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Prognostic Usefulness of Acute Kidney Injury After Transcatheter Aortic Valve Replacement
Prognostic Usefulness of Acute Kidney Injury After Transcatheter Aortic Valve Replacement Mani Arsalan, MDa,b, John J. Squiers, BSEa, Robert Farkas, MDc, Christina Worley, RNd, Morley Herbert, PhDc, Wells Stewart, BAd, William T. Brinkman, MDa, Ethan Ungchusri, BSd, David L. Brown, MDa, Michael J. Mack, MDa, and Elizabeth M. Holper, MD, MPHa,d,* Acute kidney injury (AKI) after transcatheter aortic valve replacement (TAVR) has been associated with increased postoperative morbidity and mortality. Long-term outcomes after TAVR with the Edwards SAPIEN valve in patients who develop AKI postoperatively are currently not well described. We retrospectively reviewed 384 consecutive patients undergoing TAVR at 2 institutions from August 2006 to April 2012. AKI was defined and staged according to Valve Academic Research Consortium-2 criteria. The incidence, multivariate predictors, and association of AKI with 3-year mortality were evaluated. Stage 1 AKI occurred in 24.0% of patients (92 of 384), stage 2 in 5.5% (21 of 384), and stage 3 in 8.1% (31 of 384). The overall operative mortality rate was 7.6%, with a mortality of 3.0% in patients with no kidney injury, 7.6% in stage 1, 23.8% in stage 2, and 32.3% in stage 3. The incidence of new postoperative dialysis was 3.1%. Survival at 3 years for no-AKI/stage 1/stage 2/stage 3 was 59.2 – 3.3%, 43.4 – 5.2%, 27.8 – 10.0%, and 25.4 – 7.9%, respectively. Logistic regression modeling for the combination of stage 2 or 3 AKI after surgery demonstrated that the last preoperative creatinine (for each 1 mg/dl increase, odds ratio [ 3.23, 95% CI 1.83 to 5.69; p <0.001) and dye load (for each 10 ml increase, odds ratio [ 1.04, 95% CI 1.01 to 1.08; p [ 0.006) were significant predictors for AKI. In conclusion, AKI after TAVR is associated with increased postoperative and 3-year mortality. Significant multivariate predictors are potentially modifiable before the procedure. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:1327e1331) Up to 30% of patients with severe aortic stenosis (AS) are not eligible for conventional surgical aortic valve replacement because of high surgical risk.1 Transcatheter aortic valve replacement (TAVR) with the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, California) is approved in the US for the treatment of patients with severe AS who are inoperable because of high surgical risk.2,3 It is well established that acute kidney injury (AKI) after any cardiac surgery is associated with increased morbidity4,5 and is also an independent predictor of short- and long-term mortality.6e8 In an effort to further standardize clinical research to improve comparability and interpretability of study results, the Valve Academic Research Consortium (VARC) recently updated and modified key consensus definitions of important clinical end points for TAVR, including the definition of AKI.9 Although AKI has been demonstrated as a strong, independent predictor of shortterm mortality after TAVR,10,11 long-term association a Departments of Cardiology and Cardiovascular Surgery, The Heart Hospital, Baylor, Plano, Texas; bDepartment of Cardiac Surgery, Kerckhoff Heart Center, Bad Nauheim, Germany; and cDepartment of Research, Medical City Hospital and dDepartment of Research, Baylor Research Institute, Dallas, Texas. Manuscript received October 13, 2015; revised manuscript received and accepted January 13, 2016. Drs. Arsalan and Squiers contributed equally to this work. See page 1330 for disclosure information. *Corresponding author: Tel: (þ1) 972-566-5547; fax: (þ1) 972-5668524. E-mail address: [email protected] (E.M. Holper).
