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Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation
Accepted Manuscript Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation Yigal Abramowitz, MD, Hasan Jilaihawi, MD, Tarun Chakravarty, MD, Geeteshwar Mangat, MD, Yoshio Maeno, MD, PhD, Yoshio Kazuno, MD, Nobuyuki Takahashi, MD, Hiroyuki Kawamori, MD, PhD, Wen Cheng, MD, Raj R. Makkar, MD PII:
S0002-9149(16)30300-9
DOI:
10.1016/j.amjcard.2016.02.040
Reference:
AJC 21730
To appear in:
The American Journal of Cardiology
Received Date: 22 December 2015 Revised Date:
16 February 2016
Accepted Date: 18 February 2016
Please cite this article as: Abramowitz Y, Jilaihawi H, Chakravarty T, Mangat G, Maeno Y, Kazuno Y, Takahashi N, Kawamori H, Cheng W, Makkar RR, Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.02.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation
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Yigal Abramowitz, MD, Hasan Jilaihawi, MD, Tarun Chakravarty, MD, Geeteshwar Mangat, MD, Yoshio Maeno, MD, PhD, Yoshio Kazuno, MD, Nobuyuki Takahashi, MD, Hiroyuki Kawamori MD, PhD, Wen Cheng, MD, and Raj R. Makkar, MD a
Running title: TAVI in diabetic patients
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From the Cedars-Sinai Heart Institute, Los Angeles, California
Conflicts of interest: Dr. Makkar has received grant support from Edwards Lifesciences Corporation and St. Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic;
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and holds equity in Entourage Medical. Dr. Jilaihawi is a consultant for Edwards Lifesciences Corporation, St. Jude Medical, and Venus MedTech. All other authors report no relationships that could be construed as a conflict of interest.
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Funding: department internal resources
Corresponding Author: Yigal Abramowitz, MD, Cedars-Sinai Heart Institute, Los Angeles, California. E-mail: [email protected]. Telephone number: (310) 423-3977; Fax number: (310) 423-0106. Mailing address: Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, AHSP, Suite A3600, Los Angeles, CA, 90048
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Abstract Several clinical variables have been identified as predictors of clinical outcome following
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transcatheter aortic valve implantation (TAVI). Nonetheless, there is limited and contradictive data on the impact of diabetes mellitus (DM) on the prognosis of patients that undergo TAVI. We aimed to investigate the clinical characteristics and the early and midterm outcomes after
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TAVI according to DM status. From 802 consecutive patients that underwent TAVI, we
compared 548 patients with no DM to 254 diabetic patients (177 orally treated and 77 insulin
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treated). Patients with DM were younger, had higher body mass index (BMI) and incidence of coronary artery disease (CAD) and lower incidence of frailty. Device success, 30-day mortality and major complications rates were similar between groups. One-year mortality was 12.1% for patient with DM and 12.2% for patients without DM (p=0.91). In a multivariable regression
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analysis including age, BMI, CAD and frailty, DM was associated with decreased overall survival. This was driven by increased overall mortality of the insulin treated DM subgroup (HR 2.40; 95% CI:1.32-4.37;p<0.01). In conclusion, DM does not affect short term mortality or rates
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of complications following TAVI. Insulin treated DM, but not orally treated DM, is independently associated with death at midterm follow-up and therefore aggressive
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cardiovascular risk factor modification as well as intense glycemic control should be considered for insulin treated DM patients with severe AS that undergo TAVI.
Key words: diabetic, aortic stenosis, transcatheter aortic valve replacement, TAVI
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Introduction DM adversely affects morbidity and mortality for cardiovascular diseases and procedures 1. DM
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has been independently associated with increased morbidity and mortality after surgical aortic valve replacement 2. Transcatheter aortic valve implantation (TAVI) has emerged as a treatment option for inoperable or high-risk surgical patients with severe aortic stenosis (AS) 3,4. There is
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limited and contradictive data on the impact of DM on the prognosis of patients with severe aortic stenosis that undergo TAVI 5–9. Surprisingly, in a recent sub-study of the PARTNER trial,
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1-year mortality was significantly higher in patients without DM compared to patients with diabetes, although multivariable analysis was not performed 10. The purpose of this study was to evaluate the clinical characteristics and the early and midterm clinical outcomes after TAVI according to DM status.
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Methods
We examined consecutive high-risk patients with severe symptomatic AS that underwent TAVI during a 3-year period at our institute. All patients had congestive heart failure with New-York
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Heart Association (NYHA) class II-IV symptoms. Aortic valve disease was assessed initially with transthoracic echocardiography followed by an ECG-gated, multi-slice CT angiography
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study. Decision for TAVI sizing was made by the Heart Team using data from all available imaging modalities at the time of the procedure including immediate pre-procedural 3dimensional transesophageal echocardiography (TEE). TAVI was performed under general anesthesia in all cases. All patients were worked up for “transfemoral first” approach; and alternate access was used in patients ineligible for transfemoral approach. Patients were divided into 3 groups according to their DM status and kind of treatment: patients without DM, patients
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with orally treated DM, and patients with insulin treated DM. The study was approved by the Institutional Review Board at the Cedars-Sinai Medical Center. Baseline clinical, echocardiographic and procedural details for TAVI were recorded for
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all patients including 1 month clinical and echocardiographic assessments during a follow-up visit. We compared patients without diabetes to patients with orally and insulin treated DM. Early outcomes were defined as 30-day mortality and complications rate. Mid-term outcomes
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were defined as 1-year mortality and overall mortality (mortality during the study period). TAVI endpoints, device success and adverse events were considered according to the Valve Academic
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Research consortium (VARC)-2 definitions 11.
All data were summarized and displayed as mean ± standard deviation (SD) for continuous variables and as number (percentage) of patients in each group for categorical variables. The student’s t-test and Pearson χ2 tests were used to evaluate statistical significance
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between continuous and categorical variables, respectively. Cox multivariable regression analysis was performed to identify independent variables that correlate to overall mortality in patients with and without DM. The multivariable model was built by selecting baseline and
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procedural variables that satisfied the entry criterion of p<0.05 for a difference between patients with and without DM in a univariate analysis: patient age, body mass index (BMI), coronary
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artery disease (CAD), mean aortic valve gradients and frailty. A similar model was built to compare overall mortality between patients with no DM vs. orally treated DM vs. insulin treated DM. For this model additional variables that were different between insulin treated DM patients and patients without DM were included: chronic renal failure and ejection fraction. Another model was used in order to assess predictors of overall mortality for the entire cohort. For this model we performed a Cox regression analysis including all variables that were found to
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influence overall mortality among the entire study participants (with an entry criterion of p<0.2). All of the analyses were considered significant at a 2-tailed P value of<0.05. The SPSS statistical package, version 20.0 was used to perform all statistical evaluation (SSPS Inc. Chicago, IL,
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USA).
