Outcomes after normal dobutamine stress echocardiography and predictors of adverse events: long-term follow-up of 3014 patients

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1 European Heart Journal (2006) 27, doi: /eurheartj/ehl393 Clinical research Imaging Outcomes after normal dobutamine stress echocardiography and predictors of adverse events: long-term follow-up of 3014 patients Nithima Chaowalit 1, Robert B. McCully 1, Mark J. Callahan 1, Farouk Mookadam 1, Kent R. Bailey 2, and Patricia A. Pellikka 1 * 1 Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA and 2 Department of Biostatistics, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA Received 27 December 2005; revised 24 October 2006; accepted 07 November 2006; online publish-ahead-of-print 28 November 2006 KEYWORDS Dobutamine; Ischaemic heart disease; Prognosis; Stress echocardiography Aims Normal exercise echocardiography predicts a good prognosis. Dobutamine stress echocardiography (DSE) is generally reserved for patients with comorbidities which preclude exercise testing. We evaluated predictors of adverse events after normal DSE. Methods and results We studied 3014 patients (1200 males, years) with normal DSE, defined as the absence of wall motion abnormality at rest or with stress. During median follow-up of 6.3 years, all-cause mortality and cardiac events, defined as myocardial infarction and coronary revascularization, occurred in 920 (31%) and 231 (7.7%) patients, respectively. Survival and cardiac event-free probabilities were 95 and 98% at 1 year, 78 and 93% at 5 years, and 56 and 89% at 10 years, respectively. Age, diabetes mellitus, and failure to achieve 85% age-predicted maximal heart rate were independent predictors of mortality and cardiac events. Patients with all three of these characteristics had a 13% probability of cardiac events within the first year and higher risk throughout follow-up. Conclusion Prognosis after normal DSE is not necessarily benign, but depends on patient and stress test characteristics. Careful evaluation, using clinical and stress data, is required to identify patients with normal DSE who are at increased risk of adverse outcomes during long-term follow-up. Introduction Dobutamine stress echocardiography (DSE) is an appealing alternative to exercise echocardiography in patients who are unable to exercise. Previous small studies have reported excellent short- and intermediate-term outcomes after normal DSE. 1 4 However, much less is known about longterm follow-up. Previous studies of exercise echocardiography have suggested a favourable prognosis after a normal test result, even in patients with a clinically intermediate or high pretest probability of coronary artery disease (CAD). 5 Given the relatively poor prognosis of patients who are unable to exercise and the comorbid conditions typically present in patients who undergo DSE, it is reasonable to postulate that outcomes after normal DSE may be less favourable. Attention has focused on those variables characterizing an abnormal stress echocardiogram, namely extent and severity of wall motion abnormalities (WMA), change in left ventricular (LV) end-systolic volume and ischaemic threshold, which characterize patients at risk of future cardiovascular events. 4,6 9 In contrast, risk stratification and the identification of predictors of adverse outcomes in * Corresponding author. Tel: þ ; fax: þ address: pellikka.patricia@mayo.edu patients with normal DSE have gained little attention. Whether any haemodynamic or stress variables add incremental value to clinical data in predicting long-term outcomes after normal DSE has not been determined. We, therefore, sought to evaluate the prognostic significance of normal DSE, including the value of stress haemodynamic variables, for predicting long-term outcomes. Methods Study population The Mayo Clinic Institutional Review Board approved the study. Of 7165 patients referred for clinically indicated DSE from June 1992 through December 1999, we identified 3018 patients with normal DSE; of these, four (0.12%) refused to allow access of their records for research. The remaining 3014 constituted the study population. Relevant data relating to clinical characteristics, electrocardiogram (ECG), and rest and stress echocardiography were recorded at the time of DSE into an electronic database. Diabetes mellitus was defined according to the requirement for treatment with insulin or oral hypoglycaemic agents or according to the definition by the American Diabetes Association. 10 Hypertension was defined as systolic blood pressure 140 mmhg, diastolic blood pressure 90 mmhg, or the use of antihypertensive medication. Patients & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 3040 N. Chaowalit et al. were considered to have hyperlipidaemia if their total cholesterol value was 5.17 mmol/l or if they were receiving lipid-lowering medication. Prior myocardial infarction (MI) was defined as the presence of significant Q waves on the baseline ECG or from the history. History of CAD was defined as prior MI or prior coronary revascularization. Family history of CAD was defined as the presence of premature CAD in male first-degree relative,55 years or female first-degree relative,65 years. The abnormal rest ECG was determined based on the presence of the diagnostic criteria for LV hypertrophy, bundle branch block, or significant Q waves on the baseline ECG. Risk factors considered for the evaluation of the pretest probability of CAD were hypertension, smoking, diabetes mellitus, hyperlipidaemia, defined as total cholesterol.200 mg/dl or therapy with a lipid-lowering agent, and ST-T segment wave changes (including those associated with left bundle branch block) on the