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.01.037
between AKI and mortality are not as well studied, particularly when applying VARC-2 criteria. Therefore, the goal of our study was to determine whether an association between AKI as defined by VARC-2 criteria and long-term mortality could be established in patients who underwent TAVR with the Edwards SAPIEN valve. Methods A retrospective analysis of 384 TAVR cases performed at Medical City Hospital, Dallas, Texas from August 2006 to April 2012 and at The Heart Hospital Baylor Plano, Plano, Texas from January to August 2012 was performed. The study was approved by both hospitals’ institutional review boards. The incidence of AKI, as defined and staged by VARC-2 criteria (Table 1), was evaluated.9 Multivariate predictors of AKI and association of AKI with 3-year mortality were examined. Operative mortality was defined as (1) death within 30 days after surgery and (2) death after 30 days during the same index hospitalization. Summary data are presented as percentages with counts and as means with SDs. These data were analyzed using SAS 9.4 (SAS Institute, Cary North Carolina). The patients in the study were being followed after TAVR and mortality data were available from personal contact, family contact, and clinical providers. Regular scans of obituary columns supplemented data collection. The patient names were also tested against the Social Security Death Master File. Survival curves to 3 years were created using KaplaneMeier statistics and odds ratios calculated from www.ajconline.org
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Table 1 Valve Academic Research Consortium (VARC)-2 criteria for acute kidney injury after transcatheter aortic valve replacement12 Stage 1 - Increase in serum creatinine to 150-199% (1.5-1.99 x increase compared with baseline) OR - Increase in serum creatinine of >0.3 mg/dL (>26.4 mmol/L) OR - Urine output <0/5 mL/kg/h for >6 hours but <12 hours Stage 2 - Increase in serum creatinine to 200%-299% (2.0-2.99 x increase compared with baseline) OR - Urine output <0.5 mL/kg/h for >12 hours but <24 hours Stage 3* - Increase in serum creatinine to 300% (>3 x increase compared with baseline) OR - Serum creatinine of 4.0mg/dL (354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR - Urine output <0.3 mL/kg/h for 24 hours OR - Anuria for 12 hours The increase in creatinine must occur within 48 hours. OR ¼ odds ratio. * Patients receiving renal replacement therapy are considered to meet stage 3 criteria irrespective of other criteria.
logistic regression. A multivariate logistic regression was used to determine if there were preoperative risk factors that predicted an increase in the stage of the acute kidney disease. The patients with “no-AKI” were combined with the “stage 1” patients, and the “stage 2” and “stage 3” patients were grouped together. The logistic regression was used to test for an increase in severity from stage 0/1 to stage 2/3. The independent variables in the model included patient age (years), gender, type of TAVR procedure (transapical [TA] or transfemoral [TF]), amount of dye used during each case (ml), last preoperative creatinine value (mg/dl), and estimated glomerular filtration rate (eGFR; ml/min/1.73 m2). The eGFR was calculated using the Modification of Diet in Renal Disease formula.13 Results The mean age of our study population was 82.13 8.1 years, with 48.7% (182 of 384) men and a mean Society of Thoracic Surgeons Predicted Risk of Mortality (STSPROM) of 9.42 5.69%. In 60.4% (232 of 384) of the patients, TAVR through a TF access was used (TF-TAVR), the remaining patients underwent TA-TAVR (TA-TAVR). The overall incidence of AKI was 37.5% (144 of 384). Stage 1 AKI occurred in 24.0% of patients (92 of 384), stage 2 in 5.5% (21 of 384), and stage 3 in 8.1% of patients (31 of 384). The incidence of AKI was higher in patients with increased STS-PROM, a history of peripheral vascular disease, TA-TAVR, preoperative renal failure, and increased preoperative creatinine levels. Other preoperative factors did not significantly differ between patients developing AKI and patients without AKI (Table 2). Furthermore, volume of contrast agent used was not significantly different between the groups. The overall operative mortality was higher with increased AKI stage (Table 3). The incidence of new postoperative dialysis was 3%. This association between higher AKI stage
and mortality remained at 3-year follow-up (Figure 1). Patients with significant AKI (stage 2/3) had increased longterm mortality, which persisted to 3-year follow-up (Figure 2). Logistic regression modeling for the combination of stage 2 or stage 3 AKI postoperatively demonstrated that age, gender, TAVR approach, contrast dye load, eGFR, and last preoperative creatinine were significant predictors for development of stage 2 or stage 3 AKI (Figure 3). Discussion Herein, we report the incidence, risk factors, and longterm effect on survival of postoperative AKI as defined by the updated VARC-2 criteria in a series of 383 patients implanted with the Edwards SAPIEN valve. To the investigators’ knowledge, this is the largest such series to date with 3-year follow-up. Early reports describing AKI after TAVR used various definitions for AKI until standardized definitions were developed in response to the high reported incidence of this complication after TAVR. Owing to this initial inconsistency in definitions, the reported incidence of AKI after TAVR has ranged from 8.3% to 57%, with renal replacement therapy (RRT) required by 1% to 21% of patients.14 The largest metaanalysis to investigate AKI after TAVR to date, which encompassed 24 studies and 5,971 patients, reported a mean incidence of AKI of 22.1%, but the pooled studies applied inconsistent criteria to diagnose AKI.15 To establish appropriate clinical end points with standardized definitions of both single and composite clinical end points for all TAVR clinical investigations, the first VARC consensus guidelines were published in 2011.12 In these guidelines, AKI was defined using a “modified” RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) classification system.16 Confirming wide acceptance of these criteria, a pooled metaanalysis of 16 studies, that included over 3,500 patients found an estimated 20.4% incidence of AKI after TAVR, with a total 7.5% incidence of stage 2/3 AKI.17 Subsequent series continued to apply the initial VARC criteria, reporting similar findings.18e20 However, VARC criteria may have underestimated the rate of AKI because the creatinine level of some patients with TAVR continued to increase after the 72-hour limit enforced by these criteria. In particular, Genereux et al reexamined a series of patients initially diagnosed with the original VARC criteria and discovered that 25% of patients diagnosed with no AKI or stage 1 AKI reached their peak creatinine level after the 72-hour limit, suggesting that a significant number of patients may have been “underclassified.”21 The investigators, however, did not report exactly how many of these patients were actually underclassified. Therefore, in 2013, the VARC-2 committee published an updated document that changed many of the initial definitions, including AKI.9 Two key changes were implemented: (1) the outer bound for detecting AKI was increased from 72 hours to 7 days and (2) urine output measurements were included as diagnostic factors.