Results
Between January 2012 and January 2015, 802 consecutive patients underwent TAVI at our
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institute. From this cohort, 548 patients had no DM (68.3%), 177 had orally treated DM (22.1%)
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and 77 had insulin treated DM (9.6%). The mean age of the patients was 82.0 ± 8.5. The baseline clinical, echocardiographic and CT characteristics of the study population are shown in Table 1. Several baseline characteristics were not similar between groups. Patients with DM were younger and had higher BMI compared to patients without DM. CAD was significantly more prevalent and frailty was significantly less prevalent in patients with DM.
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Procedural details are shown in Table 2. There were no significant differences in valve size, valve type or vascular access used between groups. Device success was 96.0% vs. 93.7% in the no DM vs. the DM group, respectively (p=0.16). Fluoroscopy time was similar between
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groups, but total amount of contrast used was higher in patients with DM (mean: 93.8ml vs.
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85.6ml; p=0.03). Postprocedural TEE perivalvular leak grades and postprocedural aortic valve gradients were not different between groups. The mean follow-up period was 13.2±8.3 months. All-cause mortality up to 30-days was
2.8% vs. 2.9% in patients with and without DM, respectively (p=0.90). Thirty-day VARC-2 endpoints are summarized in Table 3. There were no significant differences in all VARC-2 defined end-points between the 3 groups. One-year mortality was 12.1% for patient with DM and 12.2% for patients without DM (p=0.91). When comparing patients with DM (both insulin and orally
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treated) to patients without DM in a multivariable model, DM was independently associated with increased mortality (hazard ratio [HR] 1.51; 95% confidence interval [CI]:1.004-2.26; p=0.048) (Figure 1A). When the multivariable model included all 3 groups separately (Figure 1B), insulin
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treated DM was independently associated with increased mortality (HR 2.40; 95% CI:1.32-4.37; p<0.01) and orally treated DM was not associated with increased mortality (HR 1.22; 95%
CI:0.76-1.96; p=0.41). Frailty (HR 2.2, 95% CI 1.47-3.34; p<0.001) and chronic renal failure
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(HR 2.86, 95% CI 1.88-4.35; p<0.001) were also found to be independently associated with increased mortality in this model. Overall independent predictors of mortality for the entire
alternative access (Table 4).
Discussion
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cohort included insulin treated DM, chronic lung disease, chronic renal failure, frailty and
The results of the present study indicate that performing TAVI in patients with DM is not
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associated with increased short-term complications or mortality. Patients with DM had similar device success, 30-days mortality and major complications following the procedure. Similar finding were found when we examined separately insulin-treated diabetic patients. We also
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found that DM is associated with decreased overall survival during a mid-term follow-up period.
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This is driven mainly by increased overall mortality in the insulin treated DM subgroup. DM has reached epidemic proportions worldwide and its prevalence is rising 12. It
adversely affects morbidity and mortality for all types of cardiovascular disease including CAD, heart failure and stroke 1,13–15. Diabetes also adversely influence post-procedural outcomes after percutaneous and surgical procedures 16,17. In patients with AS, DM is associated with increased hypertrophic remodeling, decreased left ventricular function and accelerated valvular disease progression 18–20. Moreover, it has been shown that DM is associated with significantly worse
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outcomes after valve operations 2,21. DM is therefore included in the STS risk score as a poor prognostic predictor after cardiac operation 22. Moreover, in the revised EuroScore II, insulintreated DM was added to the model that predicts short-term outcome following cardiac surgery23.
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Approximately third of the patients undergoing TAVI have DM, and between a third to half of them have insulin treated DM 5,8,10. Assessment of the effect of diabetic status on both the short and long-term prognosis following this procedure has therefore considerable importance.
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There have been limited number of studies that examined the short and longer-term effects of DM on the clinical outcomes following TAVI and the findings of these studies are contradictive . Assessment of predictors of increased short and long-term complications and mortality
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5–10
from TAVI databases, registries and clinical trials has suggested a link between DM and adverse clinical outcomes following TAVI. Tamburino et al., examined 663 patients that underwent TAVI and found that in a multivariable analysis DM is only associated with increased 30-days
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mortality and not with longer-term mortality 8. Similarly, DM was found to be independently associated with increased 30-day mortality among 1,256 patients in the OBSERVANT registry 7. On the other hand, analysis of predictors of mortality in the Iberio-American TAVI Registry
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revealed that DM is independently associated with long-term mortality and not with in-hospital mortality following valve implantation 9. Recently, a large analysis of the UK TAVI registry has
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demonstrated similar results 6. A possible explanation for these contradictive results may be that vascular and bleeding complications were significantly more common in previous years when device profile and vascular access sheaths were larger. An association between major vascular and bleeding complications and insulin treated DM have been demonstrated in the past 24,25. In our present contemporary analysis of clinical outcome following TAVI we found similar 30-day mortality and complications rate including vascular and major bleeding complications (Table 3).
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Surprisingly, in a recent PARTNER Trial sub-analysis of TAVI versus surgical aortic valve replacement the rate of all-cause mortality at 1 year was lower in patients with DM compared to non-diabetic patients that underwent TAVI (18.0% vs. 27.8% in the TAVI arm) 10.
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The authors highlighted that numerous baseline clinical differences between groups may
confounded the comparison, mainly higher BMI and younger age in the diabetic group that may contributed to a protective effect. Their observation of an apparent “diabetes paradox” requires
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further specific evaluation preferably with direct comparison of patients undergoing TAVI according to their diabetic status.
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Only 1 previous study have directly evaluated the relation between the clinical outcomes following TAVI and diabetic status, including sub-division to insulin and orally treated DM 5. This analysis included 511 patients that were treated until 2011. It demonstrated a trend towards higher in-hospital mortality (4.7% vs. 6.4% vs. 9.7% for patients with no DM, orally treated and
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insulin treated DM, respectively; p=0.09). Nonetheless, there was more than 40% of major bleeding in all groups, which is an extremely high rate even when compared to historical cohorts and this may explain their trend for increased short-term mortality in diabetic patients.