rest ECG. 11 The estimation of pretest probability of CAD was determined using previously described criteria which included the presence and characteristics of chest pain, age, gender, and presence of greater than or equal to three risk factors for CAD. 5 Low, intermediate, and high pretest probability of CAD were defined as probability of 25, 26 69, and 70%, respectively. Dobutamine stress echocardiography DSE was performed according to a previously described protocol using 3 min stages and a peak dose of 40 mg/kg/min. 12 Atropine, in 0.25 mg increments to a total dose of 2 mg, was administered intravenously as needed to augment the heart rate while the dobutamine infusion was continued. The 12-lead ECG was recorded at the end of each stage and the six-lead ECG continuously monitored. Blood pressure was measured non-invasively at rest and at the end of each stage. The predetermined endpoints for test termination were extensive new or worsening WMAs, the completion of the stress protocol, achievement of target heart rate, severe angina, ST-segment elevation in ECG leads without significant Q waves, haemodynamically significant arrhythmias, severe hypertension (.220/ 110 mmhg), hypotension or.20 mmhg reduction in systolic blood pressure from the previous stage, or intolerable symptoms. DSE was reviewed by a cardiologist experienced in interpretation of regional ventricular wall motion and blinded to clinical data. Ejection fraction (EF) was evaluated by a modification of the method of Quinones et al. 13 combined with visual estimation. The reproducibility of this method and validation with biplane Simpson method have previously been described. 14 Wall motion was assessed and scored 1 through 5 in each of the 16 segments, according to a previously described model. 15 DSE was defined as normal if there was no WMA at rest or at peak stress. The target heart rate was defined as 85% of age-predicted maximal heart rate (220-age). The dose of dobutamine and heart rate at peak stress were recorded. The stress ECG was positive for ischaemia if there was horizontal or downsloping ST-segment depression of 1mm at 80 ms after the J point. Follow-up Follow-up information was obtained from review of medical records, telephone interviews, mailed questionnaires, and Social Security Death Index in all patients. The endpoints of this study included all-cause mortality and cardiac events, defined as MI and coronary revascularization. For the analysis of cardiac events, in patients who experienced more than one event, only the first event was included for the analysis and the patients censored at the time of this event. For the analysis of mortality no censoring was used. Statistical analysis Categorical variables were summarized as percentages and continuous variables as mean + SD. Comparison between groups was based on Wilcoxon rank-sum test for continuous variables and Pearson s x 2 test for categorical variables. Overall survival and events-free survival were estimated by the Kaplan Meier method. Observed survival was compared with expected survival based on an age- and gender-stratified life table data of Minnesota white population, using one-sample log-rank test. Univariable and multivariable associations of clinical, haemodynamic, and stress echocardiographic variables with the endpoint were assessed using the Cox proportional hazard model. The variables that were considered in the multivariate Cox regression for all-cause mortality were age, male sex, diabetes, known CAD, and failure to achieve target heart rate. For cardiac events, these were age, diabetes, hypertension, known CAD, pretest probability of CAD, and failure to achieve target heart rate. For these analyses, the pretest probability of CAD was classified according to a 1 3 scale (1, low; 2, intermediate; and 3, high). Variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of Results of these analyses were summarized as hazard ratios (HR) with 95% confidence intervals (CI) and associated log-likelihood ratio x 2 and P-values. We studied the stability of the final model under a bootstrap sampling scheme, drawing 1000 bootstrap samples of the dataset and repeating the forward stepwise selection using the same candidate variables for both endpoints. The proportional hazards assumption was tested. We also tested for nonlinearity (quadratic terms) of the effects of the two continuous variables, age and pretest probability of CAD. Results Clinical data The mean age was years. Baseline characteristics are summarized in Table 1. The indication for DSE was for the evaluation of suspected or known CAD in 52%, for preoperative cardiac risk assessment in 41%, and other reasons in 7%. Reasons for inability to exercise were orthopaedic limitation in 35%, peripheral vascular disease in 19%, debility in 10%, pulmonary disease in 7%, and others in 29%. Among 286 patients with prior revascularization, 138 had undergone percutaneous intervention (PCI), 112 had coronary bypass surgery, and 36 had both procedures. History of chest pain was reported in 1357 patients; among these 385 had typical angina. Among patients with typical angina, the indication for DSE was for the evaluation of suspected or known CAD in 82%, for pre-operative cardiac risk assessment in 16%, and other reasons in 2%. Twenty-six percent of patients had at least three risk factors for CAD. Table 1 DSE Baseline characteristics of 3014 patients with normal Characteristics Number % Male gender Hypertension Diabetes mellitus Smoking Family history of CAD Hyperlipidaemia History of CAD Prior MI Prior coronary revascularization Beta-blocker therapy a Abnormal rest ECG a Of the patients on beta-blocker therapy, 563 (78%) had hypertension and 153 (21%) had a history of CAD.

