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Favorable Short-Term and Long-Term Outcomes Among Patients With Prior History of Malignancy Undergoing Transcatheter Aortic Valve Implantation
Abstract: Background. Transcatheter aortic valve replacement (TAVR) is now the treatment of choice for high-surgical risk patients with symptomatic aortic stenosis. Little is known regarding the outcome of TAVR in patients with previous malignancy. Methods. We investigated 477 patients who underwent TAVR in a tertiary medical center. Subjects were divided into two groups according to malignancy status: no history of malignancy (n = 386) and positive history of malignancy (n = 91). Results. Mean age of the study population was 81 ± 7 years, and 52% were men. No major differences in baseline characteristics were found between groups. All-cause mortality was 24% for both malignancy and non-malignancy groups at a mean follow-up of 851 ± 629 days. Kaplan-Meier survival analysis demonstrated no difference in all-cause mortality between groups. Multivariate Cox regression analysis showed that malignancy status did not affect prognosis regarding overall mortality (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.5-1.4; P=.46). However, cancer therapy administered within 12-months of TAVR was significantly associated with increased total mortality among patients undergoing TAVR (HR, 4.38; 95% CI, 1.14-16.77; P=.03). Conclusions. Malignancy is a common comorbidity among TAVR candidates. Mere history of malignancy among elderly patients does not adversely affect short-term or long-term outcomes after TAVR; however, history of recent (<1 year) cancer-related treatment increases the risk for long-term mortality after TAVR. Decisions regarding TAVR among oncological patients should be individualized according to their malignancy status and anticipated life expectancy.
J INVASIVE CARDIOL 2018;30(3):105-109.
Key words: aortic stenosis, aortic valve disease, transcatheter aortic valve replacement
The incidence of both malignant tumors and aortic stenosis (AS) increases with age1 and together constitute leading causes of death in the Western world.2 The prevalence of malignancy among patients with severe AS is high, and is estimated to be >26%.3
AS is the most common native valve lesion and while untreated symptomatic severe AS is associated with a dismal prognosis, patients undergoing aortic valve replacement (AVR) have survival curves similar to normal age-matched populations without AS.4
Major advances in the treatment of cancer have led to improved survival, resulting in an increasingly large proportion of elderly patients with a past history of cancer.5 Cancer survivors have unique characteristics dependent, at least in part, on the tumor type and treatment they received.6
Transcatheter AVR (TAVR) is now the treatment of choice for high-surgical risk patients with severe AS, and recent studies have shown similar benefit for intermediate-risk patients.7
Previous studies have shown that a past history of malignant tumor is the most important prognostic factor following cardiac surgery,1 especially among patients with a prior hematologic tumor.8 On the other hand, surgical AVR (SAVR) in cancer patients with severe AS has been shown to improve survival, irrespective of the type, stage, or status of the tumor.2
However, little is known about the impact of previous malignancy on the outcome of patients undergoing TAVR. The purpose of this study was to evaluate the short-term and long-term outcomes of patients with a prior history of malignancy undergoing TAVR.
Methods
We investigated the clinical records of 477 consecutive patients who underwent TAVR at the Chaim Sheba Medical Center, Israel, between January 2008 and December 2015. Subjects were divided into two groups according to malignancy status: no history of malignancy (n = 386) and positive history of malignancy (n = 91). Patients with malignancy were further stratified into those with hematologic malignancy (eg, leukemia, lymphoma, and multiple myeloma) (n = 21; 23%) and those with solid tumors (n = 70; 77%). Patients with an expected life expectancy of <1 year were not referred for TAVR and were therefore not included in the study.
The majority of patients referred for TAVR procedure were considered to be either inoperable or high-risk based on their calculated EuroScore, Society of Thoracic Surgeons (STS) score, or physician assessment. None of the patients were enrolled in clinical trials.
Definitions and outcome measures. Malignancy history was abstracted from the patients’ electronic records. Information regarding treatment was recorded, including chemotherapy, radiation, surgery, and biological, hormonal, and immunosuppressive therapies. Chest radiation was also noted, since it may have long-term effects on the cardiovascular system.
Performance status was assessed using both the Eastern Cooperative Oncology Group (ECOG) performance status and the Karnofsky performance status scales based on symptoms documented at the clinic visit prior to the procedure or at hospitalization the day before TAVR implantation.
Chronic renal impairment was defined as baseline creatinine >1.4 mg/dL. Histories of ischemic heart disease (IHD), hypertension, diabetes mellitus, and dyslipidemia were extracted from the patients’ electronic medical history files based on known diagnoses or concurrent diabetic or lipid-lowering medications.
