Original Article

Long-Term Survival of Patients With Radiation Heart Disease Undergoing Cardiac SurgeryClinical Perspective

A Cohort Study

Willis Wu, Ahmad Masri, Zoran B. Popovic, Nicholas G. Smedira, Bruce W. Lytle, Thomas H. Marwick, Brian P. Griffin, Milind Y. Desai
https://doi.org/10.1161/CIRCULATIONAHA.113.001435
Circulation. 2013;127:1476-1484
Originally published April 8, 2013

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Abstract

Background—Thoracic radiation results in radiation-associated heart disease (RAHD), often requiring cardiothoracic surgery (CTS). We sought to measure long-term survival in RAHD patients undergoing CTS, to compare them with a matched control population undergoing similar surgical procedures, and to identify potential predictors of long-term survival.

Methods and Results—In this retrospective observational cohort study of patients undergoing CTS, matched on the basis of age, sex, and type/time of CTS, 173 RAHD patients (75% women; age, 63±14 years) and 305 comparison patients (74% women; age, 63±4 years) were included. The vast majority of RAHD patients had prior breast cancer (53%) and Hodgkin lymphoma (27%), and the mean time from radiation was 18±12 years. Clinical and surgical parameters were recorded. The preoperative EuroSCORE and all-cause mortality were recorded. The mean EuroSCOREs were similar in the RAHD and comparison groups (7.8±3 versus 7.4±3, respectively; P=0.1). Proximal coronary artery disease was higher in patients with RAHD versus the comparison patients (45% versus 38%; P=0.09), whereas redo CTS was lower in the RACD versus the comparison group (20% versus 29%; P=0.02). About two thirds of patients in either group had combination surgical procedures. During a mean follow-up of 7.6±3 years, a significantly higher proportion of patients died in the RAHD group than in the comparison group (55% versus 28%; P<0.001). On multivariable Cox proportional hazard analysis, RAHD (2.47; 95% confidence interval, 1.82–3.36), increasing EuroSCORE (1.22; 95% confidence interval, 1.16–1.29), and lack of β-blockers (0.66; 95% confidence interval, 0.47–0.93) were associated with increased mortality (all P<0.01).

Conclusions—In patients undergoing CTS, RAHD portends increased long-term mortality. Alternative treatment strategies may be required in RAHD to improve long-term survival.

Introduction

Thoracic radiation has remained an effective treatment for cancers that involve the mediastinum and thorax but is associated with substantial cardiac morbidity and mortality.1–7 The long-term cardiac effects of radiation are heterogeneous and include coronary artery disease (CAD; especially ostial/proximal), valvular disease, pericardial disease, myocardial disease with systolic and especially diastolic dysfunction, and conduction disease.8–12 The lungs, great vessels, and carotid arteries may also be involved. Although the exact prevalence of heart disease attributable to the effects of thoracic radiation is difficult to ascertain, studies have suggested that up to 42% patients may have significant valvular disease, whereas in 14%, stress-induced myocardial ischemia may occur.2–4,7,8–12 Radiation heart disease progresses over time and may manifest with symptoms decades after radiation has been completed.

Clinical Perspective on p 1484

Patients with cardiac complications of prior radiation often require surgical intervention for effective treatment. These patients have multiple cardiac lesions and have comorbidities such as pulmonary or vascular disease related to radiation that may affect their short- and long-term outcomes. Although there are multiple previous small reports,3,4,6,13–16 the absence of data on the long-term outcomes of this population, particularly compared with a standard cardiothoracic surgical population, makes decision making especially difficult. We sought to measure long-term survival in patients with radiation heart disease who underwent cardiothoracic surgery, to compare those patients with a matched population undergoing similar surgical procedures during the same time frame, and to identify potential predictors of long-term survival.

