Abstract: Background. There remains much controversy on impact of preoperative coronary artery disease (CAD) and necessity of preoperative coronary revascularization on postoperative outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). Methods. Data were collected retrospectively for 364 consecutive patients undergoing TAVR at Newark Beth Israel Medical Center, New Jersey, from May 15, 2012 to September 17, 2015. Preoperative CAD burden was calculated by three different measures of CAD: SYNTAX score, Duke Myocardial Jeopardy score (DMJS), and number of diseased coronary arteries. A composite endpoint of all-cause mortality, major adverse cardiac and cerebrovascular event, and postoperative revascularization procedures was used as the primary endpoint in the survival analysis. Association of measures of CAD to composite endpoint were evaluated by multivariate Cox regression model for the first measure and log-rank test for the last two measures, respectively. Kaplan-Meier survival curves were derived by all three CAD measures. Thirty-day and 1-year composite endpoint rates were compared among strata defined by tertiles of SYNTAX score, DMJS, and number of diseased coronary vessels. Results. A subset of 238 patients who met all inclusion criteria were eligible for final analysis. There was no significant association between the composite endpoint and SYNTAX score (hazard ratio, 0.77; 95% confidence interval, 0.47–1.23; P=.27); CAD by DMJS (P=.24), or number of diseased coronary arteries (P=.60). Independent predictors of poor postoperative outcomes included male gender, STS score, and frailty. There was no statistically significant association between preoperative CAD measures and 30-day or 1-year composite endpoint rates. Conclusion. In patients with asymptomatic CAD undergoing TAVR for severe symptomatic aortic stenosis, preoperative coronary revascularization may not be necessary.
J INVASIVE CARDIOL 2016;28(12):E179-E184.
Key words: TAVR, coronary artery disease, outcome, CAD
Coronary artery disease (CAD) is extremely common in patients with senile aortic stenosis.1-3 The incidence of CAD appears to be even greater in the TAVR population, ranging from 40%-75%.4-6 Nevertheless, the impact of significant CAD on postoperative survival in patients undergoing TAVR is not fully understood.
Current guidelines suggest addressing CAD along with TAVR when stenosis exceeds 70% or functional ischemia is present. This recommendation is based mainly on clinical experience rather than objective data.7 The PARTNER (Placement of AoRTic TraNscathetER Valve) trial (NCT00530894), the most prominent randomized clinical trial evaluating the efficacy of TAVR, excluded most patients with significant unrevascularized CAD.6,8 Although there are some data suggesting poor short-term and long-term outcomes in patients undergoing TAVR with concomitant CAD, these studies either lack specificity in definition of CAD9 or show a trend toward diminished long-term survival, rather than a statistically significant difference.10,11 Additionally, there is a small body of literature reporting no impact on survival or cardiovascular events after TAVR in patients with CAD vs patients with no CAD. 12-14
There is a theoretical concern of precipitating a myocardial infarction in patients with significant CAD during the TAVR procedure. Rapid pacing of the heart is required for deployment of the balloon-expandable valve, and the deployment of self-expanding stents precipitates transient hypotension. Although logically feasible, this theory has not yet been validated by any data. This analysis evaluated the association of CAD and myocardium at risk with postoperative survival in patients undergoing TAVR.
A retrospective analysis of patients who underwent TAVR at Newark Beth Israel Medical Center (NBIMC), New Jersey, from May 15, 2012 to September 17, 2015 was performed. This study was approved by and conducted in a manner consistent with standards established by the center’s Institutional Review Board. The informed consent was waived because of the retrospective nature of the study. All patients met the criteria of critical aortic stenosis as defined by the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.15 Patients were assessed by two surgeons independently and surgical aortic valve replacement (SAVR) was deemed inappropriate and TAVR was recommended as a feasible alternative. In total, 364 patients underwent TAVR during this time period. Patients who had a previous open bioprosthetic AVR were included in this study (n = 18). Patients undergoing valve replacement with both balloon-expandable and self-expanding valves were included. Based on previous data that reported worse short-term and long-term mortality rates in TAVR patients with coronary artery bypass graft (CABG)/percutaneous coronary intervention (PCI),6-8 patients who had undergone CABG (n = 70) or PCI (n = 18), and those who did not have preoperative cardiac catheterization (n = 28) were excluded from the study. Five patients who had PCI along with TAVR in a single operating room (OR) visit were excluded from the study. Three patients had placement of preemptive cardiopulmonary bypass for transapical TAVR; these patients were also excluded from the study. Last, we excluded patients in whom TAVR was aborted after initial attempt (n = 2). The final sample size was 238 patients. Patient comorbidities were collected using the definitions provided by the STS data collection system.16 Details of demographics and patient comorbidities are shown in Table 1.
