Impact of Diabetes Mellitus and Hemoglobin A1C on Outcome After Transcatheter Aortic Valve Implantation

Impact of Diabetes Mellitus and Hemoglobin A1C on Outcome After Transcatheter Aortic Valve Implantation Ehud Chorin, MD, PhDa,*, Ariel Finkelstein, MDa, Shmuel Banai, MDa, Galit Aviram, MDb, Michael Barkagan, MDa, Leehee Barak, MMedSca, Gad Keren, MDa, and Arie Steinvil, MDa Surgical aortic valve replacement (SAVR) is associated with an increased mortality risk in elderly or high-risk patients. Transcatheter aortic valve implantation (TAVI) is an alternative to surgery in patients with symptomatic severe aortic stenosis who are inoperable or at high operative risk. The impact of diabetes mellitus (DM) on patients referred to TAVI merits further investigation. The aim of our study was to evaluate the clinical characteristics and the impact of DM status on the updated Valve Academic Research Consortium 2 edefined outcomes of TAVI and to stratify patient outcomes according to their initial glycated hemoglobin (HbA1c) levels. We enrolled and stratified patients who underwent TAVI at our institution according to DM status. A total of 586 patients were enrolled: 348 (59%) without DM and 238 (41%) with DM. There were no significant differences in 30-day mortality patients with diabetes compared to patients without diabetes (3.3% vs 2.9%, p [ 0.974). Insulin-treated DM was not associated with adverse outcome in comparison to orally treated DM. To delineate the prognostic power of HbA1C in these patients, the cohort was divided into 3 groups according to HbA1C levels (<5.7%, 5.7% to 6.49%, and ‡6.5%). Patients with HbA1C ‡6.5% were at increased risk for mortality during follow-up (hazard ratio 2.571, 95% confidence interval 1.077 to 6.136, p [ 0.033) compared to patients with HbA1C <5.7%. In conclusion, unlike SAVR, DM is not associated with an increased mortality risk after TAVI, nor is it associated with increased complications rates. A more poorly controlled disease, as manifested by elevated HbA1c levels, may be associated with increased mortality during long-term follow-up. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-) Transcatheter aortic valve implantation (TAVI) is an alternative to surgery for patients with symptomatic severe aortic stenosis who are inoperable or at high operative risk.1e3 Diabetes mellitus (DM) has been considered a marker of poor prognosis after cardiac surgery in the Society of Thoracic Surgeons (STS) and the EuroSCORE II risk scores.4,5 The Placement of Aortic Transcatheter Valves (PARTNER) trial6,7 is a randomized study that compared TAVI with the current standard of treatment, conventional SAVR. A post hoc analysis of the PARTNER trial examined outcomes stratified according to DM status of patients randomly assigned to undergo TAVI or SAVR. Results of that analysis suggested that there was a survival benefit, no increase in stroke, and less renal failure in the patients with DM who underwent TAVI compared with those who underwent SAVR.8 Conrotto et al9 recently reported that DM did not significantly affect complication rates in patients who underwent TAVI. Nonetheless, they found that insulintreated DM, but not orally treated DM, was independently associated with death and myocardial infarction (MI) during Departments of aCardiology and bRadiology Imaging, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Manuscript received July 20, 2015; revised manuscript received and accepted September 15, 2015. See page 5 for disclosure information. *Corresponding author: Tel: (þ972) 36974762, 972527360498 (Mobile); fax: (þ972) 36968844. E-mail address: [email protected] (E. Chorin). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.09.032

a median follow-up of 400 days. To the best of our knowledge, no previous TAVI cohort study had used periprocedural glycated hemoglobin A1c (HbA1c) levels to report undiagnosed DM. The aim of our study was to evaluate the impact of DM status on the updated Valve Academic Research Consortium 2edefined outcomes of TAVI and to stratify patient outcome according to initial HbA1c levels.10 Methods We retrospectively analyzed the medical records of 586 consecutive patients, who underwent TAVI at the Tel Aviv Sourasky Medical Center from March 2009 to December 2014. Data were collected prospectively as part of the Tel-Aviv Prospective Angiography Study, as previously described,11,12 after obtaining informed consent from each patient as approved by the institutional ethics committee. As previously reported, severe aortic stenosis was diagnosed by a combination of clinical, echocardiographic, and hemodynamic criteria. A dedicated heart team, consisting of an interventional cardiologist, a cardiac surgeon, and a senior echocardiographist, decided on patient eligibility for TAVI based on predetermined criteria.13 The TAVI procedure at our institute has been previously described in depth.14 In brief, 2 types of aortic valve prostheses were implanted: the CoreValve prosthesis (Medtronic, Minneapolis, Minnesota) and the Edwards Sapien XT prosthesis (Edwards Lifesciences, Irvine, California). Three senior interventional cardiologists performed the peripheral www.ajconline.org