Valvular Heart Disease/AKI Predicts TAVR Long-Term Mortality
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Table 2 Baseline characteristics Variable
Age (years) Men Ejection Fraction (%) Height (cm) Weight (kg) STS-PROM Mean Aortic Valve Gradient (mmHg) Aortic Valve Area (cm2) Transfemoral TAVR Transapical TAVR Cerebrovascular disease Stroke Peripheral vascular disease Severe lung disease Diabetes mellitus Preoperative Myocardial infarction Blood Hematocrit (%) Serum Albumin (g/dL) Preoperative renal failure Creatinine (mg/dL) Estimated Glomerular Filtration Rate (mL/min/1.73m2) On Dialysis
VARC-2 Classification of Kidney Disease
p-Value
No AKI (n ¼ 230)
Stage 1 (n ¼ 92)
Stage 2 (n ¼ 21)
Stage 3 (n ¼ 31)
81.96 8.65 112 (49%) 53.95 12.76 167.21 10.68 73.59 18.16 8.61 4.82 46.25 14.69 0.60 0.15 158 (69%) 72 (31%) 70 (30%) 28 (12%) 72 (31%) 39 (17%) 85 (37%) 49/197 (25%) 34.64 4.42 3.28 0.38 10/214 (5%) 1.20 0.57 52.21 26.76
82.49 6.83 47 (51%) 54.10 11.98 166.08 10.44 75.96 19.81 9.96 4.96 44.72 14.61 0.58 0.15 45 (49%) 47 (51%) 31 (34%) 13 (14%) 37 (40%) 13 (14%) 41 (45%) 15/81 (19%) 32.98 5.04 3.27 0.45 9/84 (11%) 1.40 0.47 44.97 22.89
82.05 5.68 7 (33%) 54.52 13.24 163.96 9.92 73.05 18.60 8.95 3.48 47.24 14.24 0.58 0.12 10 (48%) 11 (52%) 7 (33%) 3 (14%) 13 (62%) 6 (29%) 10 (48%) 2/18 (11%) 33.77 4.85 3.27 0.35 0 0.90 0.26 62.34 21.68
82.13 9.30 16 (52%) 54.23 8.45 167.50 8.89 76.15 15.99 13.73 11.44 41.90 13.59 0.62 0.14 19 (61%) 12 (39%) 7 (23%) 4 (13%) 15 (48%) 5 (16%) 12 (39%) 3/25 (12%) 34.10 4.25 3.10 0.31 15/28 (54%) 2.66 2.15 30.78 18.19
0
0
0
11 (36%)
<
< < <
0.963 0.513 0.997 0.544 0.686 0.001 0.393 0.807 0.005 0.005 0.700 0.966 0.012 0.527 0.533 0.236 0.036 0.246 0.001 0.001 0.001
< 0.001
STS-PROM ¼ Society of thoracic surgeons predicted risk of mortality; TAVR ¼ transcatheter aortic valve replacement.