All patients had critical aortic stenosis as defined by Valve Academic Research Consortium (VARC) criteria.17 They were evaluated by two cardiac surgeons at our institution independently and were deemed candidates for TAVR. For preoperative evaluation, all patients underwent a transesophageal echocardiogram (TEE), a voltage-gated computed tomography angiogram chest/abdomen/pelvis including coronary artery cuts for evaluation of coronary arteries and access vessels, and if elective cases, a preoperative cardiac catheterization. We used balloon-expandable stent valves in the majority of the cases (n = 228) for which rapid pacing was required. This was done via a temporary venous pacemaker inserted from a central vein. Patients were transferred to dedicated cardiothoracic intensive care unit and temporary pacemaker was removed within 24 hours post operation unless the patient had major rhythm disturbances. If the patient remained hemodynamically stable within 24 hours of the postoperative period, they were transferred to a step-down unit and discharged after successful rehabilitation evaluation.
Primary outcome measures were composite endpoints of all-cause mortality, major postoperative adverse cardiovascular and cerebrovascular event (MACCE), and postoperative coronary revascularization. These endpoints were defined according to VARC criteria.17 Secondary outcomes were 30-day and 1-year composite endpoint rates.
Complexity of CAD and its impact in term of myocardium at risk differs remarkably between each patient. To define and quantify these aspects of CAD, the SYNTAX (SYNergy between PCI with TAXUS and Cardiac Surgery) score and Duke Myocardial Jeopardy score (DMJS) were calculated. All patients included in the analysis had their preoperative left heart catheterization done at either our local institution or an outside hospital. A SYNTAX score was calculated by a cardiologist for each patient by looking at catheterization films. The SYNTAX score characterizes the coronary vasculature anatomically with respect to the number of lesions and their functional impact, location, and complexity. Full methodology has been described by Sianos et al.18 After obtaining the SYNTAX score, it was divided into tertiles in order to be included in the multivariate Cox regression model. Table 2 shows the distribution of SYNTAX score by tertiles.
The DMJS, which was developed by Desh et al,19 was calculated to evaluate the severity of myocardium at risk. DMJS is more of a physiologic measurement of impact of CAD on myocardium, in contrast to the SYNTAX score, which focuses on describing the anatomical extent of the disease. For calculation of the DMJS, the coronary arterial tree is divided into six segments: posterior descending artery (PDA), left anterior descending artery (LAD), circumflex coronary artery (LCX), obtuse marginal artery (OM), diagonal branch of LAD, and septal perforator branches. Each segment is assigned 2 points, and segments distal to a location of stenosis >70% are considered to be at risk. The maximum possible score is 12. Scores were further divided into the following categories: patients with no history of CAD and DMJS of 0 were assigned to the “no CAD” group; patients with DMJS of 0 with CAD and DMJS of 2 were assigned to the “mild CAD” group; patients with DMJS of 4 and 6 were assigned to the “moderate CAD” group; and patients with DMJS from 8 to 12 were assigned to the “severe CAD” group. Table 2 shows the distribution of CAD burden by this stratification of DMJS.
If LAD, right coronary artery (RCA), or LCX had stenosis >70%, they were considered diseased. Left main was considered diseased if stenosis was >50%. Distribution of CAD by main coronary vessels is shown in Table 2.
Statistical analysis. Eighteen baseline characteristics of the patient population are presented in Table 1. Continuous variables are presented as mean ± standard deviation. Binomial variables are shown as frequencies and percentages. Unadjusted 30-day and 1-year composite endpoint rates by SYNTAX score tertiles and DMJS classification were derived. Patients who did not have follow-up for a minimal 1-year period were excluded from calculation of 1-year statistics. Chi-square tests and Fisher Exact tests were applied to evaluate association of SYNTAX score tertiles, CAD strata by DMJS, and number of diseased coronary vessels with 30-day and 1-year composite endpoint rates.
