Zellweger syndrome

Study objectives: To define the prognostic value of stress testing (STRT) in patients [greater than or equal to] 75 years of age.

Design: Multicenter prospective randomized trial.

Setting: Tertiary care centers.

Patients: Two hundred ninety-two patients of the Trial of Invasive vs Medical Treatment of Elderly Patients aged [greater than or equal to] 75 years with chronic angina despite receiving two or more antianginal drugs were prospectively observed for 1 year.

Intervention: STRT (88% exercise ECG; 12% pharmacologic stress imaging) was performed if possible, and ischemia was diagnosed using current guidelines. Death for any reason and nonfatal myocardial infarction were outcome events.

Results: Patients who could perform STRT (148 patients) were younger, had a lower risk profile, received less medication, and had less severe angina than patients who could not perform STRT (144 patients). The 1-year mortality rate was only 1.4% in patients with negative STILT results (72 patients) compared to 5.3% in patients with positive STRT results (76 patients) and 13.7% in patients who had not undergone STRT due to unstable symptoms (95 patients). The corresponding 1-year rates of death/infarction were 2.8%, 15.8%, and 26.3%, respectively. After adjustment for baseline differences, mortality rates were no longer significantly different. However, compared to patients with negative STRT results, infarction and death/infarction rates remained higher in patients with provocable ischemia (hazard ratio [HR], 8.9 [p = 0.04]; HR, 6.1 [p = 0.02], respectively) and in patients without STRT due to unstable angina (HR, 11.8 [p = 0.02]; HR, 8.6 [p = .004], respectively).

Conclusions: STRT in elderly patients is feasible and provides important prognostic information for their future management. Patients with negative STRT results after receiving therapy have a good prognosis, and their conditions may he managed conservatively.

Key words: aging; angina pectoris; coronary disease; myocardial ischemia; prognosis; stress test

Abbreviations: CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; CI = confidence interval; HR = hazard ratio; LVEF = left ventricular ejection fraction; MI = myocardial infarction; STRT = stress testing; TIME = Trial of Invasive vs Medical Therapy in the Elderly

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Stress testing (STRT) plays an important role in the diagnostic and prognostic assessment of coronary artery disease (CAD). (1) Stress may be applied as exercise, pharmacologic stress (eg, with dobutamine, dipyridamole, or adenosine), or atrial pacing. The sensitivity and specificity of the tests are largely dependent on the prevalence of CAD in the population tested (2) and are generally higher for imaging studies compared to exercise ECG alone. (3,4) Whereas these tests have been evaluated in and applied to young and middle-aged patients there are almost no data on their value in very old patients, particularly those > 75 years of age. (1,4,5) Due to the higher prevalence and severity of CAD in older patients, the sensitivity of noninvasive STRT increases with age, whereas specificity tends to decline. In addition, maximal aerobic capacity decreases by 8 to 10% per decade in sedentary men and women, and exercise capacity decreases by approximately 50% between ages 30 and 80, (1) limiting the diagnostic yield of exercise STRT in elderly populations. Possible comorbidities such as obstructive pulmonary disease, peripheral vascular disease, obesity, arthritis, neuromuscular disease, or generalized deconditioning are more prevalent limiting factors for performing the tests among elderly patients and, thus, for the diagnostic accuracy of exercise STRT. Therefore, pharmacologic STRT may be preferred (6,7) in elderly patients, however, its availability is still limited.

Prognosis can be predicted by the results of STRT and is impaired if ischemia can be documented or if there are large areas of scar tissue indicating reduced left ventricular function. In contrast, if these findings are absent, the prognosis is comparably good. However, the prognosis was worse in many studies (8-13) if STRT, particularly exercise STRT, could not be performed at all. Again, these findings are based on studies performed in young and middle-aged patients, but there are almost no data on the prognostic value of STRT in very old patients.

To fill this gap (ie, to define the prognostic value of STRT in patients > 75 years of age presenting with chest pain presumed to be angina pectoris), we performed a predefined subanalysis of all patients enrolled in the Trial of Invasive vs Medical Therapy in the Elderly (TIME) who had chronic angina (14,15) and followed them up for 1 year.