Table 3 Operative outcomes Variable
Operative Mortality Contrast dye load (ml) Total Ventilator time (hours) Total ICU Time (hours) Intraoperative Blood Products Given Creatinine (mg/dL) New-onset Renal Failure Postoperative Renal Failure requiring Dialysis
VARC-2 Classification of Kidney Disease
p-Value
No AKI (n ¼ 230)
Stage 1 (n ¼ 92)
Stage 2 (n ¼ 21)
Stage 3 (n ¼ 31)
7 (3%) 166.73 88.16 32.90 89.52 76.23 83.49 63 (27%) 1.21 0.42 0 0
7 (8%) 157.20 91.86 89.85 191.52 163.71 198.92 34 (37%) 2.02 0.66 0 0
5 (24%) 205.14 169.93 211.26 327.65 290.30 309.83 10 (48%) 2.07 0.61 8 (38%) 0
10 (32%) 186.96 112.25 243.78 354.08 341.54 345.02 11 (36%) 4.80 1.92 28 (90%) 12 (39%)
Although some evidence exists to suggest the VARC-2 criteria may capture additional cases of AKI missed by the initial definition,21 very few reports are available to assess how applying VARC-2 AKI criteria may affect what was previously demonstrated by the multitude of studies applying the initial criteria.22,23 Konigstein et al23 applied VARC-2 criteria to a series of patients with TAVR, who received either Edwards SAPIEN XT (26% of patients) or CoreValve (74%) prostheses and reported a 15.6% incidence (14% stage 1, 1.6% stage 2, and 0% stage 3) of AKI, with no patients requiring RRT. The investigators noted their uncharacteristically low incidence of reported AKI and suggested that a strict adherence to several renal protective strategies explained their success in reducing postoperative AKI. However, the low incidence of AKI may have also
< 0.001 0.153 < 0.001 < 0.001 0.121 < 0.001 < 0.001 0.003
been influenced by the low mean STS-PROM of the patients in this study (4.1%). In comparison, the STS-PROM in our cohort was 9.4% and is reported to be 7.1% in the transcatheter valve therapy registry.24 The incidence of AKI (38.0%) in our study is indeed higher than reported in previous most studies although this result may reflect the less restrictive VARC-2 criteria applied to our patient population and the significantly increased STS-PROM compared with the Konigstein cohort. In contrast, the rate of new requirement for RRT (3.1%) is consistent with previous reports, a result that is independent of VARC criteria definitions. Similar to previous studies, we demonstrate that increased baseline creatinine level, increased contrast dye load, and TA-TAVR approach were all predictive of
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Figure 1. Three-year survival by AKI stage.
significant AKI (stage 2/3) postoperatively.14 Of note, it is controversial if the more invasive TA approach itself or co-morbidities favoring this approach lead to the increased AKI rate compared with TF-TAVR. The association of contrast dye load and AKI is of importance, as this represents a modifiable factor to decrease the risk of AKI. Already reported methods of improving contrast induced AKI, including saline hydration and the RenalGuard System (PLC Medical Systems, Milford, Massachusetts) will need further evaluation in the TAVR population.25e27 AKI has been linked to increased operative mortality10,11 and mid-term mortality,10,20,21 but little is known about the impact of AKI on survival beyond 1 year. Our study is the first to study the effects of AKI after TAVR with the Edwards SAPIEN prosthesis out to 3 years. We have demonstrated that AKI after TAVR does in fact impact mortality at 3 years and that higher AKI stages (stage 2/3) are associated with an increased mortality. This suggests that efforts to reduce the incidence of AKI after TAVR may have the potential to improve outcomes for patients at high risk and inoperable patients with severe AS. Limitations of this study include those expected of a retrospective analysis of a prospectively maintained database at 2 centers. As such, the results may be subject to the effects of possible confounders or may not be generalizable to other centers. Furthermore, patients in this analysis were treated with the first generation Edwards SAPIEN valves available in the United States. Thus, the rate of perioperative complications may differ with more recently available devices. Disclosures
Figure 2. Three-year survival AKI stage 0/1 versus AKI stage 2/3.
Dr. Mack serves as an uncompensated member of the Executive Committee of the Placement of Aortic Transcatheter Valve (PARTNER) trial. The other authors have no conflicts of interest to disclose.
Figure 3. OR for AKI stage 2/3. OR ¼ odds ratio.
Valvular Heart Disease/AKI Predicts TAVR Long-Term Mortality 1. Lung B, Baron G, Butchart EG, Delahaye F, Gohlke-Barwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003;24:1231e1243. 2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG, Fontana GP, Makkar RR, Brown DL, Block PC, Guyton RA, Pichard AD, Bavaria JE, Herrmann HC, Douglas PS, Petersen JL, Akin JJ, Anderson WN, Wang D, Pocock S, Investigators PT. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363: 1597e1607. 3. Lefevre T, Kappetein AP, Wolner E, Nataf P, Thomas M, Schachinger V, De Bruyne B, Eltchaninoff H, Thielmann M, Himbert D, Romano M, Serruys P, Wimmer-Greinecker G. One year follow-up of the multicentre European PARTNER transcatheter heart valve study. Eur Heart J 2011;32:148e157. 