Kaplan-Meier analysis with log-rank test was used for time-to-event analysis for survival. For survival analysis, the outcome of interest was a composite endpoint of all-cause mortality, postoperative PCI or CABG, and MACCE rate. Patients, including those lost to follow-up or alive at last follow-up, were censored on the day of last known follow-up. Median time to event was the period of follow-up in years when 50% of uncensored patients experienced the event of interest. To evaluate association of SYNTAX score with composite endpoint, a multivariate Cox proportional hazards ratio model was used for survival analysis. All variables shown in Table 1 except DMJS were included in a multivariate model. A P-value <.05 was used as the threshold for statistical significance. The hazard ratio (HR) and 95% confidence interval (CI) were reported for each factor. All data were analyzed with the Stata 14 statistical software package (Stata Corporation).20
A log-rank test was applied to evaluate the association of DMJS to the composite endpoint. Kaplan-Meier survival function curves were derived by tertiles of SYNTAX score and classification of DMJS. Since distribution for diseased coronary arteries in our patient population was not normal, log-rank test was performed to test the association of total number of diseased coronary vessels with the primary outcome measure.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
The analysis included 238 patients. Baseline characteristics are shown in Table 1. The mean age of the sample was 82.2 years, with 41.6% male. The mean STS score of the population was 7.2%. A total of 174 patients (73.1%) underwent TAVR by transfemoral approach and 64 patients (26.9%) underwent TAVR by transthoracic (transapical/transaortic) approach. The mean SYNTAX score of the population was 6.9.
There were 2 patients who needed post-TAVR PCI in the form of balloon angioplasty and stent placement. In both patients, the indication was recurrent anginal episodes despite maximum medical therapy. One patient underwent explantation of the transcatheter valve for severe post-TAVR aortic regurgitation along with two-vessel CABG for severe LAD and PDA stenosis. Two patients had major postoperative stroke, as defined by VARC criteria. Both strokes happened in the same admission post TAVR within 30 days. Out of these 2 patients, 1 died as a result of the stroke. The other patient was discharged to a rehabilitation facility and was alive at the time of last follow-up. One patient with SYNTAX score of 19 developed ventricular fibrillation resistant to cardioversion in the OR. The patient was placed on cardiopulmonary bypass, which was reversed in the OR; the patient was then placed on intraaortic balloon pump (IABP) and transferred to the intensive care unit. IABP was weaned at postoperative day 3; however, the patient developed multiorgan failure and died on postoperative day 14.
The mean follow-up in the patient population was 14.9 ± 9.9 months (range, 3-41 months). The total time at risk was 3446 months. A multivariate Cox proportional HR model was applied to evaluate the association of SYNTAX score and composite endpoint. All variables shown in Table 1 except DMJS were included in the multivariate model.
There was no significant association between SYNTAX score divided by tertiles and the composite endpoint (HR, 0.77; 95% CI, 0.47-1.23; P=.27). Independent predictors of mortality or adverse events were male gender (HR, 2.73; 95% CI, 1.23-6.09; P=.01), STS score (HR, 1.09; 95% CI, 1.02-1.18; P=.01), and frailty (HR, 2; 95% CI, 1.38-2.89; P<.001). Kaplan-Meier survival curves by each SYNTAX score tertile are shown in Figure 1A. There is a significant amount of overlap among the Kaplan-Meier survival curves, suggesting that preoperative SYNTAX score does not have significant impact on postoperative mortality, MACCE, or incidence of postoperative PCI.
Analysis by log-rank test suggested that there was no significant association between previously defined strata of DMJS and composite endpoint (P=.24). Kaplan-Meier curves by DMJS strata are shown in Figure 1B. Again, there is significant overlap between curves, showing that preoperative myocardium at risk does not have significant impact on composite endpoint. Log-rank test showed no statistically significant association between number of diseased coronary vessels and primary outcome (P=.60). The Kaplan-Meier curves are shown in Figure 1C.
There was no significant association between composite endpoint at 30 days (P=.80) or at 1 year (P=.79). There was no significant association between composite endpoint and DMJS score at 30 days (P=.13) or at 1 year (P=.55). Similarly, number of coronary vessels involved was not associated with composite endpoint rates at 30 days (P=.98) and 1 year (P=.93). Coronary artery disease strata by DMJS and number of major coronary vessels involved are shown in Tables 3 and 4. Thirty-day and 1-year composite endpoint rates by each tertile of SYNTAX score, strata of DMJS, and number of diseased coronary vessels are shown in Table 5.
This analysis includes the largest case series to date reporting outcomes of TAVR in patients with CAD, who did not undergo dedicated coronary intervention prior to TAVR. The series includes the whole spectrum of coronary artery disease – from no CAD to the most diffuse and complex CAD. The lack of significant association between SYNTAX score and postoperative outcomes suggests that TAVR can be safely performed in patients without prior PCI if they do not have ischemic symptoms at baseline, regardless of their coronary arterial disease burden. The lack of significant association between DMJS and postoperative outcomes suggests that amount of myocardium at risk does not correlate with mortality, postoperative MACCE, or PCI rates. When tested by number of coronary arteries involved, an increase in the number of diseased vessels was also not associated with worse postoperative outcomes.