Methods

Study Design

This was a retrospective, observational cohort study of 478 consecutive patients who underwent cardiothoracic surgery at our tertiary care referral center between 2000 and 2003. The study population consisted of 2 groups. The first group was made up of 173 patients with a history of a documented malignancy requiring chest irradiation who subsequently developed coronary/valvular disease significant enough to require cardiothoracic surgery (radiation heart disease group). The diagnosis of radiation heart disease was made after a thorough clinical and echocardiographic evaluation by experienced cardiologists. In this group, type of prior malignancy and area of radiation were ascertained. When available, the year of the last radiation dose was recorded. All patients were cleared by oncology for a cardiac surgical procedure. The second group consisted of 305 patients without a history of malignancy or chest irradiation (comparison group) who were matched with group 1 for type and time of cardiothoracic surgery, age, and sex (in that order). In the vast majority of cases, we were able to achieve a 1:2 match of radiation to comparison group. In 41 instances, there was only a 1:1 match.

Clinical Data

Data were assembled after individual analysis of electronic medical records after appropriate approval by the Institutional Review Board was obtained. Demographics and clinical data were recorded prospectively in the electronic health record. History and type of prior cardiac surgery were recorded. Use of medications (including β-blockers, statins, angiotensin-converting enzyme inhibitors, aspirin and clopidogrel, and diuretics) at the time of initial presentation and if initiated in the postoperative period was recorded. The presence of permanent atrial fibrillation (defined according to guidelines)17 was ascertained at baseline and during follow-up. The presence of an automated implantable cardioverter-defibrillator and the need for permanent pacemaker were recorded.

The details of cardiac surgery were recorded prospectively and categorized as follows: (1) coronary artery bypass grafting (CABG), (2) CABG plus 1 valve repair/replacement, (3) CABG plus ≥2 valve repairs/replacements, (4) 1 valve repair/replacement, (5) ≥2 valve repairs/replacements, and (6) other (including pericardiectomy, transplantation, left ventricular [LV] assist device, aortic surgery, and myectomy). In patients who underwent CABG, the number of bypassed vessels was recorded. From the available preoperative data, the additive EuroSCORE was calculated to predict risk of postoperative mortality.18

Echocardiography

All patients (both groups 1 and 2) underwent a comprehensive echocardiogram with commercially available instruments (Philips Medical Systems, NA, Bothell, WA; General Electric Medical Systems, Milwaukee, WI; and Siemens Medical Solutions USA, Inc, Malvern, PA) as part of standard clinical diagnostic and pre–open heart surgery workup. Parameters including LV ejection fraction, dimensions, diastolic function, and degree of valvular stenosis and regurgitation were assessed according to standard guidelines and recorded prospectively.19–22 Degree of mitral, aortic, and tricuspid regurgitation was assessed on a scale of 0 to 4+ (0=none, 1+=mild, 2+=moderate, 3+=moderately severe, and 4+=severe). Right ventricular systolic pressure was recorded from tricuspid regurgitation velocity and estimated right atrial pressure. Peak/mean transvalvular gradients, velocity-time integrals across valves and the LV outflow tract, and diameter of the LV outflow tract were recorded. Aortic valve area was calculated from the continuity equation, and aortic stenosis was graded in a standard fashion. In addition, a dimensionless index (LV outflow tract velocity-time integral/aortic velocity-time integral) was calculated. Similarly, a postoperative transthoracic echocardiogram was also performed before discharge.

Follow-Up

The beginning of follow-up was considered to be the date of cardiac surgery at our institution, and the end point was all-cause mortality. Death notification was obtained from the medical record or from the US Social Security Death Index database, and survival was ascertained during follow-up (last query was in March 2011). Postoperative stroke was defined as transient or permanent neurological impairment and disability resulting from vascular causes, including episodes lasting <24 hours, which were regarded as transient ischemic attacks.