4. Karkouti K, Wijeysundera DN, Yau TM, Callum JL, Cheng DC, Crowther M, Dupuis JY, Fremes SE, Kent B, Laflamme C, Lamy A, Legare JF, Mazer CD, McCluskey SA, Rubens FD, Sawchuk C, Beattie WS. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119:495e502. 5. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 2006;1:19e32. 6. Loef BG, Epema AH, Smilde TD, Henning RH, Ebels T, Navis G, Stegeman CA. Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol 2005;16:195e200. 7. Lok CE, Austin PC, Wang H, Tu JV. Impact of renal insufficiency on short- and long-term outcomes after cardiac surgery. Am Heart J 2004;148:430e438. 8. Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP. Influence of renal dysfunction on mortality after cardiac surgery: modifying effect of preoperative renal function. Kidney Int 2005;67:1112e1119. 9. Kappetein AP, Head SJ, Genereux 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, RodesCabau 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. 10. Sinning JM, Ghanem A, Steinhauser H, Adenauer V, Hammerstingl C, Nickenig G, Werner N. Renal function as predictor of mortality in patients after percutaneous transcatheter aortic valve implantation. JACC Cardiovasc Interv 2010;3:1141e1149. 11. Tamburino C, Capodanno D, Ramondo A, Petronio AS, Ettori F, Santoro G, Klugmann S, Bedogni F, Maisano F, Marzocchi A, Poli A, Antoniucci D, Napodano M, De Carlo M, Fiorina C, Ussia GP. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299e308. 12. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the Valve Academic Research Consortium. Eur Heart J 2011;32:205e217. 13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130: 461e470. 14. Elhmidi Y, Bleiziffer S, Deutsch MA, Krane M, Mazzitelli D, Lange R, Piazza N. Acute kidney injury after transcatheter aortic valve
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implantation: incidence, predictors and impact on mortality. Arch Cardiovasc Dis 2014;107:133e139. Gargiulo G, Sannino A, Capodanno D, Perrino C, Capranzano P, Barbanti M, Stabile E, Trimarco B, Tamburino C, Esposito G. Impact of postoperative acute kidney injury on clinical outcomes after transcatheter aortic valve implantation: a meta-analysis of 5,971 patients. Catheter Cardiovasc Interv 2015;86:518e527. Lameire N, Van Biesen W, Vanholder R. The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol 2006;2:364e377. Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K, Smith C, Serruys PW, Kappetein AP, Leon MB. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. J Am Coll Cardiol 2012;59:2317e2326. Alassar A, Roy D, Abdulkareem N, Valencia O, Brecker S, Jahangiri M. Acute kidney injury after transcatheter aortic valve implantation: incidence, risk factors, and prognostic effects. Innovations (Phila) 2012;7:389e393. Barbash IM, Ben-Dor I, Dvir D, Maluenda G, Xue Z, Torguson R, Satler LF, Pichard AD, Waksman R. Incidence and predictors of acute kidney injury after transcatheter aortic valve replacement. Am Heart J 2012;163:1031e1036. Saia F, Ciuca C, Taglieri N, Marrozzini C, Savini C, Bordoni B, Dall’Ara G, Moretti C, Pilato E, Martin-Suarez S, Petridis FD, Di Bartolomeo R, Branzi A, Marzocchi A. Acute kidney injury following transcatheter aortic valve implantation: incidence, predictors and clinical outcome. Int J Cardiol 2013;168:1034e1040. Genereux P, Kodali SK, Green P, Paradis JM, Daneault B, Rene G, Hueter I, Georges I, Kirtane A, Hahn RT, Smith C, Leon MB, Williams MR. Incidence and effect of acute kidney injury after transcatheter aortic valve replacement using the new valve academic research consortium criteria. Am J Cardiol 2013;111:100e105. Konigstein M, Ben-Assa E, Abramowitz Y, Steinvil A, Leshem Rubinow E, Havakuk O, Arbel Y, Halkin A, Keren G, Banai S, Finkelstein A. Usefulness of updated valve academic research consortium-2 criteria for acute kidney injury following transcatheter aortic valve implantation. Am J Cardiol 2013;112:1807e1811. Konigstein M, Ben-Assa E, Banai S, Shacham Y, Ziv-Baran T, Abramowitz Y, Steinvil A, Leshem Rubinow E, Havakuk O, Halkin A, Keren G, Finkelstein A, Arbel Y. Periprocedural bleeding, acute kidney injury, and long-term mortality after transcatheter aortic valve implantation. Can J Cardiol 2015;31:56e62. Holmes DR Jr, Brennan JM, Rumsfeld JS, Dai D, O’Brien SM, Vemulapalli S, Edwards FH, Carroll J, Shahian D, Grover F, Tuzcu EM, Peterson ED, Brindis RG, Mack MJ. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA 2015;313: 1019e1028. Mueller C, Buerkle G, Buettner HJ, Petersen J, Perruchoud AP, Eriksson U, Marsch S, Roskamm H. Prevention of contrast mediaassociated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:329e336. Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P, Hewett J. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract 2003;93:C29eC34. Barbanti M, Gulino S, Capranzano P, Imme S, Sgroi C, Tamburino C, Ohno Y, Attizzani GF, Patane M, Sicuso R, Pilato G, Di Landro A, Todaro D, Di Simone E, Picci A, Giannetto G, Costa G, Deste W, Giannazzo D, Grasso C, Capodanno D, Tamburino C. Acute kidney injury with the RenalGuard System in patients undergoing transcatheter aortic valve replacement: the PROTECT-TAVI (PROphylactic effecT of furosEmide-induCed diuresis with matched isotonic intravenous hydraTion in Transcatheter Aortic Valve Implantation) trial. JACC Cardiovasc Interv 2015;12:1595e1604.