3 Long-term prognostic significance of normal dobutamine echo 3041 The pretest probability of CAD was low in 55%, intermediate in 33%, and high in 12% of patients. Haemodynamic and stress echocardiographic data EF was %, range 50 80%. The peak dose of dobutamine infusion averaged mg/kg/min. Atropine, mean dose mg, was administered in 38% of patients. The ECG was positive for ischaemia in 166 (6%) patients. Heart rate increased from to b.p.m., and rate-pressure product from to The percent of age-predicted maximal heart rate attained was %. Among the 427 (14%) patients who failed to achieve target heart rate, 186 (44%) were receiving beta-blocker therapy. The reasons for test termination were achievement of target heart rate in 83%, completion of the stress protocol in 7%, intolerable adverse effects in 8%, and arrhythmias in 2%. Among those who were on beta-blockers, 26% failed to achieve target heart rate. Outcomes The median follow-up was 6.3 years (IQR years). Cardiac events or death occurred in 1052 patients. All-cause mortality occurred in 920 patients. Cardiac events occurred in 231 patients, including as the first event, MI in 93 and coronary revascularization in 138 patients (PCI in 72 patients and coronary artery bypass surgery in 66). The estimated cardiac event-free probabilities at 1, 3, 5, 7, and 10 years were 98, 95, 93, 91, and 89%, respectively. The 1, 3, 5, 7, and 10-year survival probabilities were 95, 86, 78, 69, and 56%, respectively. Overall survival of the study population was lower than the expected survival of an age- and gendermatched population (P, ), as shown in Figure 1. Survival was worse in men than in women (P ¼ 0.029), as shown in Figure 2. Survival was also worse in patients with a history of CAD (P, 0.001), as shown in Figure 3. Survival probabilities of patients in the low, intermediate, and high pretest probability subgroups were similar (P ¼ 0.16). Tables 2 and 3, and multivariable predictors in Table 4. Neither beta-blocker therapy nor a positive stress ECG was predictive of either mortality or cardiac events. Thus, failure to achieve target heart rate was an independent predictor of both mortality (P ¼ 0.004) and cardiac events (P ¼ 0.001). In patients with normal DSE, failure to achieve target heart rate identified subjects who were at increased risk for adverse events with a 31% increased risk of mortality and a 74% increased risk of cardiac events. Based on the presence or absence of the variables which were most strongly predictive in the multivariate model, namely diabetes mellitus, history of CAD, and failure to achieve target heart rate, we estimated survival for patients in four categories, depending on the number of risk variables present (Figure 4). By the end of the first year, the probability of having a cardiac event for those with three risk factors was 13% and for those with no, one, or two risk factors, was 1, 3, and 6% respectively. Robustness of predictive models For the mortality model, each of the four variables in the final model appeared in the bootstrap models over 90% of the time, while the variable history of CAD also appeared but in only 18% of the models. For the endpoint of cardiac Predictors of outcomes The univariate analysis of clinical, haemodynamic, and stress variables in predicting adverse events are listed in Figure 2 DSE. Kaplan Meier survival curves of females vs. males with normal Figure 1 Kaplan Meier survival curves of patients with normal DSE(observed, n ¼ 3014) and an age- and gender-matched population obtained from life tables (expected). Figure 3 Kaplan Meier survival curves of patients with and without a history of CAD and with normal DSE.