Statistical Analysis

Continuous variables were expressed as mean±SD or median. When appropriate, continuous variables were also divided into 2 groups based on median for further analyses. Categorical data are presented as percentage frequency. Differences between groups were compared with the use of the Student t test or ANOVA (for parametric variables) and Mann-Whitney test (for nonparametric variables) for continuous variables. The χ2 test was used for categorical variables. Cumulative event rates as a function over time were obtained by Kaplan-Meier method, and event curves of different outcomes were compared by use of the log-rank test. A univariable and multivariable Cox proportional hazards model was developed to determine the independent predictors of mortality. In a first step, all univariable predictors were assessed with bootstrapping (to increase the reliable assessment of risk factors by improving the precision of estimate). A total of 1000 bootstrapped models were generated; variables that entered the model at least 75 times were considered significant (at P<0.1) and included in the final multivariable model. Subsequently, stepwise multivariable regression analysis was performed, and the variables with a value of P<0.05 remained as independent predictors. The final univariate and multivariate results are represented by hazard ratios and their 95% confidence intervals. To incorporate matching into the analysis, we further stratified the study population (radiation group) and the corresponding comparison group patients together, creating 173 matched pairs. Subsequently, we also performed conditional Cox regression analysis accounting for the matched pairs in the strata statement. All statistical analysis was performed with SPSS version 11.5 (SPSS Inc, Chicago, IL). A value of P<0.05 was considered significant.

Results

Clinical Characteristics

The baseline clinical and echocardiographic characteristics of both groups are shown in Tables 1 and 2. This was a relatively young population, and all patients had advanced symptoms necessitating cardiac surgery. The few clinical differences between the groups (a higher proportion of patients in the comparison group had hypertension and prior cardiothoracic surgery and a lesser number had implantable cardioverter-defibrillators) placed the comparison group subjects at slightly greater preoperative risk. On the other hand, there was a trend toward higher proportion of proximal obstructive CAD in the radiation group. Although the comparison group members had better LV ejection fraction, they had larger LV and left atrial size.

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Table 1.

Clinical Characteristics of the Study and Comparison Population

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Table 2.

Baseline Echocardiographic Characteristics of the Study and Comparison Populations

Specific Characteristics in the Radiation Heart Disease Group

Nearly half the population (45%) had evidence of obstructive proximal CAD, including 28 patients (17%) with significant (≥50%) left main disease and 32 patients (20%) with severe (≥70%) proximal left anterior descending artery disease. In addition, a quarter of the study population had a history of prior open heart surgery, with 28 (16%) having prior CABG. The distributions of prior malignancies and average radiation doses were as follows: 91 (53%) had malignancies in the breast (50–60 Gy), 12 (7%) had malignancies in the lung (60 Gy), 46 (27%) had Hodgkin lymphoma (40–45 Gy), 11 (6%) had non-Hodgkin lymphoma (40–50 Gy), and 13 (8%) had other malignancies (thymoma and testicular and thyroid cancers; 40–50 Gy). No patient had a known recurrence of malignancy at the time of cardiac surgery. The mean duration between current cardiac surgery and the last chest radiation was 18±12 years. The distribution of LV ejection fraction was as follows: 118 patients (68%) with ejection fraction ≥55%, 51 (29%) with ejection fraction between 30% and 55%, and 19 (11%) with ejection fraction <30%. There was a high prevalence of valvular heart disease: 88 patients (51%) with at least moderate (2+) mitral regurgitation, 11 (6%) with severe mitral stenosis, 49 (29%) with at least moderate (2+) aortic regurgitation, 40 (23%) with severe aortic stenosis, and 58 (34%) with at least moderate (2+) tricuspid regurgitation. Significantly elevated right ventricular systolic pressure (>55 mm Hg) was seen in 19 patients (11%).

Outcomes in the Radiation Therapy and Comparison Groups

The clinical and echocardiographic results in the postoperative period for both groups are shown in Table 3. In addition to a longer length of stay, patients with radiation heart disease more frequently had atrial fibrillation, permanent pacemaker implantation, ventricular dysfunction, and valvular regurgitation and had higher 30-day mortality than those in the comparison group. No patients had wound healing complications in the perioperative period.

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Table 3.

Postoperative Findings in the Study and Comparison Population

During a mean follow-up of 7.6±3 years, there were 179 deaths (37%) in the total study population. A significantly higher proportion of patients in the radiation heart disease group died compared with the comparison group (95 of 173 [55%] versus 84 of 305 [28%]; hazard ratio, 2.54; 95% confidence interval, 1.89–3.43; P=0.001; Figure 1). Within the radiation heart disease group, the cause of death was ascertained to be cardiopulmonary disease in 47 patients (49%) and recurrent malignancy in 5 patients (5%). In the remaining 43 patients, cause of death could not be definitively ascertained.

