observational study are also involved. Overall, our observations focusing on immediate, peri-interventional alterations of BNP levels complement a recent analysis from the PARTNER trial13 and a study by Gotzman et al25 showing that BNP levels measured at 30 days after TAVI correlate with higher mid- and long-term mortality rate, respectively. BNP and NT-pro-BNP have previously shown comparable but not identical predictive performance in different clinical settings.26,27 This study shows that preintervention levels of the 2 peptides are equivalent prognostic markers for a priori identification of TAVI candidates more likely to experience unfavorable outcomes. Notably, NT-pro-BNP measured early after intervention outperformed the prognostic discrimination of all other measurements for prediction of long-term mortality. It is important to note that, similar to all previous reports that assessed NPs and other biomarkers in a serial fashion before and after an intervention,16e19 post-TAVI measurements in this study were
by necessity limited to subjects who were discharged alive. This fact relates to overall lower 2-year event rates in the subset of inhospital survivors with serial peptide assessment compared with the entire population with baseline peptide measurement, and it inherently limits direct comparison of the predictive value of preintervention versus postintervention measurement. The differential predictive efficacy of the 2 biomarkers, which is in line with the somewhat superior prognostic performance of NT-pro-BNP over BNP in patients with heart failure,26,27 might relate in part to differing clearance characteristics4 despite the fact that BNP and its N-terminal equivalent are released in a 1:1 fashion. Along these lines, serial changes of the 2 biomarkers were substantially but not completely concordant in our cohort, in that BNP increased in a quarter of patients with a decrease of NT-pro-BNP between before and after intervention (Supplementary Figure 1). This study adds to the cumulative evidence supporting the value of NPs as risk predictors after TAVI by demonstrating an independent association of BNP levels with longterm outcomes; by showing an additive value of serial, early peri-interventional measurements of BNP for refining risk stratification; and by comparing the prognostic discrimination of BNP and NT-pro-BNP in this setting. Although the information conferred by increased NP levels cannot be used currently to guide selection or exclusion of patients suitable for TAVI, it may be useful for identification of higher-risk patients who might benefit from continued, closer vigilance after TAVI. Direct evidence from prospective studies would be required to explore the therapeutic implications of detecting most pronounced neurohormonal activation for guiding and monitoring therapy in patients with severe AS. This study has limitations. Although all data were prospectively collected, this is a retrospective, single-center analysis with all inherent limitations of such analyses. Because only two-thirds of all patients treated with TAVI had baseline BNP measurement, this is not a consecutive patient series; no significant differences, however, were observed in baseline characteristics or clinical outcomes between patients with and those without BNP assessment, suggesting minimal selection bias. Although the primary end points were recorded at 2 years, data regarding repeat hospitalization and thereby regarding the composite VARC-2 clinical efficacy end point were available only for 1 year of follow-up. Finally, although the measured NPs were independently associated with long-term outcomes, their predictive performance was moderate and thus needs to be considered in conjunction with established risk predictors in patients undergoing TAVI. Disclosures Dr. Windecker has received research grants to the institution from Abbott, Biotronik, Boston Scientific, Edwards Lifesciences, Medtronic, Medicines Company, and St Jude and speaker fees from Astra Zeneca, Eli Lilly, Abbott, Biotronik, Boston Scientific, Bayer, and Biosensors. Dr. Wenaweser has received honoraria and lecture fees from Medtronic and Edwards Lifesciences. The other authors have no conflicts of interest to report.