0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.01.037
between AKI and mortality are not as well studied, particularly when applying VARC-2 criteria. Therefore, the goal of our study was to determine whether an association between AKI as defined by VARC-2 criteria and long-term mortality could be established in patients who underwent TAVR with the Edwards SAPIEN valve. Methods A retrospective analysis of 384 TAVR cases performed at Medical City Hospital, Dallas, Texas from August 2006 to April 2012 and at The Heart Hospital Baylor Plano, Plano, Texas from January to August 2012 was performed. The study was approved by both hospitals’ institutional review boards. The incidence of AKI, as defined and staged by VARC-2 criteria (Table 1), was evaluated.9 Multivariate predictors of AKI and association of AKI with 3-year mortality were examined. Operative mortality was defined as (1) death within 30 days after surgery and (2) death after 30 days during the same index hospitalization. Summary data are presented as percentages with counts and as means with SDs. These data were analyzed using SAS 9.4 (SAS Institute, Cary North Carolina). The patients in the study were being followed after TAVR and mortality data were available from personal contact, family contact, and clinical providers. Regular scans of obituary columns supplemented data collection. The patient names were also tested against the Social Security Death Master File. Survival curves to 3 years were created using KaplaneMeier statistics and odds ratios calculated from www.ajconline.org
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Table 1 Valve Academic Research Consortium (VARC)-2 criteria for acute kidney injury after transcatheter aortic valve replacement12 Stage 1 - Increase in serum creatinine to 150-199% (1.5-1.99 x increase compared with baseline) OR - Increase in serum creatinine of >0.3 mg/dL (>26.4 mmol/L) OR - Urine output <0/5 mL/kg/h for >6 hours but <12 hours Stage 2 - Increase in serum creatinine to 200%-299% (2.0-2.99 x increase compared with baseline) OR - Urine output <0.5 mL/kg/h for >12 hours but <24 hours Stage 3* - Increase in serum creatinine to 300% (>3 x increase compared with baseline) OR - Serum creatinine of 4.0mg/dL (354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR - Urine output <0.3 mL/kg/h for 24 hours OR - Anuria for 12 hours The increase in creatinine must occur within 48 hours. OR ¼ odds ratio. * Patients receiving renal replacement therapy are considered to meet stage 3 criteria irrespective of other criteria.
logistic regression. A multivariate logistic regression was used to determine if there were preoperative risk factors that predicted an increase in the stage of the acute kidney disease. The patients with “no-AKI” were combined with the “stage 1” patients, and the “stage 2” and “stage 3” patients were grouped together. The logistic regression was used to test for an increase in severity from stage 0/1 to stage 2/3. The independent variables in the model included patient age (years), gender, type of TAVR procedure (transapical [TA] or transfemoral [TF]), amount of dye used during each case (ml), last preoperative creatinine value (mg/dl), and estimated glomerular filtration rate (eGFR; ml/min/1.73 m2). The eGFR was calculated using the Modification of Diet in Renal Disease formula.13 Results The mean age of our study population was 82.13 8.1 years, with 48.7% (182 of 384) men and a mean Society of Thoracic Surgeons Predicted Risk of Mortality (STSPROM) of 9.42 5.69%. In 60.4% (232 of 384) of the patients, TAVR through a TF access was used (TF-TAVR), the remaining patients underwent TA-TAVR (TA-TAVR). The overall incidence of AKI was 37.5% (144 of 384). Stage 1 AKI occurred in 24.0% of patients (92 of 384), stage 2 in 5.5% (21 of 384), and stage 3 in 8.1% of patients (31 of 384). The incidence of AKI was higher in patients with increased STS-PROM, a history of peripheral vascular disease, TA-TAVR, preoperative renal failure, and increased preoperative creatinine levels. Other preoperative factors did not significantly differ between patients developing AKI and patients without AKI (Table 2). Furthermore, volume of contrast agent used was not significantly different between the groups. The overall operative mortality was higher with increased AKI stage (Table 3). The incidence of new postoperative dialysis was 3%. This association between higher AKI stage