4 3042 N. Chaowalit et al. Table 2 Univariate predictors of all-cause mortality Variables x 2 HR 95% CI P-value Age a , Male gender Diabetes mellitus , History of CAD Prior MI Prior coronary artery bypass surgery Rest heart rate b Peak heart rate b , Rest systolic blood pressure b Peak diastolic blood pressure b Variables considered, but not significant, included pretest probability of CAD, hypertension, family history of CAD, smoking, beta-blocker therapy, abnormal rest ECG, peak systolic blood pressure, rest diastolic blood pressure, and failure to achieve target heart rate. a Per decade. b Per 10 unit increment. Table 3 Univariate predictors of cardiac events Variables x 2 HR 95% CI P-value Age a Diabetes mellitus , Hypertension History of CAD , Prior MI Prior revascularization , Pretest probability of CAD b Peak heart rate c Rest systolic blood pressure c Rest diastolic blood pressure c Failure to achieve target heart rate Variables considered, but not significant, included gender, smoking, family history of CAD, beta-blocker therapy, abnormal rest ECG, rest heart rate, peak systolic blood pressure, peak diastolic blood pressure, and positive ECG. a Per decade. b Per 1 unit. c Per 10 unit increment. events, diabetes, history of CAD, failure to achieve target heart rate, and age appeared in 100, 99, 93, and 85%, respectively, of the bootstrap models. Hypertension and pretest probability of CAD appeared in 57 and 56% of the bootstrap models, respectively. Table 4 also shows the average parameter estimates for the variables in the final model averaged across bootstrap samples in which the final model was, or was not, the selected model thus showing the shrinkage that should be applied because of the use of stepwise selection. The only variable and model in which proportional hazards was not satisfied was for the association of age with mortality. Specifically, the log (HR) per decade of age increased for every natural logarithmic unit increase in time of follow-up in years, which implies a HR of 1.26 per decade of age at 4 months, vs per decade of age at 1 year, and 1.95 per decade of age at 5 years. This may represent an initial phase where the indication for the DSE plays a more important role than the age of the individual, whereas later in follow-up, age takes on its more usual role in modifying the risk of mortality. In addition, it may simply reflect the non-linear relation of age with mortality in the population. When non-linear effects were considered, only age led to statistically significant but modest quadratic effects in each of the two models. Discussion Data regarding the prognostic significance of abnormal DSE have been well demonstrated in several previous studies. 4,7,9,16 18 On the contrary, less is known about the clinical importance and long-term outcomes after normal DSE in a large population. The present study reports a relatively high mortality after normal DSE in a large group of 3014 patients during long-term follow-up of up to 12 years. Our findings identify clinical and haemodynamic predictors of long-term adverse outcomes in the setting of normal DSE. Older age, male gender, diabetes mellitus, hypertension, history of CAD, and increased pretest probability of CAD identified a high-risk group among patients with normal DSE. Furthermore, failure to achieve target heart rate was an important haemodynamic stress variable, incremental to clinical data, for predicting long-term adverse outcomes, and identified those with a 31% increased hazard of mortality and 74% increased hazard of cardiac events. Prognostic significance of clinical and haemodynamic variables despite normal DSE Although data describing overall mortality and cardiac events after normal DSE are scarce, prognostic information to identify independent predictors of adverse outcomes is much less available. 19 The ability to predict poor outcomes in the setting of normal study, using clinical and haemodynamic variables, is clinically meaningful. In the present study, traditional CAD risk factors, including older age, male gender, diabetes mellitus, hypertension, history of CAD were predictors of long-term adverse outcomes in patients with normal DSE. This finding emphasizes the importance of clinical data, even in the setting of a normal study, for risk stratification. When is further testing indicated after normal DSE? As shown in Figure 4, the survival curves of patients stratified according to the number of risk variables begin to diverge immediately, suggesting that in those with diabetes mellitus, history of CAD, and failure to reach target heart rate, despite normal DSE, further testing is indicated. Each of these variables was an independent predictor of adverse events. The association of a higher resting heart rate with an increased risk of mortality has previously been described. 19,20 On the other hand, less is known about the predictive value of failure to achieving target heart rate after pharmacologic stress testing. Since inadequate chronotropy reduces the diagnostic sensitivity of DSE, some investigators may consider a non-ischaemic study in patients who failed to achieve target heart rate as a non-diagnostic, 21 while others have not paid much attention to the degree of chronotropic response at