MATERIALS AND METHODS

Patients

Enrolled into the TIME study were 301 patients aged [greater than or equal to] 75 years who were referred to one of 14 Swiss centers for assessment of class 2 or greater angina pectoris according to the classification of the Canadian Cardiovascular Society (CCS) despite having received at least two antianginal drugs. In every, patient, STRT was recommended as part of a routine clinical evaluation in order to document angina/ischemia despite receiving standard antianginal therapy. Then, and after informed consent had been given, patients were randomized to an invasive strategy with coronary angiography followed by revascularization if feasible, or to an optimized medical strategy. Not included in the study were patients who had experienced acute myocardial infarction (MI) within the previous 10 days, those who had concomitant valvular or other heart disease, predominant heart failure, and life-limiting concomitant diseases such as cancer or severe renal failure, those who were unwilling to undergo revascularization, or those for whom it was impossible to undergo revascularization or to increase or optimize medical therapy. The TIME study was approved by the Ethics Committee of the Swiss Academy of Medical Sciences and by the local ethics committees of each of the 14 Swiss centers. Patients gave written informed consent.

STRT

STRT was strongly recommended in all patients but it was left to the discretion of the local investigators to decide what type of STRT would he appropriate and available. If STRT could not be performed, it was asked whether this was due to the severity or instability of symptoms, to comorbidities, to refused by the patient, or to logistic reasons. Investigators were advised to perform these tests while patients were receiving their current medications and to follow the standard guidelines. Usually a symptom-limited bicycle exercise test was performed, but in patients who were unable to perform exercise, dobutamine stress echocardiography or dipyridamole myocardial perfusion scintigraphy was allowed.

An STRT result was considered to be positive if the following criteria were fulfilled: (1) development of a horizontal or downsloping ST-segment depression or elevation [greater than or equal to] 1 mm for at least 80 ms after the end of the QRS complex in the ECG in exercise STRT (1); (2) new segmental wall motion abnormalities during perfusion of dobutamine in stress echocardiography that were not present at rest (4); and (3) reversible perfusion defects during the application of dipyridamole in myocardial perfusion scintigraphy. (3)

Analysis and Follow-up

For prognostic evaluation, all 301 TIME patients were observed for 1 year for the occurrence of death or nonfatal MI. According to the TIME study protocol, (14) 150 of the 292 analyzed patients (51%) were randomized to an invasive management with coronary angioplasty followed by revascularization, if feasible, whereas 142 (49%) received optimized medical treatment. Since both anti-ischemic treatment strategies yielded similar outcomes after 1 year, (15) patients were not subdivided by TIME treatment assignment for the present outcome analysis. To assess whether a positive STRT result may predict the need for later hospitalizations for acute corollary syndrome or revascularization, this was specifically analyzed in the subgroup of patients randomized to optimized medical therapy.

Statistical Analysis

The study was designed as a multicenter study, and all statistical analyses were performed at the study center in Basel, Switzerland. Continuous variables were summarized as the mean [+ or -] SD, and comparison between groups was performed using the Student t test or the Wilcoxon-Mann-Whitney test. A comparison of categoric variables between groups was performed using the [chi square] test or the Fisher exact test. Time variables with censored values were described using the Kaplan-Meier method, and comparison between groups was performed using the log rank test and Cox proportional hazards model adjusting for baseline differences in sex, age, comorbidities, risk factors, history of MI, and left ventricular ejection fraction (LVEF). All p values were two-sided, and values < 0.05 were considered to be statistically significant.

RESULTS

Patients and Stress Tests

In 292 of the 301 TIME study patients (97%), pertinent STRT data were available. In the remaining nine patients (3%), test data were not available for unreported reasons, and the patients were excluded from this analysis. The 292 patients formed the study population for the present analysis.