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In the present study we found in a multivariable model that diabetes is associated with increased mid-term all-cause mortality. Moreover, we have demonstrated that this was driven by
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increased overall mortality in the insulin treated DM subgroup and not in the orally treated DM subgroup (Figure 1). This is in concordance with the study of Conrotto et al. that demonstrated similar association 5. Interestingly, we did not find a diabetic paradoxical influence on the outcome although the baseline clinical differences were similar to those noted by Lindman et al. 10
. In both studies, patients with diabetes were younger and had higher BMI but our multivariable
model did not demonstrate independent association between age or BMI and mortality (Table 4).
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Frailty was a strong predictor of mortality in our present analysis. Nonetheless, the difference in frailty status between patient with and without DM was not presented in the subgroup PARTNER Trial analysis mentioned above and may partially explain their findings.
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The present study has several limitations. It is a single-center non-randomized observational study. Glycemic control (e.g. HgA1C) and duration of DM prior TAVI were not systematically collected and therefore were not available for analysis. Thus, it cannot be excluded that the level
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of diabetic control is more related to the outcome than the type of medication used. Furthermore, the current study did not examine the influence of surgical therapy for patients with severe AS in
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diabetic patients with severe AS and therefore the results should be interpreted with caution. Prospective and longer follow-up studies are needed to evaluate more comprehensively the
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prognostic value of diabetic status as a predictor of clinical outcomes following TAVI.
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Acknowledgments Funding: department internal resources.
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Conflicts of interest: Dr. Makkar has received grant support from Edwards Lifesciences Corporation and St. Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic; and holds equity in Entourage Medical. Dr. Jilaihawi is a consultant for Edwards Lifesciences Corporation, St. Jude Medical, and Venus MedTech. All other authors report no relationships
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that could be construed as a conflict of interest.
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1109.
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Figure Legend Figure 1: Cox regression survival curves up to 2 years of follow up for patients with and without
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DM that underwent TAVI. A) DM was independently associated with increased mortality (HR 1.51; 95% CI:1.004-2.26; p=0.048). The model was adjusted to age, BMI, mean aortic valve gradient, CAD, and frailty. B)
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Insulin treated DM was independently associated with increased mortality (HR 2.40; 95% CI:1.32-4.37; p<0.01). Orally treated DM was not significantly associated with increased
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mortality (HR 1.22; 95% CI:0.76-1.96; p=0.41). The model was adjusted to age, BMI, mean
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aortic valve gradient, CAD, frailty, ejection fraction and chronic renal failure.
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Table 1: Baseline patient characteristics.
Diabetes Mellitus No (n=548)
Orally treated (n=177)
Insulin treated (n=77)
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Variable Age (years) 82.9 ± 8.8 81.2 ± 7.9 77.2±8.7 Male 326 (59.5%) 108 (61.0%) 48 (62.3%) 2 25.8 ± 5.0 28.2 ± 6.4 30.8 ± 7.5 Body mass index (kg/m ) Hypertension 496 (90.5%) 164 (92.7%) 72 (93.5%) Coronary artery disease 337 (61.5%) 121 (68.4%) 59 (76.6%) Previous myocardial 86 (15.7%) 29 (16.4%) 15 (19.5%) infarction Previous coronary artery 134 (24.5%) 49 (27.7%) 26 (33.8%) bypass graft Previous valve surgery 44 (8.0%) 15 (8.5%) 8 (10.4%) Peripheral artery disease 201 (36.7%) 59 (33.3%) 24 (31.2%) Previous Stroke 67 (12.2%) 22 (12.4%) 14 (18.2%) Chronic lung disease 203 (37.0%) 63 (35.6%) 34 (44.2%) Chronic renal failure† 104 (19.0%) 30 (16.9%) 7 (9.1%) Previous pacemaker 106 (19.3%) 42 (23.7%) 18 (23.4%) Atrial fibrillation 187 (34.1%) 55 (31.1%) 27 (35.1%) Frailty 206 (37.6%) 56 (31.6%) 15 (19.5%) Society of Thoracic 7.9 ± 4.9 8.4 ± 5.4 8.8 ± 4.8 Surgeons score, (%) EuroScore II (%) 10.7 ± 7.4 8.9 ± 6.4 11.8 ± 8.4 Ejection fraction (%) 57.2 ± 14.5 58.1 ± 14.5 51.9 ± 17.2 2 Aortic valve area (cm ) 0.63 ± 0.15 0.65 ± 0.17 0.64 ± 0.18 Aortic valve mean 46.2 ± 13.3 45.2± 13.3 41.6± 14.7 gradient (mmHG) Aortic valve maximal 77.4 ± 20.6 75.5 ± 21.8 71.1 ± 23.5 gradient (mmHG) CT mean annulus 24.3 ± 2.7 24.2 ± 2.6 24.3 ± 2.8 diameter (mm) CT mean AV Agatston 3672 ± 2144 3576 ± 2237 3085 ± 1886 calcification score (AU)‡ Values are mean ± SD or n (%). ⃰ P<0.05 for patients with insulin treated DM vs. patients without DM † Glomerular filtration rate <30mL/min/m2 ‡Data was available for 612/802 patients Abbreviations: AU- Agatston Units; DM – diabetes mellitus.