Figure 1.
Figure 1.

Kaplan-Meier curve analysis demonstrating significant differences in long-term mortality in patients with radiation heart disease who underwent cardiac surgery and an age-, sex-, and time/type of surgery–matched comparison population.

Mortality was significantly higher in all subgroups within the radiation heart disease groups compared with the comparison group (Table 4). Specifically, in subgroups with expected low mortality (ie, age <65 years and low EuroSCORE), the mortality in the radiation group remained high during follow-up (43% and 45%, respectively). In addition, for every surgical category, the mortality in the radiation group was significantly higher than in the comparison population. Kaplan-Meier curves comparing the mortality between the radiation and comparison groups are shown in Figure 1. In addition, Kaplan-Meier curves comparing the mortality within different radiation and comparison subgroups are shown in Figures 2 through 4.

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Table 4.

Mortality in the Study Population, Separated Into Different Subgroups

Figure 2.
Figure 2.

Kaplan-Meier curve analysis demonstrating significant differences in long-term mortality in 4 subgroups: comparison group ≥65 years (median age) or <65 years of age and radiation group ≥65 or <65 years of age.

Figure 3.
Figure 3.

Kaplan-Meier curve analysis demonstrating significant differences in long-term mortality in 4 subgroups: comparison group with or without prior cardiac surgeries and radiation group with or without prior cardiac surgeries.

Figure 4.
Figure 4.

Kaplan-Meier curve analysis demonstrating significant differences in long-term mortality in 4 subgroups: comparison group with EuroSCORE ≥8 (median) or <8 and radiation group with EuroSCORE ≥8 or <8.

Association of Outcomes

We subsequently performed univariable and multivariable Cox proportional hazard analyses in the whole study population group to identify potential predictors that were associated with survival. The results are shown in Table 5. Because significant individual predictors like age, LV ejection fraction, creatinine, and prior open heart surgery were already included in the calculation of EuroSCORE, they were not included in the multivariable model. The presence of radiation heart disease, higher EuroSCORE, and lack of β-blockers were associated with significantly worse long-term survival. Finally, we performed conditional Cox regression analysis, accounting for the matched pairs in the strata statement. It demonstrated that radiation heart disease (hazard ratio, 3.7; 95% confidence interval, 2.4–5.6; P<0.001), lack of β-blockers (hazard ratio, 0.59; 95% confidence interval, 0.35–0.99; P=0.04), and EuroSCORE (hazard ratio, 1.23; 95% confidence interval, 1.12–1.36; P<0.001) remained significant predictors of mortality.

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Table 5.

Cox Proportional Hazard Associations of Mortality in the Study Population

Discussion

This study demonstrates that patients with radiation heart disease undergoing cardiothoracic surgery have greater short-term and long-term mortality compared with age- and sex-matched comparison group patients who underwent similar surgeries in the same time frame. Compared with a healthy population of a similar age not undergoing cardiac surgery (86% survival at 10 years), the survival of radiation heart disease patients was far worse.6 During follow-up, there was a 72% survival rate in the comparison group compared with 45% survival in the radiation group. This finding was consistent across various subgroups, including those in which the expected mortality is lower (eg, younger age and low perioperative risk). We also demonstrate that patients <65 years of age in the radiation group fared significantly worse than older patients in the comparison group. In fact, the survival of comparison patients with a EuroSCORE higher than the median was similar to that of the radiation group with a EuroSCORE lower than the median. A subgroup of radiation patients who did especially poorly included those with a prior history of cardiac surgery despite a higher proportion of hypertensives and diabetics and a trend toward lower use of aspirin and angiotensin-converting enzyme inhibitors in the comparison group. Radiation patients had a higher postoperative in-hospital stay and a higher frequency of postoperative atrial fibrillation and right ventricular dysfunction compared with the comparison group. In the patients with radiation heart disease in whom the cause of death could be ascertained, we found that the majority of these patients died of a cardiorespiratory cause compared with recurrent malignancies.