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Table 1 Baseline patient characteristics Variable

Age (mean  SD) (years) Women Hypertension Dyslipidemia Ever smoker Peripheral Vascular Disease Ejection Fraction < 50% Coronary Artery Disease before evaluation Previous Myocardial Infarction Prior coronary artery bypass graft surgery Prior valve surgery Prior Stroke Atrial Fibrillation Chronic Obstructive Pulmonary Disease Creatinine Clearance Test Dialysis Echocardiography parameters (Baseline) Echo Ejection Fraction (mean  SD) Echo peak gradient Echo mean gradient Echo Aortic Valve Area Echo EPASP Risk scores to predict operative mortality STS Score Euroscore 2 Logistic Euroscore 1

Total (n¼586)

Diabetes Mellitus

P value

Yes (n ¼238)

No (n¼ 348)

82.58 5.910 338 (57.7%) 512 (87.4%) 475 (81.1%) 166 (28.3%) 38 (6.5%) 98 (16.7%) 357(60.9%) 111 (18.9%) 104 (17.7%) 12 (2%) 67 (11.4%) 184 (31.4%) 98(16.7%) 51.4219.1 12 (2%)

81.54 6.215 129 (54.2%) 218 (91.6%) 212(89.1%) 68 (28.6%) 13 (5.5%) 38 (16%) 150 (63%) 51 (21.4%) 51 (21.4%) 7 (2.9%) 26 (10.9%) 73 (30.7%) 40 (16.8%) 51.8021.21 6 (2.5%)

83.3  5.7589 209 (60.1%) 294 (84.5%) 263 (75.6%) 98 (28.2%) 25 (7.2%) 60 (17.2%) 207 (59.5%) 60 (17.2%) 53 (15.2%) 5 (1.4%) 41 (11.8%) 111 (31.9%) 58 (16.7%) 51.1617.54 6 (1.7%)

<0.001 0.159 0.011 <0.001 0.931 0.406 0.685 0.388 0.204 0.054 0.207 0.749 0.754 0.964 0.705 0.504

55.748.070 76.64 22.369 46.8614.607 0.7250.1795 38.6716.574

55.738.481 72.4719.435 44.0712.873 0.7450.1714 40.0617.057

55.757.790 79.4923.781 48.7415.414 0.7110.1837 37.7516.207

0.975 <0.001 <0.001 0.023 0.120

4.182.5 6.2325.00 16.3810.38

4.72.6 6.6445.37 16.310.78

3.82.4 5.9514.72 16.43110.09

<0.001 0.100 0.879

Hypertension: Includes patients with previously documented diagnoses of hypercholesterolemia. Dyslipidemia: Includes patients with previously documented diagnoses of Dyslipidemia.

aspects of all the TAVI procedures (i.e., introduction of the sheaths, Prostar deployment, and the suturing of the entry ports). Valve type and size were planned before the procedure according to clinical, echocardiographic, angiographic, and computerized tomography parameters and at the discretion of the senior interventional cardiologist. The available valve sizes for the Edwards Sapien XT prosthesis were 23 and 26 mm, and the valve sizes for the CoreValve prosthesis were 26, 29, and 31 mm. After the valve was implanted, the patients were monitored at the cardiac intensive care unit, where vital signs were recorded continuously during the first 24 hours after the procedure and at least 3 times daily thereafter. All complications following the procedure were defined as such according to the Valve Academic Research Consortium.10 The diagnosis of previous DM was documented according to patient history using a prespecified registry questionnaire, current admission, previous medical records, and baseline medications. The patients were further divided into insulintreated DM or orally treated DM. Blood samples for HbA1C levels were obtained within the first 24 hours after the procedure. In the present analysis, we used previously described HbA1c cutoffs15 for defining no DM, pre-DM, and DM (<5.7%, 5.7% to 6.49%, and 6.5%, respectively) to stratify outcome. As recommended in those guidelines,15 patients without a known history of DM or under DM treatment with a HbA1c level of 6.5% were defined as having DM. This led to the classification of 26 patients (4%) with no