p-value (DM vs. no DM)
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<0.001 0.60 ˂0.001 0.26 0.01 0.56 0.13 0.63 0.27 0.44 0.76 0.13 ⃰ 0.31 0.69 0.008 0.10 0.35 0.42 ⃰ 0.10 0.04 0.04 0.74 0.24
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Table 2: Procedural details
No (n = 548)
Diabetes Mellitus Orally treated Insulin treated (n = 177) (n = 77) p-value⃰
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Implanted valve size (mm): 157 (28.7%) 55 (31.1%) 19 (24.7%) 23 26 259 (47.3%) 71 (40.1%) 30 (39%) 46 (26%) 25 (32.5%) 29 120 (21.9%) 31 12 (2.2%) 5 (2.8%) 3 (3.9%) Implanted valve type: 143 (26.1%) 46 (26.0%) 17 (22.1%) Sapien† Sapien-XT† 236 (43.1%) 71 (40.1%) 41 (53.2%) 127 (23.2%) 42 (23.7%) 10 (13.0%) Sapien 3† Corevalve‡ 42 (7.7%) 18 (10.2%) 9 (11.7%) Vascular access: Transfemoral 469 (85.6%) 154 (87%) 69 (89.6%) Transapical 30 (5.5%) 10 (5.6%) 1 (1.3%) Transaortic 41 (7.5%) 13 (7.3%) 7 (9.1%) Subclavian 8 (1.5%) 0 0 Device success 526 (96.0%) 165 (93.2%) 73 (94.8%) 2nd valve 19 (3.5%) 8 (4.5%) 4 (5.2%) Postdilatation 55 (10.0%) 24 (13.6%) 8 (10.4%) Valve embolization 3 (0.5%) 2 (1.1%) 1 (1.3%) Fluoroscopy time (min.) 16.7 ± 8.4 17.0 ± 10.3 15.5 ± 6.1 Total contrast used (ml) 85.6 ± 43.2 92.7 ± 42.1 96.3 ± 52.2 TEE Postprocedural PVL: None/trace 394 (71.9%) 130 (73.4%) 66 (85.7%) Mild 136 (24.8%) 41 (23.2%) 10 (13.0%) Moderate/severe 18 (3.3%) 6 (3.4%) 1 (1.3%) Postprocedural AV 5.8 ± 5.2 5.7 ± 4.9 4.7 ± 4.7 gradient (mmHG) Values are mean ± SD or n (%). ⃰ p-value for patients with no DM vs. patients with DM † Edwards Lifesciences, Irvine, CA, USA ‡ Medtronic, Minneapolis, MN, USA Abbreviations: DM – diabetes mellitus; PVL – perivalvular leak; TEE- transesophageal echocardiography.
0.20
0.47
0.37
0.16 0.39 0.28 0.39 0.74 0.03 0.43
0.32
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Table 3: Clinical 30-days outcome.
No (n = 548)
Diabetes Mellitus Orally treated (n = 177)
Mortality
16 (2.9%)
5 (2.8%)
Cerebrovascular accident /
15 (2.7%)
3 (1.7%)
Myocardial infarction
3 (0.5%)
0 (0%)
1 (1.3%)
1
Respiratory failure
19 (3.5%)
3 (1.7%)
3 (3.9%)
0.40
Cardiogenic shock
9 (1.6%)
4 (2.3%)
2 (2.6%)
0.48
Cardiac tamponade
3 (0.5%)
1 (0.6%)
0 (0%)
1
Major bleeding
23 (4.2%)
6 (3.4%)
3 (3.9%)
0.66
Major vascular complications
16 (2.9%)
5 (2.8%)
2 (2.6%)
0.90
Minor vascular complications
53 (9.7%)
14 (7.9%)
4 (5.2%)
0.23
New permanent pacemaker
54 (12.1%)
15 (10.9%)
7 (11.5%)
0.70
8 (1.5%)
4 (2.3%)
1 (1.3%)
0.56
1.75 ± 0.7
1.64 ± 0.6
1.76 ± 0.8
0.25
Acute kidney injury stage 3
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New-York Heart Association functional class
Values are mean ± SD or n (%). ⃰ p-value for patients with no DM vs. patients with DM
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2 (2.6%)
0.90
2 (2.6%)
0.52
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implantation
p-value⃰
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transient ischemic attack
Insulin treated (n = 77)
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Table 4: Univariate and multivariate Cox proportional hazard analysis of overall mortality. Univariate analysis Hazard Ratio
Confidence Interval
p-value
Hazard Ratio
Age (years)
1.03
1.00-1.05
0.04
1.02
0.99-1.04
0.31
Body mass index (kg/m2)
0.96
0.93-99
0.03
1.00
0.96-1.04
1
Orally treated
1.13
0.77-1.78
0.59
1.21
0.75-1.98
0.42
Insulin treated
1.70
0.98-2.9
0.06
2.31
1.25-4.27
0.01
Chronic lung disease
1.46
1.02-2.11
0.05
1.68
1.10-2.58
0.02
Peripheral artery disease
1.63
Chronic renal failure*
3.27
Previous pacemaker
1.66
Atrial fibrillation
1.44
Frailty
2.48
Society of Thoracic Surgeons score, (%)
Valve type:
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1.34
0.90-1.98
0.15
2.23-4.80
<0.001
2.46
1.52-3.99
<0.001
1.10-2.49
0.02
1.03
0.64-1.66
0.90
0.99-2.09
0.06
1.38
0.91-2.10
0.13
1.71-3.61
<0.001
1.99
1.30-3.03
0.001
1.09
1.06-1.11
<0.001
1.03
0.99-1.06
0.14
0.98
0.97-0.99
0.002
1.01
0.99-1.02
0.48
0.98
0.97-0.99
0.005
0.99
0.98-1.00
0.08
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Aortic valve mean gradient (mmHG)
p-value
1.12-2.36
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Ejection fraction
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DM:
Confidence Interval
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Variable
Multivariate analysis
1.58
1.07-2.33
0.02
1.04
0.68-1.59
0.87
S3 vs. Sapien/XT/CV
0.41
0.21-0.80
0.01
0.74
0.37-1.50
0.41
Alternative access (transapical/ transaortic /subclavian)
2.40
1.57-3.67
<0.001
1.80
1.12-2.90
0.02
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Sapien vs. XT/S3/CV
* Glomerular filtration rate <30mL/min/m2 Abbreviations: CV – Corevalve; DM – diabetes mellitus; S3 - Sapien 3; XT - Sapien XT.
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S0002-9149(16)30300-9
DOI:
10.1016/j.amjcard.2016.02.040
Reference:
AJC 21730
To appear in:
The American Journal of Cardiology
Received Date: 22 December 2015 Revised Date:
16 February 2016
Accepted Date: 18 February 2016
Please cite this article as: Abramowitz Y, Jilaihawi H, Chakravarty T, Mangat G, Maeno Y, Kazuno Y, Takahashi N, Kawamori H, Cheng W, Makkar RR, Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.02.040. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Impact of Diabetes Mellitus on Outcomes After Transcatheter Aortic Valve Implantation
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Yigal Abramowitz, MD, Hasan Jilaihawi, MD, Tarun Chakravarty, MD, Geeteshwar Mangat, MD, Yoshio Maeno, MD, PhD, Yoshio Kazuno, MD, Nobuyuki Takahashi, MD, Hiroyuki Kawamori MD, PhD, Wen Cheng, MD, and Raj R. Makkar, MD a
Running title: TAVI in diabetic patients
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From the Cedars-Sinai Heart Institute, Los Angeles, California
Conflicts of interest: Dr. Makkar has received grant support from Edwards Lifesciences Corporation and St. Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic;
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and holds equity in Entourage Medical. Dr. Jilaihawi is a consultant for Edwards Lifesciences Corporation, St. Jude Medical, and Venus MedTech. All other authors report no relationships that could be construed as a conflict of interest.