Valvular Heart Disease/Natriuretic Peptides and Prognosis After TAVI
Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. amjcard.2015.08.016. 1. Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, Gleason TG, Buchbinder M, Hermiller J Jr, Kleiman NS, Chetcuti S, Heiser J, Merhi W, Zorn G, Tadros P, Robinson N, Petrossian G, Hughes GC, Harrison JK, Conte J, Maini B, Mumtaz M, Chenoweth S, Oh JK; U.S. CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;370:1790e1798. 2. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, Fontana GP, Dewey TM, Thourani VH, Pichard AD, Fischbein M, Szeto WY, Lim S, Greason KL, Teirstein PS, Malaisrie SC, Douglas PS, Hahn RT, Whisenant B, Zajarias A, Wang D, Akin JJ, Anderson WN, Leon MB; PARTNER Trial Investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686e1695. 3. Gotzmann M, Czauderna A, Hehnen T, Aweimer A, Lind A, Kloppe A, Bösche L, Mügge A, Ewers A. Three-year outcomes after transcatheter aortic valve implantation with the CoreValve prosthesis. Am J Cardiol 2014;114:606e611. 4. Volpe M, Rubattu S, Burnett J Jr. Natriuretic peptides in cardiovascular diseases: current use and perspectives. Eur Heart J 2014;35:419e425. 5. O’Sullivan CJ, Stortecky S, Heg D, Jüni P, Windecker S, Wenaweser P. Impact of B-type natriuretic peptide on short-term clinical outcomes following transcatheter aortic valve implantation. EuroIntervention 2015;10:e1ee8. 6. Ben-Dor I, Minha S, Barbash IM, Aly O, Dvir D, Deksissa T, Okubagzi P, Torguson R, Lindsay J, Satler LF, Pichard AD, Waksman R. Correlation of brain natriuretic peptide levels in patients with severe aortic stenosis undergoing operative valve replacement or percutaneous transcatheter intervention with clinical, echocardiographic, and hemodynamic factors and prognosis. Am J Cardiol 2013;112:574e579. 7. López-Otero D, Trillo-Nouche R, Gude F, Cid-Álvarez B, OcaranzaSanchez R, Alvarez MS, Lear PV, Gonzalez-Juanatey JR. Pro B-type natriuretic peptide plasma value: a new criterion for the prediction of short- and long-term outcomes after transcatheter aortic valve implantation. Int J Cardiol 2013;168:1264e1268. 8. Elhmidi Y, Bleiziffer S, Piazza N, Ruge H, Krane M, Deutsch MA, Hettich I, Voss B, Mazzitelli D, Lange R. The evolution and prognostic value of N-terminal brain natriuretic peptide in predicting 1-year mortality in patients following transcatheter aortic valve implantation. J Invasive Cardiol 2013;25:38e44. 9. Kefer J, Beauloye C, Astarci P, Renkin J, Glineur D, Dekleermaeker A, Vanoverschelde JL. Usefulness of B-type natriuretic peptide to predict outcome of patients treated by transcatheter aortic valve implantation. Am J Cardiol 2010;106:1782e1786. 10. Spargias K, Polymeros S, Dimopoulos A, Manginas A, Pavlides G, Balanika M, Smirli A, Stavridis G, Dangas G, Cokkinos DV. The predictive value and evolution of N-terminal pro-B-type natriuretic peptide levels following transcutaneous aortic valve implantation. J Interv Cardiol 2011;24:462e469. 11. Ribeiro HB, Urena M, Le Ven F, Nombela-Franco L, Allende R, Clavel MA, Dahou A, Côté M, Laflamme J, Laflamme L, DeLarochellière H, DeLarochellière R, Doyle D, Dumont E, Bergeron S, Pibarot P, Rodés-Cabau J. Long-term prognostic value and serial changes of plasma N-terminal prohormone B-type natriuretic peptide in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2014;113:851e859. 12. Pfister R, Wahlers T, Baer FM, Scherner M, Strauch J, Erdmann E. Utility of NT-pro-BNP in patients undergoing transapical aortic valve replacement. Clin Res Cardiol 2010;99:301e307. 13. O’Neill BP, Guerrero M, Thourani VH, Kodali S, Heldman A, Williams M, Xu K, Pichard A, Mack M, Babaliaros V, Herrmann HC,
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27.
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