and mortality remained at 3-year follow-up (Figure 1). Patients with significant AKI (stage 2/3) had increased longterm mortality, which persisted to 3-year follow-up (Figure 2). Logistic regression modeling for the combination of stage 2 or stage 3 AKI postoperatively demonstrated that age, gender, TAVR approach, contrast dye load, eGFR, and last preoperative creatinine were significant predictors for development of stage 2 or stage 3 AKI (Figure 3). Discussion Herein, we report the incidence, risk factors, and longterm effect on survival of postoperative AKI as defined by the updated VARC-2 criteria in a series of 383 patients implanted with the Edwards SAPIEN valve. To the investigators’ knowledge, this is the largest such series to date with 3-year follow-up. Early reports describing AKI after TAVR used various definitions for AKI until standardized definitions were developed in response to the high reported incidence of this complication after TAVR. Owing to this initial inconsistency in definitions, the reported incidence of AKI after TAVR has ranged from 8.3% to 57%, with renal replacement therapy (RRT) required by 1% to 21% of patients.14 The largest metaanalysis to investigate AKI after TAVR to date, which encompassed 24 studies and 5,971 patients, reported a mean incidence of AKI of 22.1%, but the pooled studies applied inconsistent criteria to diagnose AKI.15 To establish appropriate clinical end points with standardized definitions of both single and composite clinical end points for all TAVR clinical investigations, the first VARC consensus guidelines were published in 2011.12 In these guidelines, AKI was defined using a “modified” RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) classification system.16 Confirming wide acceptance of these criteria, a pooled metaanalysis of 16 studies, that included over 3,500 patients found an estimated 20.4% incidence of AKI after TAVR, with a total 7.5% incidence of stage 2/3 AKI.17 Subsequent series continued to apply the initial VARC criteria, reporting similar findings.18e20 However, VARC criteria may have underestimated the rate of AKI because the creatinine level of some patients with TAVR continued to increase after the 72-hour limit enforced by these criteria. In particular, Genereux et al reexamined a series of patients initially diagnosed with the original VARC criteria and discovered that 25% of patients diagnosed with no AKI or stage 1 AKI reached their peak creatinine level after the 72-hour limit, suggesting that a significant number of patients may have been “underclassified.”21 The investigators, however, did not report exactly how many of these patients were actually underclassified. Therefore, in 2013, the VARC-2 committee published an updated document that changed many of the initial definitions, including AKI.9 Two key changes were implemented: (1) the outer bound for detecting AKI was increased from 72 hours to 7 days and (2) urine output measurements were included as diagnostic factors.
Valvular Heart Disease/AKI Predicts TAVR Long-Term Mortality
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Table 2 Baseline characteristics Variable
Age (years) Men Ejection Fraction (%) Height (cm) Weight (kg) STS-PROM Mean Aortic Valve Gradient (mmHg) Aortic Valve Area (cm2) Transfemoral TAVR Transapical TAVR Cerebrovascular disease Stroke Peripheral vascular disease Severe lung disease Diabetes mellitus Preoperative Myocardial infarction Blood Hematocrit (%) Serum Albumin (g/dL) Preoperative renal failure Creatinine (mg/dL) Estimated Glomerular Filtration Rate (mL/min/1.73m2) On Dialysis
VARC-2 Classification of Kidney Disease
p-Value
No AKI (n ¼ 230)
Stage 1 (n ¼ 92)
Stage 2 (n ¼ 21)
Stage 3 (n ¼ 31)
81.96 8.65 112 (49%) 53.95 12.76 167.21 10.68 73.59 18.16 8.61 4.82 46.25 14.69 0.60 0.15 158 (69%) 72 (31%) 70 (30%) 28 (12%) 72 (31%) 39 (17%) 85 (37%) 49/197 (25%) 34.64 4.42 3.28 0.38 10/214 (5%) 1.20 0.57 52.21 26.76
82.49 6.83 47 (51%) 54.10 11.98 166.08 10.44 75.96 19.81 9.96 4.96 44.72 14.61 0.58 0.15 45 (49%) 47 (51%) 31 (34%) 13 (14%) 37 (40%) 13 (14%) 41 (45%) 15/81 (19%) 32.98 5.04 3.27 0.45 9/84 (11%) 1.40 0.47 44.97 22.89
82.05 5.68 7 (33%) 54.52 13.24 163.96 9.92 73.05 18.60 8.95 3.48 47.24 14.24 0.58 0.12 10 (48%) 11 (52%) 7 (33%) 3 (14%) 13 (62%) 6 (29%) 10 (48%) 2/18 (11%) 33.77 4.85 3.27 0.35 0 0.90 0.26 62.34 21.68
82.13 9.30 16 (52%) 54.23 8.45 167.50 8.89 76.15 15.99 13.73 11.44 41.90 13.59 0.62 0.14 19 (61%) 12 (39%) 7 (23%) 4 (13%) 15 (48%) 5 (16%) 12 (39%) 3/25 (12%) 34.10 4.25 3.10 0.31 15/28 (54%) 2.66 2.15 30.78 18.19
0
0
0
11 (36%)
<
< < <
0.963 0.513 0.997 0.544 0.686 0.001 0.393 0.807 0.005 0.005 0.700 0.966 0.012 0.527 0.533 0.236 0.036 0.246 0.001 0.001 0.001
< 0.001
STS-PROM ¼ Society of thoracic surgeons predicted risk of mortality; TAVR ¼ transcatheter aortic valve replacement.