Periprocedural complications were recorded according to the Valve Academic Research Consortium (VARC)-2.9Mortality rates were ascertained with the Israeli Ministry of Interior mortality database on January 2016.
The primary outcome of the current study was all-cause mortality during long-term follow-up. Secondary outcomes were defined as long-term mortality among patients with hematologic and solid tumors (separately).
Statistical analysis. Continuous data were compared with Student’s t-test and one-way ANOVA. Categorical data were compared with the use of Chi-square test or Fisher’s exact test. The probability of mortality events during follow-up by prespecified groups was estimated and graphically displayed according to the Kaplan-Meier method, with comparison of cumulative events across strata by the log-rank test.
Multivariable Cox proportional hazard regression modeling was used to evaluate hazard ratios (HRs) for mortality. In the model that assessed the association between history of malignancy and mortality, additional prespecified baseline covariates included age, gender, IHD, hypertension, diabetes mellitus, dyslipidemia, and chronic renal impairment.
Statistical significance was accepted for a 2-sided P<.05. The statistical analyses were performed with SPSS version 23.0 (IBM).
Results
Mean age of the study population was 81.3 ± 7.4 years, and 52% were men. Mean STS score for the entire study population was 5.5 ± 3.7. The majority of patients were implanted with a CoreValve (Medtronic), followed by the Sapien valve (Edwards Lifesciences). Baseline characteristics of patients undergoing TAVR with and without a history of past malignancy are shown in Table 1. Patients with a history of malignancy were younger, had a lower STS score, and had lower incidence of dyslipidemia than those without history of previous malignancy. No other major differences in baseline characteristics were found between groups.
Information regarding the malignancy subtype was available for 79 patients, of whom 64 (81%) had a solid tumor, while 15 (19%) had a hematologic malignancy. While patients with solid tumors had slightly better preprocedural performance statuses compared to those with hematologic malignancy (Karnofsky performance status: 74 vs 67, respectively [P=.10]; mean ECOG performance status: 1.7 vs 2.1, respectively [P=.12]), these did not achieve statistical significance.
Mean time of last cancer treatment was 95 ± 131 months and median time of last treatment was 54 months (25th-75th quartiles, 4.5-120), while 22% of the patients underwent treatment for cancer within the 12 months prior to TAVR implantation. Remote chest irradiation therapy was administered to 12 patients at a mean of 23 years prior to TAVR implantation.
Femoral access was the predominant route in both groups (94% in patients with past malignancy and 80% in patients without malignancy; P<.01). No major differences were noted regarding valve type or size. Similar procedural success rates were recorded in both groups (97% for both groups). Among those with malignancy, 5 patients had a non-transfemoral access, of whom 2 had transapical approach and 3 had transaxillary approach.
Procedural complications. No major differences in VARC-2 complications were noted between patients with prior malignancy when compared to other patients. However, new documentation of atrial fibrillation was significantly higher among patients without history of malignancy (13.1% vs 4.5% in those with history of malignancy; P=.02). Numerically higher rates of the following complications were noted in patients without history of malignancy: ischemic stroke (3.1% vs 1.1%), heart failure (13.7% vs 7%), and level 4 vascular complications (3.8% vs 0.0%). None of these achieved statistical significance. A full comparison of procedural complications is provided in Table 2.
Mortality. The Kaplan-Meier survival analysis in Figure 1 demonstrated no difference in all-cause mortality between patients with and without a history of malignancy. Total and cardiovascular mortality rates are summarized in Table 3. In-hospital mortality was numerically lower in patients with prior malignancy, possibly due to their slightly lower risk profile (younger age, lower STS score); however, long-term cardiovascular and all-cause mortality rates were similar between groups at a mean follow-up of 851 ± 629 days.
Overall survival rates of patients with hematologic malignancies and solid tumors were similar, as shown in the Kaplan-Meier survival analysis in Figure 2. There were no differences noted between those with hematologic malignancies compared to solid tumors regarding chest radiation (HR, 0.36; P=.24), remission (HR, 0.39; P=.09), time from last treatment (HR, 0.99; P=.36), and type of treatment.
Total mortality was numerically lower among patients who received previous chest irradiation compared with those who did not (0% vs 25%, respectively; P=.05). There was a trend toward a lesser degree of paravalvular leak among patients who received chest radiation; however, these differences did not reach statistical significance. Patients who received their last cancer therapy within the last year prior to TAVR were statistically more likely to die (Figure 3).
