Clinical outcomes after transcatheter aortic valve replacement in cancer survivors treated with ionizing radiation

We studied 610 consecutive patients who underwent TAVR for symptomatic severe AS at our institute from January 2012 to September 2017. The study subjects were divided into 2 groups. The first group (XRT; N = 75) had prior history of C-XRT for thoracic malignancy. The second group (non-XRT; N = 535) had no history of C-XRT. The determination of prior C-XRT in cancer survivors was made based on chart review, or through a personal interview during their pre-TAVR evaluation visit.

Baseline patient characteristics including demographics, clinical symptomatology, surgical history, radiation history, laboratory, medications use, echocardiographic and pulmonary function test were obtained at the pre-TAVR evaluation visit. Procedural and peri-procedural complications and outcomes were obtained from the procedure notes and inpatient chart review. Baseline functional status was assessed using Kansas City Quality of Life Questionnaire (KCCQ-12) at their pre-procedure clinic visit. Surgical risk was assessed using Society of Thoracic Surgery (STS) risk score.

All patients underwent a comprehensive echocardiogram as part of the standard clinical diagnostic evaluation during their pre-procedure assessment for TAVR. Cardiac chamber measurements, left ventricular ejection fraction (LVEF), aortic valve area and LV stroke volume index (LV-SVI) were obtained according to current American Society of Echocardiography recommended methods [16, 17].

The date of TAVR was considered as the beginning of the follow-up. Procedural and immediate postoperative data, length of intensive care unit or hospital stay and postoperative complications were retrieved from electronic medical records. All patients were routinely followed up after TAVR at 30 days and up to 1 year at our structural heart clinic. Beyond 1 year, data on all-cause mortality and MACE outcomes were obtained by reviewing shared electronic medical records with their primary care or health systems and by telephone follow-up.

The primary event was all cause mortality. Data on survival were obtained from medical record review, US Social Security Death Index or telephone follow-up. Cardiovascular mortality was defined as any death attributed to sudden cardiac arrest, myocardial infarction, arrhythmia, heart failure, or other cardiovascular causes. Major bleeding was defined as per the definitions of the International Society on Thrombosis and Hemostasis bleeding scale [18, 19].

Secondary events were composite end-point of MACE, defined as cardiovascular mortality, stroke, acute myocardial infarction (AMI) or revascularization and heart failure (HF) hospitalizations until the date of last follow up. The incidence of atrial fibrillation (AF) and atrioventricular (AV) conduction abnormalities requiring permanent pacemaker (PPM) implant were obtained through individual review of medical records, including from device clinic or through follow-up with their primary care provider. Quality of Life Questionnaire (KCCQ-12) for each patient was assessed at 30 days and at 1-year follow-up after TAVR.

Categorical and continuous variables were expressed as percentage or frequency and mean ± standard deviation (SD) respectively where appropriate. Baseline clinical and procedural characteristics were compared between the groups using the student’s t test or the Wilcoxon rank-sum test, as appropriate, for quantitative variables; and the Pearson chi-square test for categorical variables.

All the available relevant clinical, echocardiographic, laboratory and pre/post-operative variables were used in univariate cox proportional hazard analysis to determine the association with all-cause mortality. The variables that were significant (p < 0.05) on univariate analysis were used to construct the multivariate cox proportional hazard model. Kaplan-Meier survival curves for all-cause mortality, composite and each component of MACE free survival were performed. A p-value of < 0.05 was considered statistically significant for all statistical analyses. All statistical analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC).

Perioperative and post-operative characteristics are shown in Table 2. There were no differences in intravascular access, procedure duration or type of valves used among the groups.

The overall incidence of moderate to severe paravalvular leak post-TAVR was less than 1.5% in the entire study subjects and there were no significant differences among the groups.

The short and long-term events and quality of life measures after TAVR are shown in Table 3.

Our data demonstrated that the patients with prior C-XRT had nearly 2-fold increase in mortality after the median follow-up duration of 17 months after TAVR. The mortality differences between the XRT and control groups were discernible at the early in-hospital period and became more prominent with increasing follow-up interval. Our multivariate analysis revealed prior C-XRT, post-operative anemia requiring blood transfusion and poor renal function as the significant predictors of reduced survival. Larger multicenter studies on the long-term outcomes of RIVHD are limited. Based on a recent study in patients with SAVR and CABG, presence of prior C-XRT was associated with worse longer-term survival [8]. Other smaller studies in prior C-XRT have also reported the presence of constrictive pericarditis, reduced pre-operative LVEF, concomitant pulmonary fibrosis, longer cardiopulmonary bypass time and hostile chest environment (radiation induced fibrosis/adhesions, and presence of multiple cardiac lesions) to be strongly associated with increased mortality [20‐23]. In our study, we found no significant differences in pre-operative LVEF and FEV1 in patients with prior C-XRT and hostile chest environment likely have less impact in these patients since TAVR involves percutaneous approaches. Besides, there was higher incidence of HF, AF, stroke and AV conduction abnormalities requiring PPM in the XRT subsets, which might also have contributed to the increased mortality. These data are important for prior adjudication and counseling of patients prone to develop such complications.