Table 3 Operative outcomes Variable
Operative Mortality Contrast dye load (ml) Total Ventilator time (hours) Total ICU Time (hours) Intraoperative Blood Products Given Creatinine (mg/dL) New-onset Renal Failure Postoperative Renal Failure requiring Dialysis
VARC-2 Classification of Kidney Disease
p-Value
No AKI (n ¼ 230)
Stage 1 (n ¼ 92)
Stage 2 (n ¼ 21)
Stage 3 (n ¼ 31)
7 (3%) 166.73 88.16 32.90 89.52 76.23 83.49 63 (27%) 1.21 0.42 0 0
7 (8%) 157.20 91.86 89.85 191.52 163.71 198.92 34 (37%) 2.02 0.66 0 0
5 (24%) 205.14 169.93 211.26 327.65 290.30 309.83 10 (48%) 2.07 0.61 8 (38%) 0
10 (32%) 186.96 112.25 243.78 354.08 341.54 345.02 11 (36%) 4.80 1.92 28 (90%) 12 (39%)
Although some evidence exists to suggest the VARC-2 criteria may capture additional cases of AKI missed by the initial definition,21 very few reports are available to assess how applying VARC-2 AKI criteria may affect what was previously demonstrated by the multitude of studies applying the initial criteria.22,23 Konigstein et al23 applied VARC-2 criteria to a series of patients with TAVR, who received either Edwards SAPIEN XT (26% of patients) or CoreValve (74%) prostheses and reported a 15.6% incidence (14% stage 1, 1.6% stage 2, and 0% stage 3) of AKI, with no patients requiring RRT. The investigators noted their uncharacteristically low incidence of reported AKI and suggested that a strict adherence to several renal protective strategies explained their success in reducing postoperative AKI. However, the low incidence of AKI may have also
< 0.001 0.153 < 0.001 < 0.001 0.121 < 0.001 < 0.001 0.003
been influenced by the low mean STS-PROM of the patients in this study (4.1%). In comparison, the STS-PROM in our cohort was 9.4% and is reported to be 7.1% in the transcatheter valve therapy registry.24 The incidence of AKI (38.0%) in our study is indeed higher than reported in previous most studies although this result may reflect the less restrictive VARC-2 criteria applied to our patient population and the significantly increased STS-PROM compared with the Konigstein cohort. In contrast, the rate of new requirement for RRT (3.1%) is consistent with previous reports, a result that is independent of VARC criteria definitions. Similar to previous studies, we demonstrate that increased baseline creatinine level, increased contrast dye load, and TA-TAVR approach were all predictive of
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The American Journal of Cardiology (www.ajconline.org)
Figure 1. Three-year survival by AKI stage.
significant AKI (stage 2/3) postoperatively.14 Of note, it is controversial if the more invasive TA approach itself or co-morbidities favoring this approach lead to the increased AKI rate compared with TF-TAVR. The association of contrast dye load and AKI is of importance, as this represents a modifiable factor to decrease the risk of AKI. Already reported methods of improving contrast induced AKI, including saline hydration and the RenalGuard System (PLC Medical Systems, Milford, Massachusetts) will need further evaluation in the TAVR population.25e27 AKI has been linked to increased operative mortality10,11 and mid-term mortality,10,20,21 but little is known about the impact of AKI on survival beyond 1 year. Our study is the first to study the effects of AKI after TAVR with the Edwards SAPIEN prosthesis out to 3 years. We have demonstrated that AKI after TAVR does in fact impact mortality at 3 years and that higher AKI stages (stage 2/3) are associated with an increased mortality. This suggests that efforts to reduce the incidence of AKI after TAVR may have the potential to improve outcomes for patients at high risk and inoperable patients with severe AS. Limitations of this study include those expected of a retrospective analysis of a prospectively maintained database at 2 centers. As such, the results may be subject to the effects of possible confounders or may not be generalizable to other centers. Furthermore, patients in this analysis were treated with the first generation Edwards SAPIEN valves available in the United States. Thus, the rate of perioperative complications may differ with more recently available devices. Disclosures
Figure 2. Three-year survival AKI stage 0/1 versus AKI stage 2/3.
Dr. Mack serves as an uncompensated member of the Executive Committee of the Placement of Aortic Transcatheter Valve (PARTNER) trial. The other authors have no conflicts of interest to disclose.
Figure 3. OR for AKI stage 2/3. OR ¼ odds ratio.
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