Consistent with the known pattern of radiation heart disease,8–12,23 there was a high prevalence of proximal CAD and valvular heart disease in this group. In the study population, the vast majority of surgical procedures performed were complex (only 14% of patients underwent isolated CABG, whereas 82% had multiple procedures like valve procedures with or without CABG and a quarter of the population underwent redo cardiac surgery).

We further tested for the potential predictors of increased mortality in the study population. Radiation heart disease, higher EuroSCORE, and lack of β-blockers were associated with significantly worse long-term survival. The type of cardiac surgery performed was not independently predictive of long-term survival in the study population. However, the mortality rates for each type of surgery were significantly higher in the radiation group than in the comparison group.

The present study also demonstrates that in radiation heart disease patients undergoing cardiac surgery, the prediction of mortality risk based solely on standard preoperative scores is suboptimal. As mentioned, on the basis of scores, the study population would have been deemed at intermediate risk with an expected mortality of ≈3% to 5%.18 However, the mortality in radiation heart disease group was much higher than what would be expected from a similar age group. Previous studies of long-term outcomes (with or without cardiac surgery) in radiation heart disease patients are limited but demonstrate increased morbidity and mortality.1–4,6,13–16 Previous surgical reports have demonstrated various predictors of short-term (constrictive pericarditis, reduced preoperative ejection fraction, longer cardiopulmonary bypass times) and long-term outcomes (radiation dose, duration of radiation).2–4 However, these studies had significantly smaller sample sizes and patients with complex surgeries (eg, CABG plus valve procedures) were excluded. Another study demonstrated that prior history of extensive radiation (versus tangential exposure) was associated with worse survival after cardiac surgery.6 To the best of our knowledge, ours is the largest study to assess long-term survival in this population undergoing complex cardiac surgery and to compare them with a well-matched comparison population.

Our findings suggest that surgical intervention should be applied cautiously to patients who have previously had significant thoracic radiation because the realized survival does not necessarily match what would be expected in a nonradiated population. Survival is even worse in those who have already undergone an open heart surgical procedure. Although our data on cause of death after surgery in the radiation group are limited, it would appear that cardiopulmonary disease was a common mechanism of death. Why this should be the case in a group of patients who received potentially life-preserving revascularization, valve, and other procedures is currently unknown. These patients remained in hospital for a considerable period after surgery, suggesting that although short-term mortality was surprisingly low, the procedures and their aftermath were significantly complicated. Radiation patients frequently develop pulmonary complications as a result of open heart surgery, not least of which are recurrent pleural effusions and severe restrictive lung disease. It is our experience that respiratory complications may significantly compromise function and survival in patients with extensive prior radiation. Additionally, the presence of myocardial disease either as a result of the underlying cardiac condition (potentially exacerbated by prior concomitant chemotherapy) or as a consequence of a restrictive-type cardiomyopathy produced by the effects of radiation may play a role in impaired survival and is not necessarily improved by valvular or revascularization surgery.

It seems appropriate to examine other types of treatment options in patients with radiation heart disease who have significant valvular, coronary, or myocardial disease. In patients in whom aortic stenosis is a problem, we and others have used transaortic technology to replace the aortic valve with concomitant use of percutaneous intervention on high-grade coronary disease when required.24,25 Although data on short-term survival of transaortic valve replacement patients appear promising, the long-term outcomes of such an approach are as yet unknown.26,27 However, a percutaneous transaortic approach may circumvent specific technical difficulties such as extensive calcification of the ascending aorta that may occur with radiation disease and reduces the likelihood of lung or pleural damage from surgery. Another consideration is heart transplantation or heart-lung transplantation in selected patients with evidence of significant myocardial disease that appears disproportionate to the coronary or valvular issues or in whom there is significant restrictive lung disease. Heart or heart-lung transplantation in this group has significant associated concerns. Recurrent malignancy may be more common after graft versus host chemotherapy in these patients. Additionally, the effect of radiation on the pulmonary vasculature and thoracic volume may render lung transplantation difficult or even impossible. Our findings of poor long-term survival from conventional cardiothoracic surgery in those with radiation heart disease suggest that other modalities of treatment may be required in the future to improve the long-term survival in this complex population.