5 Long-term prognostic significance of normal dobutamine echo 3043 Table 4 Multivariate predictors of adverse events Variables HR 95% CI P-value Selected model of bootstrap sample Final model (n ¼ 651) Other model (n ¼ 349) HR HR All-cause mortality Age a , Male gender Diabetes mellitus , Failure to achieve target heart rate Cardiac events n ¼ 209 n ¼ 791 Age a Diabetes mellitus , Hypertension History of CAD , Pretest probability of CAD b Failure to achieve target heart rate x 2 for all-cause mortality and cardiac events were 246 and 95, respectively. a Per decade. b Per 1 unit. Figure 4 Event-free survival is estimated for patients with normal DSE according to the number of risk factors present. Risk factors include diabetes mellitus, history of CAD, and failure to achieve target heart rate. the test conclusion. 4,18 According to our findings, failure to achieve target heart rate was an important predictor of the patient at increased risk. Previous studies of normal stress echocardiography McCully et al. 5 reported a favourable outcome in 1325 patients with normal exercise echocardiography. During the median follow-up of 23 months, all-cause mortality, nonfatal MI, and coronary revascularization were reported in 17, 10, and 20 patients, respectively. Survival rates free of all cardiac events (cardiac death, non-fatal MI, and coronary revascularization) at 1 and 3 years were 99.5 and 98.6%, respectively. Clinical characteristics of the patients in McCully s study and the current study were similar except patients in our study were older, underwent DSE because of the inability to exercise, and had a longer follow-up, which contributes to the higher event rate in our patient population despite the normal test result. Regarding the prognostic value of normal DSE, previous studies have reported a low event rate at short- and intermediate-term follow-up. 1 4 Steinberg et al. 4 described a favourable 5-year prognosis after normal DSE in the subgroup of 42 male patients with a high pretest probability of CAD. Allcause mortality and MI occurred in 9.5 and 4.8%, respectively. However, coronary revascularization was performed in a relatively high number of patients (28.5%), resulting in a high hard event rate (42.9% of combined all-cause mortality, MI, and coronary revascularization). Geleijnse et al. 2 studied 200 patients with a stable chest pain syndrome and normal DSE and reported the combined events of death, MI, and coronary revascularization in 6.5% during months of follow-up. Of note, the number of patients was relatively small with a short follow-up period. Dhond et al. 1 reported a low MI and cardiac death rate (1.5 and 0.13% per patient/year, respectively) in 171 patients with normal DSE during intermediate-term follow-up. Mesa et al. 3 reported a 2-year prognostic value of normal DSE in 100 women with suspected CAD, with allcause mortality of 6% and combined death, MI and coronary revascularization of 8%. Of note, target heart rate was achieved in all patients, reflecting a low-risk population. Recently, Sozzi et al. 19 demonstrated a favourable outcome during long-term follow-up in 401 patients with normal DSE. All-cause mortality and non-fatal MI occurred in 11 and 3.2%, respectively. Compared with this group, our population was older ( years vs years), fewer of our patients achieved target heart rate (86% vs. 97%), and our follow-up was longer ( years vs years). Biagini et al. 22 recently reported outcome after DSE in 3381 patients during follow-up of years. Independent predictors of cardiac events,

6 3044 N. Chaowalit et al. including cardiac death and MI, were male gender, age, history of heart failure, previous MI, and diabetes mellitus. In 1170 patients with normal DSE, subgroup analysis for predictors of events was not performed. However, in this subgroup, men had less favourable outcomes than women with a two-fold greater cardiac event rate. In our population, the mean age was 7 years greater, and gender differences were less striking, although male sex was an independent predictor of mortality. Unrecognized importance of normal DSE To our knowledge, this is the largest study to evaluate the long-term survival and prognostic value after normal DSE. Compared with previous studies, we found a relatively high rate of adverse outcomes, probably due to the longer period of follow-up. As a result of a longer follow-up, the progression of pre-existing non-obstructive coronary lesions and the development of new, obstructive lesions may explain the observation of higher event rates. Event rate was significantly higher than that of an age and sex matched referent group, not surprising, as the patients undergoing DSE were unable to perform an exercise test. The 3-year survival and cardiac event-free probabilities in our study were 86 and 95%, respectively. We identified higher-risk subgroups of patients after normal DSE (e.g. those with advancing age, male gender, diabetes mellitus, hypertension, history of CAD, increased pretest probability of CAD, and failure to achieve target heart rate) that may need either further risk stratification or an earlier follow-up study. The low-risk guarantee of normal DSE may not be applicable to all patients during long-term follow-up. A normal dobutamine stress echocardiogram should not prevent the performance of further testing and therapeutic intervention in patients who are at increased risk of adverse outcomes during long-term follow-up. Study limitations The combined endpoint of MI and coronary revascularization was used in the present study. Generally, coronary revascularization has been influenced by the physician s decision and thus regarded as a soft endpoint. However, subsequent coronary revascularization can be considered an unexpected outcome after normal DSE. We, therefore, considered coronary revascularization as a cardiac event. Although it may be useful to repeat DSE after a previous normal study, an appropriate time interval has never been determined. Further studies are required to establish the appropriate timing of such a test. Conclusions In patients undergoing clinically indicated DSE, long-term mortality is substantial, despite normal test results. Age, diabetes mellitus, and failure to achieve target heart rate identify patients at increased risk. Acknowledgement N.C. was supported by a grant from Siriraj Hospital, Mahidol University, Bangkok, Thailand. Conflict of interest: none declared. 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