reported history of DM or lacking DM treatment as having DM. Because prior studies relied on patient report for the definition of DM, all analyses were repeated with and without the guideline-derived definition of DM15 to compare our results to previous ones. All data are displayed as mean (standard deviation) for continuous variables and as the number (percentage) of patients in each group for categorical variables. The Student t test and the chi-square test were used to evaluate the statistical significance of differences between continuous and categorical variables, respectively. Multivariate adjusted Cox proportional hazard models were fitted for all-cause mortality as the dependent variable and adjusted to variables previously associated with mortality after TAVI. To avoid overfitting, we decided on a more restrictive variable selection and included only variables that have a p value <0.1 on univariate analysis and/or that are significantly different between the HbA1C groups and were not suspected for co-linearity. All the analyses were considered significant at a 2-tailed p value of <0.05. The SPSS statistical package was used to perform all statistical evaluation (version 21; SPSS, Chicago, Illinois). Results A total of 586 consecutive patients (57% women) who underwent TAVI at our institution from March 2009 to

Valvular Heart Disease/Prognostic Value of DM and Hemoglobin A1C After TAVI

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Table 2 Patients outcomes stratified by DM Variable

In Hospital Outcomes New Atrial Fibrillation Conduction defect New Pacemaker Venous thromboembolism Sepsis In hospital mortality Hospitalization days 30 Days Outcome Hospitalization for exacerbation/Pulmonary congestion Myocardial Infarction Cardiogenic Shock Respiratory Failure Ventricular Tachycardia Ventricular Fibrillation Acute Kidney Injury Stage 2 or 3 Vascular complications - Major Stroke Conversion to open Surgery Unplanned use of cardiopulmonary bypass Coronary Obstruction Ventricular septal perforation Mitral valve damage Tamponade Endocarditis Valve thrombosis Valve migration Valve embolization TAV-in-TAV Mortality Extended follow-up 1 year mortality* All time mortality

Total (n¼586)

Diabetes Mellitus

P value

Yes (n ¼238)

No (n¼ 348)

33 (5.6%) 191 (32.6%) 103 (17.6%) 4 (0.68%) 12 (2) 17 (2.9%) 8.095.27

10 (4.2%) 81 (34%) 46 (19.3%) 0 5 (2.1) 7(2.9%) 8.176.09

23 (6.3%) 110 (31.6%) 57(16.4%) 4 (1.06%) 7 (2) 10 (2.9%) 8.03 4.63

0.214 0.539 0.357 0.252 0.940 0.962 0.742

26 (4.4%) 0 13 (2.2%) 33 (5.6%) 1 (0.2%) 2 (0.3%) 12 (2%) 52(8.9%) 9 (1.5%) 3 (0.5%) 0 2 (0.3%) 0 2 (0.3%) 7 (1.2%) 2 (0.3%) 0 2 (0.3%) 5 (0.9%) 3 (0.5%) 17 (2.9)

12 (5%) 0 6 (2.5%) 14 (5.9%) 1 (0.4%) 2 (0.8%) 7 (3%) 19 (8%) 3 (1.3%) 1 (0.4%) 0 0 0 1 (0.4%) 1 (0.4%) 1 (0.4%) 0 0 2 (0.8%) 1 (0.4%) 7 (3% )

14 (4%) 0 7 (2%) 19 (5.4%) 0 0 5 (1.5%) 33 (9.5%) 6 (1.7%) 2 (0.6%) 0 2 (0.6%) 0 1 (0.3%) 6 (1.7%) 1 (0.3%) 0 2 (0.6%) 3 (0.9%) 2 (0.6%) 10 (2.9%)

0.556

65 (11.1%) 122 (21%)

31 (17.6%) 51 (21.4%)

34 (12.3%) 71 (20.4%)

0.114 0.764

0.681 0.827 0.226 0.087 0.207 0.531 0.654 0.797 0.241 0.787 0.154 0.787 0.241 0.978 0.797 0.974

* 453 (77%) patients with at least 1 year follow up.