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Funding: department internal resources
Corresponding Author: Yigal Abramowitz, MD, Cedars-Sinai Heart Institute, Los Angeles, California. E-mail: [email protected]. Telephone number: (310) 423-3977; Fax number: (310) 423-0106. Mailing address: Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, AHSP, Suite A3600, Los Angeles, CA, 90048
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Abstract Several clinical variables have been identified as predictors of clinical outcome following
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transcatheter aortic valve implantation (TAVI). Nonetheless, there is limited and contradictive data on the impact of diabetes mellitus (DM) on the prognosis of patients that undergo TAVI. We aimed to investigate the clinical characteristics and the early and midterm outcomes after
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TAVI according to DM status. From 802 consecutive patients that underwent TAVI, we
compared 548 patients with no DM to 254 diabetic patients (177 orally treated and 77 insulin
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treated). Patients with DM were younger, had higher body mass index (BMI) and incidence of coronary artery disease (CAD) and lower incidence of frailty. Device success, 30-day mortality and major complications rates were similar between groups. One-year mortality was 12.1% for patient with DM and 12.2% for patients without DM (p=0.91). In a multivariable regression
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analysis including age, BMI, CAD and frailty, DM was associated with decreased overall survival. This was driven by increased overall mortality of the insulin treated DM subgroup (HR 2.40; 95% CI:1.32-4.37;p<0.01). In conclusion, DM does not affect short term mortality or rates
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of complications following TAVI. Insulin treated DM, but not orally treated DM, is independently associated with death at midterm follow-up and therefore aggressive
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cardiovascular risk factor modification as well as intense glycemic control should be considered for insulin treated DM patients with severe AS that undergo TAVI.
Key words: diabetic, aortic stenosis, transcatheter aortic valve replacement, TAVI
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Introduction DM adversely affects morbidity and mortality for cardiovascular diseases and procedures 1. DM
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has been independently associated with increased morbidity and mortality after surgical aortic valve replacement 2. Transcatheter aortic valve implantation (TAVI) has emerged as a treatment option for inoperable or high-risk surgical patients with severe aortic stenosis (AS) 3,4. There is
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limited and contradictive data on the impact of DM on the prognosis of patients with severe aortic stenosis that undergo TAVI 5–9. Surprisingly, in a recent sub-study of the PARTNER trial,
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1-year mortality was significantly higher in patients without DM compared to patients with diabetes, although multivariable analysis was not performed 10. The purpose of this study was to evaluate the clinical characteristics and the early and midterm clinical outcomes after TAVI according to DM status.
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Methods
We examined consecutive high-risk patients with severe symptomatic AS that underwent TAVI during a 3-year period at our institute. All patients had congestive heart failure with New-York
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Heart Association (NYHA) class II-IV symptoms. Aortic valve disease was assessed initially with transthoracic echocardiography followed by an ECG-gated, multi-slice CT angiography
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study. Decision for TAVI sizing was made by the Heart Team using data from all available imaging modalities at the time of the procedure including immediate pre-procedural 3dimensional transesophageal echocardiography (TEE). TAVI was performed under general anesthesia in all cases. All patients were worked up for “transfemoral first” approach; and alternate access was used in patients ineligible for transfemoral approach. Patients were divided into 3 groups according to their DM status and kind of treatment: patients without DM, patients
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with orally treated DM, and patients with insulin treated DM. The study was approved by the Institutional Review Board at the Cedars-Sinai Medical Center. Baseline clinical, echocardiographic and procedural details for TAVI were recorded for
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all patients including 1 month clinical and echocardiographic assessments during a follow-up visit. We compared patients without diabetes to patients with orally and insulin treated DM. Early outcomes were defined as 30-day mortality and complications rate. Mid-term outcomes
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were defined as 1-year mortality and overall mortality (mortality during the study period). TAVI endpoints, device success and adverse events were considered according to the Valve Academic
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Research consortium (VARC)-2 definitions 11.
All data were summarized and displayed as mean ± standard deviation (SD) for continuous variables and as number (percentage) of patients in each group for categorical variables. The student’s t-test and Pearson χ2 tests were used to evaluate statistical significance
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between continuous and categorical variables, respectively. Cox multivariable regression analysis was performed to identify independent variables that correlate to overall mortality in patients with and without DM. The multivariable model was built by selecting baseline and
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procedural variables that satisfied the entry criterion of p<0.05 for a difference between patients with and without DM in a univariate analysis: patient age, body mass index (BMI), coronary
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artery disease (CAD), mean aortic valve gradients and frailty. A similar model was built to compare overall mortality between patients with no DM vs. orally treated DM vs. insulin treated DM. For this model additional variables that were different between insulin treated DM patients and patients without DM were included: chronic renal failure and ejection fraction. Another model was used in order to assess predictors of overall mortality for the entire cohort. For this model we performed a Cox regression analysis including all variables that were found to
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influence overall mortality among the entire study participants (with an entry criterion of p<0.2). All of the analyses were considered significant at a 2-tailed P value of<0.05. The SPSS statistical package, version 20.0 was used to perform all statistical evaluation (SSPS Inc. Chicago, IL,
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USA).
Results
Between January 2012 and January 2015, 802 consecutive patients underwent TAVI at our
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institute. From this cohort, 548 patients had no DM (68.3%), 177 had orally treated DM (22.1%)
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and 77 had insulin treated DM (9.6%). The mean age of the patients was 82.0 ± 8.5. The baseline clinical, echocardiographic and CT characteristics of the study population are shown in Table 1. Several baseline characteristics were not similar between groups. Patients with DM were younger and had higher BMI compared to patients without DM. CAD was significantly more prevalent and frailty was significantly less prevalent in patients with DM.
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Procedural details are shown in Table 2. There were no significant differences in valve size, valve type or vascular access used between groups. Device success was 96.0% vs. 93.7% in the no DM vs. the DM group, respectively (p=0.16). Fluoroscopy time was similar between
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groups, but total amount of contrast used was higher in patients with DM (mean: 93.8ml vs.