Multivariate Cox regression analysis was performed for factors likely to be associated with total mortality (Table 4). Malignancy status itself was not independently associated with total mortality. However, cancer treatment administered within the past 12 months was significantly associated with increased all-cause mortality (HR, 4.38; 95% confidence interval, 1.14-16.77; P=.03). None of the other variables included in the model showed an independent effect on mortality.
Discussion
The major findings of our study indicate that malignancy is a common comorbidity among TAVR candidates, with 19% of patients in our series having a history of prior cancer. Mere history of malignancy among elderly patients does not adversely affect short-term or long-term outcomes after TAVR; however, history of recent (<1 year) cancer-related treatment increases the risk for long-term mortality after TAVR. Few previous studies have addressed this common issue. In the pre-TAVR era, Yusuf et al2 evaluated the management and outcomes of cancer patients with severe AS. They included 50 patients with a prior history of cancer with documented severe AS. Thirteen patients underwent SAVR, while the rest were medically managed. They found that AVR was the only significant predictor of longer survival and concluded that cancer patients undergoing intervention have favorable outcomes, regardless of cancer status. A small case series10 reported on 5 elderly patients undergoing TAVR with baseline hematological malignancy (myelodysplastic syndrome, chronic leukemia, and Hodgkin’s lymphoma). Successful implantation was reported in 4 of 5 patients, and these 4 patients were alive with normally functioning aortic prostheses at 12-month follow-up. Longer follow-up was not available for these patients. A recent paper by Watanabe et al11 reported on the results of 749 patients undergoing TAVR. Active cancer, defined as cancers with a stage >T2, and/or N1, and/or M1, as well as any malignancy considered refractory, relapsing, or recurrent, was found in 47 of these patients. No differences in mid-term survival (mean follow-up, 272 days) were shown for these patients compared with patients without active cancer. Metastatic disease, however, was one of the most significant predictors for late mortality in this study.
Our study adds information from a real-life cohort of patients undergoing TAVR for severe symptomatic AS. Notably, almost 1 in 5 patients undergoing TAVR had a history of prior malignancy, and 20 patients had received active treatment within the 12 months prior to TAVR, as an indirect measure of cancer activity. Patients with prior malignancy were slightly younger and had a slightly lower STS risk score. Possibly, some of these patients were taken for TAVR despite being reasonable surgical candidates due to their history of malignancy. Indeed, the in-hospital mortality rate was numerically lower for these patients, probably due to their lower overall risk profile. Importantly, long-term outcomes were not influenced by cancer status and patients with and without a history of malignancy had equivalent long-term mortality. However, this is probably due to cautious inclusion of patients with a history of malignancy. We have no data on patients with malignancy who were turned down for TAVR due to their disease and thus cannot compare. Previous chest irradiation, which is a major cause of inoperability due to calcification and adhesions, did not seem to affect the outcomes of the 12 patients in this cohort. Importantly, the only factor associated with increased mortality in the entire study group was cancer treatment within the year prior to TAVR. This suggests that the activity of malignancy has a significant impact on patient survival and should be taken into account when deciding whether or not to perform TAVR in patients with cancer.
Study limitations. This article is based on a moderately sized cohort emanating from a single center. The relatively small number of patients with prior history of malignancy and the wide range of different cancers included does not allow us to perform subgroup analyses according to cancer type and to address the risk of specific cancers and treatments. Unfortunately, we do not have information regarding cancer-related mortality, and as such, no definite conclusions could be made regarding long-term cancer mortality. In addition, only partial information was available for 12/91 cancer patients (13%), which may influence the results. Lastly, our current findings are applicable to only patients with a prior history of malignancy and an estimated life expectancy >1 year, given that TAVR was not offered to patients with an expected life expectancy of <1 year. Larger cohorts are necessary to further assess the prognostic impact of cancer on outcomes after TAVR.
Conclusion
Malignancy is a common comorbidity among TAVR candidates. Mere history of malignancy among elderly patients does not adversely affect short-term or long-term outcomes after TAVR; however, history of recent (<1 year) cancer-related treatment increases the risk of long-term mortality after TAVR. Decisions regarding TAVR among oncological patients should be individualized according to their malignancy status and anticipated life expectancy.
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From the 1Leviev Heart Center, Sheba Medical Center, Tel Hashomer, Israel; 2Department of Internal Medicine D, Sheba Medical Center, Tel Hashomer, Israel; 3Pinchas Borenstein Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, Israel; and 4Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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 December 19, 2017, provisional acceptance given January 8, 2018, final version accepted January 25, 2018.
Address for correspondence: Dr Paul Fefer, Leviev Heart Institute, Sheba Medical Center, Tel Hashomer, Israel 52621. Email: Paul.Fefer@sheba.health.gov.il