December 2014 were included in the study. HbA1c levels could be obtained for 531 (91%) of all patients included in the study. From the 586 patients, 212 had been previously diagnosed as having DM. An additional 26 patients (4%) had HbA1c levels of 6.5 g/dl and were newly defined as having DM, yielding a total of 238 patients with DM (41%). Demographic data, clinical characteristics, and baseline echocardiographic characteristics of the study population stratified by DM status are presented in Table 1. The patients with DM were younger and had a higher prevalence of hypertension and dyslipidemia than the nondiabetic patients. The patients with DM had lower mean peak and mean aortic valve gradients, as measured by echocardiography at baseline. The DM and non-DM groups did not show any significant differences in other characteristics. The mean follow-up time was 641 and 729 days for the DM and non-DM groups, respectively. There were no significant differences between the patients with and without DM regarding the incidence of allcause mortality during hospitalization, during the first 30 days after undergoing TAVI, at 1 year, or during the entire post-TAVI follow-up (Table 2). Similarly, no

differences were found regarding MI, stroke, and reinterventions at follow-up. KaplaneMeier curves for all-cause mortality up to 4 years of follow-up are presented in Figure 1: there were no differences in mortality between patients with and without DM (p ¼ 0.381 log-rank test). Fifty-seven of the 238 patients with DM were untreated. In a subanalysis, the remaining 181 patients with DM were divided into insulin-treated versus orally treated groups (Supplementary Table 1). Insulin-treated patients were younger than orally treated patients (78.3 vs 81.5, p ¼ 0.002), and the incidence of a previous MI, a previous coronary artery bypass grafting, and a reduced ejection fraction was higher in the insulin-treated patients. Nevertheless, complications were not significantly higher for the insulin-treated patients with DM compared to the orally treated ones (Supplementary Table 2). Patients with HbA1c level 6.5 were younger with a higher incidence of dyslipidemia. They had larger aortic valve area and lower mean peak and mean aortic valve gradients, as measured by echocardiography at baseline (Supplementary Table 3). There was a trend toward higher incidence of all-cause mortality during hospitalization with

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Figure 1. KaplaneMeier curves for all-cause mortality after TAVI stratified by DM status.

rising HbA1c levels, during the first 30 days after TAVI, at 1 year, or during the entire post-TAVI follow-up in univariate models (Supplementary Table 4). However, when analyzing results between the HbA1c >6.5 patients versus HbA1c <5.7 patients, we found a significant correlation with all-cause mortality (p ¼ 0.048) Furthermore, in multivariate Cox regression analysis, HbA1c level 6.5 was independently correlated with allcause mortality compared with HbA1c of <5.7% (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.18 to 6.64, p ¼ 0.019), whereas an HbA1c level from 5.7 to 6.49 was found to be only marginally significant (multivariate Cox proportional hazard model: Table 3, Figure 2). In a similar Cox proportional hazard model for all-cause mortality with extensive restriction on variable selection (variables with a p value <0.1 in the baseline characteristics according to HbA1C category, Supplementary Table 3), we found that HbA1c level 6.5 was independently correlated with all-cause mortality compared with HbA1c of <5.7% (HR 1.861, 95% CI 1.055 to 3.283, p ¼ 0.032), whereas an HbA1c level from 5.7 to 6.49 was not (HR 1.470, 95% CI 0.9 to 2.401, p ¼ 0.124; Supplementary Table 5). As mentioned previously, all these analyses were repeated with and without the guideline-derived definition of DM,14 with similar results. Discussion In this study, we evaluated the impact of DM status on the outcome of TAVI and stratified outcome according to the patients’ initial HbA1c levels. The main findings of the present analysis are (1) >40% of patients who underwent TAVI in our institution during the study period had DM and about 20% of them were insulin treated; (2) DM did not