The present study had the following strengths and limitations. It was a large, observational study with potential tertiary care referral bias; hence, the data are not generalizable to all patients with a prior history of thoracic radiation. All patients uniformly had postoperative/predischarge echocardiographic and clinical data available, and the patients who were followed up for ≥1 year had no further reduction in ejection fraction or worsening of valvular function. Advanced diastolic function evaluation, including tissue Doppler and strain analysis, which could have a potential role in the evaluation of such patients, was not available at the time when surgery was performed in these patients. Precise data on the total radiation dose and chemotherapeutic regimen, both of which could have an impact on outcomes, were not available in these patients. However, it is well known that radiation results in a different pattern of heart disease (proximal/ostial CAD, valvular disease, pericardial constriction, etc) compared with chemotherapy-induced cardiotoxicity (LV dysfunction, abnormal myocardial mechanics, diastolic dysfunction, etc). In addition, the adverse effects of chemotherapy manifest much earlier than the effects of radiation (in months as opposed to years). We chose all-cause mortality because it is considered to be more objective and unbiased than cardiac mortality.28,29 We chose the Social Security Death Index because it is more specific (>99%) and potentially less biased than the National Death Index.28 Data on cancer recurrence during follow-up (at the site of radiation or a remote site) were not uniformly available. However, all patients were deemed free of malignancy at the time of cardiac surgery.

Conclusions

Patients with advanced radiation heart disease have a high incidence of proximal CAD and valvular heart disease, requiring complex cardiac surgery. On undergoing cardiothoracic surgery, despite having good procedural success, the presence of radiation heart disease is independently associated with significantly worse long-term survival compared with a comparison group. Our findings of poor long-term results from comprehensive conventional cardiothoracic surgery in those with radiation heart disease suggest that other modalities of treatment or perhaps earlier treatment may be required in the future to improve long-term survival. Additional studies are needed to further understand this high-risk population.

Disclosures

None.

Footnotes

  • Received August 16, 2012.
  • Accepted February 22, 2013.

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Clinical Perspective

In this observational cohort study of patients undergoing cardiothoracic surgery, matched on basis of age, sex, and type and time of cardiothoracic surgery, we studied 173 patients with radiation heart disease (75% women; age, 63±14 years) and 305 comparison patients (74% women; age, 63±14 years). In the radiation group, the vast majority had prior breast cancer (53%) and Hodgkin lymphoma (27%), and the mean time from radiation was 18±12 years. Just over one third of patients in either group had isolated single-valve or coronary bypass procedure; the rest were combination procedures. We demonstrate that, during a mean follow-up of 7.6±3 years, a significantly higher proportion of patients in the radiation group died compared with the comparison group (55% versus 28%; log-rank statistic, 42; P<0.001). On multivariable Cox proportional hazard analysis, the presence of radiation heart disease (hazard ratio, 2.47; 95% confidence interval, 1.82–3.36), increasing EuroSCORE (hazard ratio, 1.22; 95% confidence interval, 1.16–1.29), and lack of β-blockers (hazard ratio, 0.66; 95% confidence interval, 0.47–0.93) were associated with increased mortality (all P<0.01). In patients undergoing cardiothoracic surgery, radiation heart disease portends significantly increased long-term mortality. Alternative treatment strategies may be required in radiation heart disease patients to improve long-term survival.

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  • Long-Term Survival of Patients With Radiation Heart Disease Undergoing Cardiac SurgeryClinical Perspective
    Willis Wu, Ahmad Masri, Zoran B. Popovic, Nicholas G. Smedira, Bruce W. Lytle, Thomas H. Marwick, Brian P. Griffin and Milind Y. Desai
    Circulation. 2013;127:1476-1484, originally published April 8, 2013
    https://doi.org/10.1161/CIRCULATIONAHA.113.001435
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