These results infer that as long as patients are asymptomatic from the CAD, TAVR can be performed safely without any revascularization procedures regardless of burden of preoperative CAD. Currently, preoperative cardiac catheterization is standard of care in most centers performing TAVR in the United States. Our analysis questions the usefulness of this practice in patients who are not candidates for a combined SAVR + CABG because of their higher surgical risk. Maybe the coronary imaging can be performed less invasively by performing a gated computed tomography angiogram of coronary arteries instead in this specific subset of patients. In our own practice after this analysis, we have started to perform TAVRs without a preoperative cardiac catheterization in patients with asymptomatic CAD who are high risk for SAVR + CABG.
Previous retrospective studies addressing a similar question have been limited. Wenaweser et al compared outcomes in 256 patients undergoing TAVR between PCI + TAVR (n = 59) vs TAVR only (n = 197) and concluded that PCI was safely performed as a staged or concomitant intervention. In this study, the SYNTAX score was calculated only in patients undergoing PCI along with TAVR.13 Candidacy for PCI was determined by DMJS. The impact of SYNTAX score or DMJS on outcomes was not reported. Another study done by Masson et al included 136 patients undergoing TAVR and compared outcomes in patients with CAD vs without CAD and demonstrated that there was no difference in 30-day mortality.10 In their methodology, they took only DMJS into account to evaluate CAD burden.
Our study suggests that the theoretical concern of precipitating a myocardial infarction during rapid pacing may not be a significant one, as long as the patient does not have coronary ischemic symptoms at baseline. Most of our patients (n = 228) underwent placement of balloon-expandable stent valve placement and rapid pacing was induced while deploying these valves. It is possible that this brief period of rapid pacing, which consists of only a few seconds, does not compromise coronary circulation enough to precipitate a myocardial infarction. As long as the patient does not have angina at rest, TAVR can be safely performed without performing preoperative coronary revascularization, regardless of disease burden or myocardium at risk. This study presents evidence to answer an important and extremely common question faced by clinicians performing TAVR.
The currently ongoing ACTIVATION trial on patients undergoing PCI prior to TAVR is going to shed more light on this subject. The main objective of the trial is to prove non-inferiority of pre-TAVR PCI in patients with significant CAD compared with non-invasive treatment.21 The ongoing PARTNER II US trial (NCT01314313) and SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation; NCT01586910) trial are recruiting patients with significant CAD who were excluded in the PARTNER trial (NCT00530894). The analysis of the patient subgroup with significant CAD will generate more evidence for this specific question.
Study limitations. Our study has important limitations. The data have been collected retrospectively. The multivariate regression models are limited by the variables selected. Although we tried to be all-inclusive, there may be some unknown factors for which the effect on outcomes could not be determined. Our hypothesis should be tested in randomized clinical trials or large TAVR registries to confirm our findings. The study included a majority of balloon-expandable (n = 228) and a few self-expanding (n = 10) valve placements with different generations of valves and delivery systems; as such, the results cannot be extrapolated to any one specific valve type or delivery system. Also, the study excluded patients who underwent CABG because the SYNTAX score is not reliable in calculating disease burden in these patients. Furthermore, our case series did not have patients with ischemic symptoms at rest. As such, the conclusions of this study cannot be extended to this subgroup of patients and preoperative coronary revascularization may be necessary in them.
In patients with asymptomatic CAD, burden of CAD as measured by SYNTAX score, DMJS, and number of diseased coronary arteries is not associated with short-term combined outcome of all-cause mortality, MACCE, and coronary revascularization following TAVR. In these patients in the setting of severe symptomatic aortic stenosis, preoperative coronary revascularization may not be necessary if they are undergoing TAVR.
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From the 1Department of Surgery, Rutgers – New Jersey Medical School, Newark, New Jersey; 2Cardiovascular Clinical Research Unit, Barnabas Heart Hospitals, Newark, New Jersey; and 3Department of Cardiology, Newark Beth Israel Medical Center, Barnabas Heart Hospitals, Newark, New Jersey.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted July 5, 2016, provisional acceptance given July 19, 2016, final version accepted August 2, 2016.
Address for correspondence: Dhaval Chauhan, MD, 201 Lyons Ave, Suite G5, Newark, NJ 07112. Email: email@example.com