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85.6ml; p=0.03). Postprocedural TEE perivalvular leak grades and postprocedural aortic valve gradients were not different between groups. The mean follow-up period was 13.2±8.3 months. All-cause mortality up to 30-days was
2.8% vs. 2.9% in patients with and without DM, respectively (p=0.90). Thirty-day VARC-2 endpoints are summarized in Table 3. There were no significant differences in all VARC-2 defined end-points between the 3 groups. One-year mortality was 12.1% for patient with DM and 12.2% for patients without DM (p=0.91). When comparing patients with DM (both insulin and orally
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treated) to patients without DM in a multivariable model, DM was independently associated with increased mortality (hazard ratio [HR] 1.51; 95% confidence interval [CI]:1.004-2.26; p=0.048) (Figure 1A). When the multivariable model included all 3 groups separately (Figure 1B), insulin
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treated DM was independently associated with increased mortality (HR 2.40; 95% CI:1.32-4.37; p<0.01) and orally treated DM was not associated with increased mortality (HR 1.22; 95%
CI:0.76-1.96; p=0.41). Frailty (HR 2.2, 95% CI 1.47-3.34; p<0.001) and chronic renal failure
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(HR 2.86, 95% CI 1.88-4.35; p<0.001) were also found to be independently associated with increased mortality in this model. Overall independent predictors of mortality for the entire
alternative access (Table 4).
Discussion
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cohort included insulin treated DM, chronic lung disease, chronic renal failure, frailty and
The results of the present study indicate that performing TAVI in patients with DM is not
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associated with increased short-term complications or mortality. Patients with DM had similar device success, 30-days mortality and major complications following the procedure. Similar finding were found when we examined separately insulin-treated diabetic patients. We also
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found that DM is associated with decreased overall survival during a mid-term follow-up period.
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This is driven mainly by increased overall mortality in the insulin treated DM subgroup. DM has reached epidemic proportions worldwide and its prevalence is rising 12. It
adversely affects morbidity and mortality for all types of cardiovascular disease including CAD, heart failure and stroke 1,13–15. Diabetes also adversely influence post-procedural outcomes after percutaneous and surgical procedures 16,17. In patients with AS, DM is associated with increased hypertrophic remodeling, decreased left ventricular function and accelerated valvular disease progression 18–20. Moreover, it has been shown that DM is associated with significantly worse
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outcomes after valve operations 2,21. DM is therefore included in the STS risk score as a poor prognostic predictor after cardiac operation 22. Moreover, in the revised EuroScore II, insulintreated DM was added to the model that predicts short-term outcome following cardiac surgery23.
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Approximately third of the patients undergoing TAVI have DM, and between a third to half of them have insulin treated DM 5,8,10. Assessment of the effect of diabetic status on both the short and long-term prognosis following this procedure has therefore considerable importance.
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There have been limited number of studies that examined the short and longer-term effects of DM on the clinical outcomes following TAVI and the findings of these studies are contradictive . Assessment of predictors of increased short and long-term complications and mortality
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5–10
from TAVI databases, registries and clinical trials has suggested a link between DM and adverse clinical outcomes following TAVI. Tamburino et al., examined 663 patients that underwent TAVI and found that in a multivariable analysis DM is only associated with increased 30-days
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mortality and not with longer-term mortality 8. Similarly, DM was found to be independently associated with increased 30-day mortality among 1,256 patients in the OBSERVANT registry 7. On the other hand, analysis of predictors of mortality in the Iberio-American TAVI Registry
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revealed that DM is independently associated with long-term mortality and not with in-hospital mortality following valve implantation 9. Recently, a large analysis of the UK TAVI registry has
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demonstrated similar results 6. A possible explanation for these contradictive results may be that vascular and bleeding complications were significantly more common in previous years when device profile and vascular access sheaths were larger. An association between major vascular and bleeding complications and insulin treated DM have been demonstrated in the past 24,25. In our present contemporary analysis of clinical outcome following TAVI we found similar 30-day mortality and complications rate including vascular and major bleeding complications (Table 3).
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Surprisingly, in a recent PARTNER Trial sub-analysis of TAVI versus surgical aortic valve replacement the rate of all-cause mortality at 1 year was lower in patients with DM compared to non-diabetic patients that underwent TAVI (18.0% vs. 27.8% in the TAVI arm) 10.
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The authors highlighted that numerous baseline clinical differences between groups may
confounded the comparison, mainly higher BMI and younger age in the diabetic group that may contributed to a protective effect. Their observation of an apparent “diabetes paradox” requires
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further specific evaluation preferably with direct comparison of patients undergoing TAVI according to their diabetic status.
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Only 1 previous study have directly evaluated the relation between the clinical outcomes following TAVI and diabetic status, including sub-division to insulin and orally treated DM 5. This analysis included 511 patients that were treated until 2011. It demonstrated a trend towards higher in-hospital mortality (4.7% vs. 6.4% vs. 9.7% for patients with no DM, orally treated and
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insulin treated DM, respectively; p=0.09). Nonetheless, there was more than 40% of major bleeding in all groups, which is an extremely high rate even when compared to historical cohorts and this may explain their trend for increased short-term mortality in diabetic patients.
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In the present study we found in a multivariable model that diabetes is associated with increased mid-term all-cause mortality. Moreover, we have demonstrated that this was driven by
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increased overall mortality in the insulin treated DM subgroup and not in the orally treated DM subgroup (Figure 1). This is in concordance with the study of Conrotto et al. that demonstrated similar association 5. Interestingly, we did not find a diabetic paradoxical influence on the outcome although the baseline clinical differences were similar to those noted by Lindman et al. 10
. In both studies, patients with diabetes were younger and had higher BMI but our multivariable
model did not demonstrate independent association between age or BMI and mortality (Table 4).
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Frailty was a strong predictor of mortality in our present analysis. Nonetheless, the difference in frailty status between patient with and without DM was not presented in the subgroup PARTNER Trial analysis mentioned above and may partially explain their findings.
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The present study has several limitations. It is a single-center non-randomized observational study. Glycemic control (e.g. HgA1C) and duration of DM prior TAVI were not systematically collected and therefore were not available for analysis. Thus, it cannot be excluded that the level
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of diabetic control is more related to the outcome than the type of medication used. Furthermore, the current study did not examine the influence of surgical therapy for patients with severe AS in
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diabetic patients with severe AS and therefore the results should be interpreted with caution. Prospective and longer follow-up studies are needed to evaluate more comprehensively the
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prognostic value of diabetic status as a predictor of clinical outcomes following TAVI.