significantly affect rates of procedural complications in patients who underwent TAVI; (3) insulin-treated DM was not associated with adverse outcome in comparison to orally treated DM; and (4) chronic hyperglycemia, as measured by HbA1c, may be associated with a higher mortality rate during follow-up of post-TAVI patients. The prognostic impact of HbA1c is a major revelation of our study that was not addressed in previous publications. TAVI has been shown to serve as a feasible option for inoperable patients. Mortality rates at 30 days after TAVI ranged from 5.4% to 11.5% and from 15% to 30% after 1 year of follow-up in large multicenter registries and the PARTNER trial.6 In a recent analysis, however, it was reported that most post-TAVI patients died from noncardiac reasons.16 Thus, a comprehensive evaluation of patient co-morbidities is crucial before undergoing the TAVI procedure to determine clinical outcome. Similar to previous reports, about 40% of the patients included in our “real-world” registry were diabetic and 20% of them were insulin treated. DM has been included as a marker of poor prognosis after cardiac surgery in STS risk score,4 and insulin-treated DM has now been specifically included in EuroSCORE II.5 Both the STS score and the EuroSCORE II were validated to predict 30-day mortality after cardiac surgery. However, analyses of the impact of DM status on patient outcome after TAVI have shown mixed results. Conrotto et al9 found that DM does not significantly affect rates of complications in patients who underwent TAVI. They also suggested that insulin-treated DM, but not orally treated DM, was independently associated with mortality and MI at midterm follow-up and should be included in future TAVI-dedicated scores. Puls et al17 identified DM as a significant predictor of short- and long-term mortality after TAVI (18.3% vs 7.3%, p ¼ 0.004; and 56% vs 30%, p <0.0001; respectively). The post hoc stratified analysis of the PARTNER trial, which examined outcomes stratified according to DM status of patients randomly assigned to receive transcatheter or SAVR, suggested there was a survival benefit, no increase in stroke, and less renal failure in patients with DM undergoing TAVI compared to SAVR.8 In the present study, 30-day mortality rate was not significantly higher in patients with DM than in patients without DM (3.3% vs 2.9% p ¼ 0.974), and we did not find any differences in complication rates (Table 2). Moreover, in a subanalysis of patients with DM, complications were not significantly higher in patients with orally treated DM compared to insulin-treated DM. At 1-year follow-up, patients with DM had a nonsignificantly higher mortality rate (17.6% vs 12.3%, p ¼ 0.114) compared with patients without DM. To the best of our knowledge, the impact of HbA1c levels on the clinical outcomes of patients after TAVI has not been previously reported. Our finding that patients with higher HbA1c have a greater mortality risk is, therefore, novel and should be examined in further research. Our study has some limitations that need to be mentioned. HbA1c levels could not be obtained for all patients included in the study. We acknowledge that our multivariate analysis did not address all possible procedural and postprocedural variables that may have affected the studied outcomes. However, because the procedure is still novel and evolving and there are many methodologic

Valvular Heart Disease/Prognostic Value of DM and Hemoglobin A1C After TAVI

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Table 3 Cox proportional hazard model for all-cause mortality Variable

HR (CI 95%)

Age >80 Body Mass Index <25 Body Mass Index 25-30 Body Mass Index >30 NYHA 4 Echo baseline, Ejection Fraction >50% Echo baseline, Ejection Fraction 30-50% Echo baseline, Ejection Fraction <30% Gender (Male) Frailty Dialysis Chronic Obstructive Pulmonary Disease Prior Atrial Fibrillation Prior heart surgery Peripheral vascular disease Echo base, Mitral Regurgitation (moderate or severe) Creatinine Clearance Test - base Echo Baseline pulmonary artery systolic pressure HbA1C <5.7 HbA1C 5.7-6.49 HbA1C >6.5 Hypertension Dyslipidemia DM by Hba1C Echo baseline Aortic Valve Area (cm2)

1.81 Ref. 1.257 1.750 0.932 Ref. 0.877 2.364 0.747 1.503 2.334 1.282 1.842 1.307 1.561 0.820 1.076 1.719 Ref. 1.635 2.8 1.748 0.542 0.776 0.511

P value

95% CI Lower

Upper

0.054

0.990

3.310

.611 0.282 0.777

0.521 0.631 0.574

3.033 4.855 1.515

0.614 0.134 0.232 0.162 0.150 0.352 0.006 0.362 0.225 0.674 0.784 0.072

0.527 0.768 0.464 0.849 0.737 0.760 1.191 0.736 0.760 0.325 0.869 0.952

1.459 7.281 1.205 2.661 7.392 2.162 2.848 2.321 3.207 2.068 1.820 3.103

0.067 0.019 0.118 0.008 0.456 0.323

0.966 1.181 0.869 0.344 0.399 0.135

2.766 6.643 3.516 0.855 1.511 1.937

Disclosures Dr. Finkelstein receives consultation fees from Medtronic Cardiovascular and Edwards Lifesciences.

Supplementary Data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.amjcard.2015.09.032.

Figure 2. Cox proportional hazard curves for all-cause mortality after TAVI stratified by HbA1c level at baseline.

variations in the current research, preprocedural and postprocedural clinical risk factors that affect mortality after TAVI remain to be defined.18e20 We do not have full medications data which might be a major confounder. Finally, our data could not determine what were the main causes for long-term mortality.

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