We noted higher incidence of AF in XRT cohorts after TAVR. Prior study from Siregar and associates showed increased incidence of AF after cardiac surgery in Hodgkin’s lymphoma survivors with history of C-XRT [24]. Other studies have also demonstrated a higher prevalence of AF in patients with history of cancer. One plausible explanation for this observation is the presence of shared risk factors for AF and cancer including age, higher body mass index, hypertension and history of smoking [25]. There is evidence that radiation induces a low-grade inflammation in the myocardium which can lead to progressive interstitial fibrosis [26]. Presence of inflammation and fibrosis in the atrial tissues can increase the propensity to develop AF. Ascertainment of the mechanisms of increased incidence of AF in these patients will probably need cardiac MRI with comprehensive tissue characterization or histological analysis of the affected cardiac tissue.

Additionally, patients with prior C-XRT showed nearly double the incidence of stroke post-TAVR. The incidence of stroke in our patients without prior C-XRT was identical to previously reported incidence at 3–6% [27]. Patients with prior C-XRT also had higher incidence of AF, which might have contributed to the increased incidence of stroke, but it’s also plausible that these patients have higher incidence of atherosclerosis and aortic calcifications that are known to increase the propensity for stroke with percutaneous vessel manipulation during TAVR [14, 28, 29]. With increasing use of distal protective devices during TAVR, the incidence of stroke, particularly related to atheroma breakdown, is expected to decline [30]. Moreover, patients with Hodgkin’s lymphoma had higher incidence of stroke compared to other cancer subtypes which may relate to increased risk of atherosclerosis from higher dose of mediastinal radiation on the large arteries. Future prospective studies will need to address whether oral anticoagulation is beneficial in these patients.

The incidence of HF hospitalization was almost double in the XRT group (nearly 31%) despite no differences in their baseline LVEF. Prior studies have demonstrated that nearly a quarter of the patients return to hospital within a year due to HF post-TAVR [31]. A seminal study by Durand and associates reported that pre-TAVR low aortic mean gradient, left atrial dilation, post-procedure anemia requiring blood transfusion and persistent severe pulmonary hypertension post-TAVR were associated with increased incidence of HF hospitalization [31]. In our XRT group, aortic mean gradients before and after TAVR, and right ventricular systolic pressure at baseline were similar compared to non-XRT group. However, the incidence of anemia and need for blood transfusion was higher in XRT group which is consistent with earlier findings and might have played a contributory role for cardiac decompensation. It is also important to state the role of diastolic function in HF patients with C-XRT since it is known to induce myocardial fibrosis perpetuating diastolic dysfunction, which was not completely addressed in our study [26, 32].

The incidence of PPM implant in our patients undergoing TAVR was ~ 10%. Notably, patients with C-XRT had double the incidence (~ 20%) of conduction abnormalities requiring PPM. While the exact mechanisms for these conduction abnormalities are not well understood, these are likely contributed by microvascular damage, ischemia of the conducting myocytes or direct injury of the sinoatrial node, atrioventricular node and conducting myocytes [32]. This is an important finding since TAVR procedure in itself has higher incidence of high-grade conduction abnormalities compared to SAVR with need for PPM approaching up to 25% in some studies. In patients with prior C-XRT, a close monitoring is needed to detect and treat these life-threating conduction diseases [33].

We noted higher incidence of all-cause mortality in male counterparts compared to females who had prior C-XRT but no significant differences in MACE or cardiac mortality. Though males had higher prevalence of underlying CAD and lower pulmonary functional capacity at baseline, females had more anginal symptoms compared to male counterparts who had prior chest XRT. Previous studies by Chandrasekhar et al. and Hayashida et al. showed that females had better survival at 1 year after TAVR compared to male counterparts [34, 35]. Thus, it is important to note that outcomes of TAVR based on gender analysis is similar in patients with prior C-XRT versus general population undergoing TAVR and male had overall worse outcomes. The effects of chest radiation on gender in these subsets of patients are unknown and warrant further studies.

The overall baseline functional status of all the patients was poor based on KCCQ-12 score categorization, with a trend towards a very poor category in patients with prior C-XRT [36]. The overall functional status seemed similar to previously reported data from the TVT registry [37]. On average, post TAVR, there were similar improvements in both the groups by more than average of 40 points in the KCCQ12 scores at 30 days and at 1-year after TAVR which are slightly higher than previously reported in clinical trials or data from TVT registry [36‐38]. Our study also shows that patients with lower pre-procedure and smaller improvement of the KCCQ-12 score post-TAVR are likely to have higher mortality. This finding can further guide the clinicians in selecting patients who can benefit from TAVR and help prognosticating the outcomes after TAVR.

We acknowledge the following limitations. First, our study is an observational cohort study and lacks the inherent strength of a randomized controlled trial. However, this study provides important insight into the natural history of TAVR for symptomatic severe aortic stenosis patients with prior history of C-XRT. Second, there remains the concern for an adequate capture of clinical outcomes mainly resulting from lack of formal follow-up beyond 12-months. For patients who did not follow up clinically in our health-care system, we obtained their data by shared clinical chart review and standardized telephone interview. Besides, the trends of primary and secondary events separated significantly early between the two groups and continued to widen over the duration of follow-up which suggests a potentially even greater magnitude of difference over time. Third, our study was not able to specify the radiation dose and adjuvant chemotherapy regimens which might have impacted the cardiovascular outcomes. We know that anthracyclines can cause cardiotoxicity leading to cardiomyopathy and heart failure, but antracyclines are not known to cause valvular stenosis. The effect of additional adjuvant regimens in patients with prior C-XRT undergoing TAVR is undefined and needs further study [39] [40].,