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Acknowledgments Funding: department internal resources.
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Conflicts of interest: Dr. Makkar has received grant support from Edwards Lifesciences Corporation and St. Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic; and holds equity in Entourage Medical. Dr. Jilaihawi is a consultant for Edwards Lifesciences Corporation, St. Jude Medical, and Venus MedTech. All other authors report no relationships
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that could be construed as a conflict of interest.
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CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A,
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Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation
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14. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–234.
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15. Peters SAE, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet Lond Engl 2014;383:1973–1980.
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16. Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patients. The National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation 1996;94:1818–1825.
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17. Thourani VH, Weintraub WS, Stein B, Gebhart SS, Craver JM, Jones EL, Guyton RA.
Ann Thorac Surg 1999;67:1045–1052.
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Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting.
18. Falcão-Pires I, Hamdani N, Borbély A, Gavina C, Schalkwijk CG, Velden J van der, Heerebeek L van, Stienen GJM, Niessen HWM, Leite-Moreira AF, Paulus WJ. Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial
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structure and cardiomyocyte stiffness. Circulation 2011;124:1151–1159. 19. Lindman BR, Arnold SV, Madrazo JA, Zajarias A, Johnson SN, Pérez JE, Mann DL. The adverse impact of diabetes mellitus on left ventricular remodeling and function in patients with
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severe aortic stenosis. Circ Heart Fail 2011;4:286–292. 20. Kamalesh M, Ng C, El Masry H, Eckert G, Sawada S. Does diabetes accelerate progression
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of calcific aortic stenosis? Eur J Echocardiogr 2009;10:723–725. 21. Hansen L, Winkel S, Kuhr J, Bader R, Bleese N, Riess F-C. Factors influencing survival and postoperative quality of life after mitral valve reconstruction. Eur J Cardio-Thorac Surg 2010;37:635–644.
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Thoracic Surgeons Quality Measurement Task Force. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2--isolated valve surgery. Ann Thorac Surg 2009;88:S23–42. 23. Nashef SAM, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, Lockowandt U.
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EuroSCORE II. Eur J Cardio-Thorac Surg 2012;41:734–744; discussion 744–745.
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Eisenhauer AC, Makkar RR, Bergman GW, Babaliaros V, Bavaria JE, Velazquez OC, Williams
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MR, Hueter I, Xu K, Leon MB, PARTNER Trial Investigators. Vascular complications after transcatheter aortic valve replacement: insights from the PARTNER (Placement of AoRTic
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TraNscathetER Valve) trial. J Am Coll Cardiol 2012;60:1043–1052.
25. Généreux P, Cohen DJ, Williams MR, Mack M, Kodali SK, Svensson LG, Kirtane AJ, Xu K, McAndrew TC, Makkar R, Smith CR, Leon MB. Bleeding complications after surgical aortic valve replacement compared with transcatheter aortic valve replacement: insights from the
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1109.
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PARTNER I Trial (Placement of Aortic Transcatheter Valve). J Am Coll Cardiol 2014;63:1100–
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Figure Legend Figure 1: Cox regression survival curves up to 2 years of follow up for patients with and without
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DM that underwent TAVI. A) DM was independently associated with increased mortality (HR 1.51; 95% CI:1.004-2.26; p=0.048). The model was adjusted to age, BMI, mean aortic valve gradient, CAD, and frailty. B)
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Insulin treated DM was independently associated with increased mortality (HR 2.40; 95% CI:1.32-4.37; p<0.01). Orally treated DM was not significantly associated with increased
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mortality (HR 1.22; 95% CI:0.76-1.96; p=0.41). The model was adjusted to age, BMI, mean
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Table 1: Baseline patient characteristics.
Diabetes Mellitus No (n=548)
Orally treated (n=177)
Insulin treated (n=77)
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Variable Age (years) 82.9 ± 8.8 81.2 ± 7.9 77.2±8.7 Male 326 (59.5%) 108 (61.0%) 48 (62.3%) 2 25.8 ± 5.0 28.2 ± 6.4 30.8 ± 7.5 Body mass index (kg/m ) Hypertension 496 (90.5%) 164 (92.7%) 72 (93.5%) Coronary artery disease 337 (61.5%) 121 (68.4%) 59 (76.6%) Previous myocardial 86 (15.7%) 29 (16.4%) 15 (19.5%) infarction Previous coronary artery 134 (24.5%) 49 (27.7%) 26 (33.8%) bypass graft Previous valve surgery 44 (8.0%) 15 (8.5%) 8 (10.4%) Peripheral artery disease 201 (36.7%) 59 (33.3%) 24 (31.2%) Previous Stroke 67 (12.2%) 22 (12.4%) 14 (18.2%) Chronic lung disease 203 (37.0%) 63 (35.6%) 34 (44.2%) Chronic renal failure† 104 (19.0%) 30 (16.9%) 7 (9.1%) Previous pacemaker 106 (19.3%) 42 (23.7%) 18 (23.4%) Atrial fibrillation 187 (34.1%) 55 (31.1%) 27 (35.1%) Frailty 206 (37.6%) 56 (31.6%) 15 (19.5%) Society of Thoracic 7.9 ± 4.9 8.4 ± 5.4 8.8 ± 4.8 Surgeons score, (%) EuroScore II (%) 10.7 ± 7.4 8.9 ± 6.4 11.8 ± 8.4 Ejection fraction (%) 57.2 ± 14.5 58.1 ± 14.5 51.9 ± 17.2 2 Aortic valve area (cm ) 0.63 ± 0.15 0.65 ± 0.17 0.64 ± 0.18 Aortic valve mean 46.2 ± 13.3 45.2± 13.3 41.6± 14.7 gradient (mmHG) Aortic valve maximal 77.4 ± 20.6 75.5 ± 21.8 71.1 ± 23.5 gradient (mmHG) CT mean annulus 24.3 ± 2.7 24.2 ± 2.6 24.3 ± 2.8 diameter (mm) CT mean AV Agatston 3672 ± 2144 3576 ± 2237 3085 ± 1886 calcification score (AU)‡ Values are mean ± SD or n (%). ⃰ P<0.05 for patients with insulin treated DM vs. patients without DM † Glomerular filtration rate <30mL/min/m2 ‡Data was available for 612/802 patients Abbreviations: AU- Agatston Units; DM – diabetes mellitus.
p-value (DM vs. no DM)
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<0.001 0.60 ˂0.001 0.26 0.01 0.56 0.13 0.63 0.27 0.44 0.76 0.13 ⃰ 0.31 0.69 0.008 0.10 0.35 0.42 ⃰ 0.10 0.04 0.04 0.74 0.24
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Table 2: Procedural details
No (n = 548)
Diabetes Mellitus Orally treated Insulin treated (n = 177) (n = 77) p-value⃰
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Implanted valve size (mm): 157 (28.7%) 55 (31.1%) 19 (24.7%) 23 26 259 (47.3%) 71 (40.1%) 30 (39%) 46 (26%) 25 (32.5%) 29 120 (21.9%) 31 12 (2.2%) 5 (2.8%) 3 (3.9%) Implanted valve type: 143 (26.1%) 46 (26.0%) 17 (22.1%) Sapien† Sapien-XT† 236 (43.1%) 71 (40.1%) 41 (53.2%) 127 (23.2%) 42 (23.7%) 10 (13.0%) Sapien 3† Corevalve‡ 42 (7.7%) 18 (10.2%) 9 (11.7%) Vascular access: Transfemoral 469 (85.6%) 154 (87%) 69 (89.6%) Transapical 30 (5.5%) 10 (5.6%) 1 (1.3%) Transaortic 41 (7.5%) 13 (7.3%) 7 (9.1%) Subclavian 8 (1.5%) 0 0 Device success 526 (96.0%) 165 (93.2%) 73 (94.8%) 2nd valve 19 (3.5%) 8 (4.5%) 4 (5.2%) Postdilatation 55 (10.0%) 24 (13.6%) 8 (10.4%) Valve embolization 3 (0.5%) 2 (1.1%) 1 (1.3%) Fluoroscopy time (min.) 16.7 ± 8.4 17.0 ± 10.3 15.5 ± 6.1 Total contrast used (ml) 85.6 ± 43.2 92.7 ± 42.1 96.3 ± 52.2 TEE Postprocedural PVL: None/trace 394 (71.9%) 130 (73.4%) 66 (85.7%) Mild 136 (24.8%) 41 (23.2%) 10 (13.0%) Moderate/severe 18 (3.3%) 6 (3.4%) 1 (1.3%) Postprocedural AV 5.8 ± 5.2 5.7 ± 4.9 4.7 ± 4.7 gradient (mmHG) Values are mean ± SD or n (%). ⃰ p-value for patients with no DM vs. patients with DM † Edwards Lifesciences, Irvine, CA, USA ‡ Medtronic, Minneapolis, MN, USA Abbreviations: DM – diabetes mellitus; PVL – perivalvular leak; TEE- transesophageal echocardiography.
0.20
0.47
0.37
0.16 0.39 0.28 0.39 0.74 0.03 0.43
0.32
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Table 3: Clinical 30-days outcome.
No (n = 548)
Diabetes Mellitus Orally treated (n = 177)
Mortality
16 (2.9%)
5 (2.8%)
Cerebrovascular accident /
15 (2.7%)
3 (1.7%)
Myocardial infarction
3 (0.5%)
0 (0%)
1 (1.3%)
1
Respiratory failure
19 (3.5%)
3 (1.7%)
3 (3.9%)
0.40
Cardiogenic shock
9 (1.6%)
4 (2.3%)
2 (2.6%)
0.48
Cardiac tamponade
3 (0.5%)
1 (0.6%)
0 (0%)
1
Major bleeding
23 (4.2%)
6 (3.4%)
3 (3.9%)
0.66
Major vascular complications
16 (2.9%)
5 (2.8%)
2 (2.6%)
0.90
Minor vascular complications
53 (9.7%)
14 (7.9%)
4 (5.2%)
0.23
New permanent pacemaker
54 (12.1%)
15 (10.9%)
7 (11.5%)
0.70
8 (1.5%)
4 (2.3%)
1 (1.3%)
0.56
1.75 ± 0.7
1.64 ± 0.6
1.76 ± 0.8
0.25
Acute kidney injury stage 3
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New-York Heart Association functional class
Values are mean ± SD or n (%). ⃰ p-value for patients with no DM vs. patients with DM
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2 (2.6%)
0.90
2 (2.6%)
0.52
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p-value⃰
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transient ischemic attack
Insulin treated (n = 77)
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Table 4: Univariate and multivariate Cox proportional hazard analysis of overall mortality. Univariate analysis Hazard Ratio
Confidence Interval
p-value
Hazard Ratio
Age (years)
1.03
1.00-1.05
0.04
1.02
0.99-1.04
0.31
Body mass index (kg/m2)
0.96
0.93-99
0.03
1.00
0.96-1.04
1
Orally treated
1.13
0.77-1.78
0.59
1.21
0.75-1.98
0.42
Insulin treated
1.70
0.98-2.9
0.06
2.31
1.25-4.27
0.01
Chronic lung disease
1.46
1.02-2.11
0.05
1.68
1.10-2.58
0.02
Peripheral artery disease
1.63
Chronic renal failure*
3.27
Previous pacemaker
1.66
Atrial fibrillation
1.44
Frailty
2.48
Society of Thoracic Surgeons score, (%)
Valve type:
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1.34
0.90-1.98
0.15
2.23-4.80
<0.001
2.46
1.52-3.99
<0.001
1.10-2.49
0.02
1.03
0.64-1.66
0.90
0.99-2.09
0.06
1.38
0.91-2.10
0.13
1.71-3.61
<0.001
1.99
1.30-3.03
0.001
1.09
1.06-1.11
<0.001
1.03
0.99-1.06
0.14
0.98
0.97-0.99
0.002
1.01
0.99-1.02
0.48
0.98
0.97-0.99
0.005
0.99
0.98-1.00
0.08
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Aortic valve mean gradient (mmHG)
p-value
1.12-2.36
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Ejection fraction
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DM:
Confidence Interval
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Variable
Multivariate analysis
1.58
1.07-2.33
0.02
1.04
0.68-1.59
0.87
S3 vs. Sapien/XT/CV
0.41
0.21-0.80
0.01
0.74
0.37-1.50
0.41
Alternative access (transapical/ transaortic /subclavian)
2.40
1.57-3.67
<0.001
1.80
1.12-2.90
0.02
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Sapien vs. XT/S3/CV
* Glomerular filtration rate <30mL/min/m2 Abbreviations: CV – Corevalve; DM – diabetes mellitus; S3 - Sapien 3; XT - Sapien XT.
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