STRT could be performed in 148 of these 292 study patients (51%), whereas a test was not performed in 95 patients (33%) because of severe or unstable symptoms, in 24 patients (8%) because of limiting comorbidities, in 24 patients (8%) due to logistic reasons, and in 1 patient (0.5%) due to no consent. Among the 148 patients who underwent STRT, a bicycle exercise test was performed in 130 patients (88%), and 18 patients (12%) underwent pharmacologic STRT (ie, dobutamine stress echocardiography, nine patients; dipyridamole myocardial perfusion scintigraphy, nine patients). In these 148 patients, ischemia could be detected in 76 patients (51%), whereas the test result was negative while receiving current medication in 72 patients (49%). Therefore, the following patient groups were formed for prognostic comparison: (1) patients with a positive STRT result (76 patients); (2) patients with a negative STRT result (72 patients); (3) patients who had not undergone a test possibly due to unstable angina (95 patients); and (4) patients with no test possible due to other reasons for exclusion (ie, limiting comorbidities, logistic reasons, or refusal, 49 patients). Patients who underwent a bicycle exercise test performed a mean workload of 79 [+ or -] 26 W, and reached a mean maximal heart rate of 115 [+ or -] 21 beats/min, a mean maximal systolic BP of 165 [+ or -] 25 mm Hg, and an average diastolic BP of 83 [+ or -] 12 mm Hg. These exercise variables did not differ significantly between patients with positive and negative STRT results, and angina was reported in 72% of patients with objective evidence of ischemia vs 64% of those without (p = 0.4).

Baseline Characteristics

Baseline characteristics are shown in Table 1. On average, patients were 80 years old, and almost half of them were women (43%). All patients were severely symptomatic despite an average of 2.5 [+ or -] 0.6 antianginal drugs being received per patient. Most patients had a considerable CAD risk profile with a known history of CAD in more than half. Almost one third of the patients had two or more significant comorbidities.

Compared to patients who had not undergone STRT, patients who had performed STRT were younger, more likely to be men, had less severe angina, had fewer comorbidities, and less often had a history of congestive heart failure or MI. They reported less severe angina by CCS class and had received a lower average number of antianginal drugs per patient, particularly nitrates as well as diuretics and digitalis. The noninvasively determined LVEF was higher in patients who had undergone STRT than in those without. Patients who were unable to perform STRT were referred more often to a hospital for treatment of acute coronary syndrome than were patients who could perform STRT.

There were no significant baseline differences among patients who had performed STRT between those with ischemia vs those without. Among patients who had not performed STRT, those who did not perform it for reasons other than unstable angina more often presented also with dyspnea (71% vs 51%, respectively; p = 0.02) and less often had a history of MI (37% vs 61%, respectively; p = 0.006) or hypertension (55% vs 73%, respectively; p = 0.03) than those who had not performed STRT for unstable symptoms.

One-Year Outcome in Relation to Stress Test Findings

During the 1-year follow-up, 24 patients (8%) died, 27 patients (9%) experienced a nonfatal MI, and 48 patients (16%) experienced either one or both (Table 2). Mortality was significantly lower in patients who had performed STRT compared to those who had not and was lowest in patients with a negative STRT result (Fig 1). The same was true for the rates of nonfatal MI, which were significantly lower in patients who had performed STRT vs those who had not and was lowest in those without provocable ischemia. It may be noteworthy that the highest rate of nonfatal MIs occurred in patients who had not performed STRT due to unstable symptoms at presentation. In accordance with these findings, the 1-year death/MI rates were significantly lower in patients who had performed STRT vs those who had not, was lowest in patients without provocable ischemia, and was highest in patients who had not performed STRT due to unstable symptoms (Fig 2). After adjustment for baseline differences such as sex, age, comorbidities, elevated risk, previous MI, and LVEF, the hazard ratios (HRs) for death were 3.3 for patients with a positive STRT result (95% confidence interval [CI], 0.4 to 29.5; p = 0.29) and 5.8 for patients who had not performed STRT due to unstable angina (95% CI, 0.7 to 46.4; p = 0.09) if compared to patients with a negative STRT result (ie, the differences were no longer significant). In contrast, differences in the rates of nonfatal MIs remained significant after adjustment for baseline differences compared to patients with a negative STRT result with HRs of 8.9 for patients with a positive STRT result (95% CI, 1.1 to 71.4; p = 0.04) and 11.8 for patients who had not performed STRT due to unstable symptoms (95% CI, 1.5 to 90.6; p = 0.018). Similarly, HRs remained significant for death and/or MI compared to patients with a negative STILT result, as follows: for patients with a positive STRT result, 6.1 (95% CI 1.4 to 27.4; p = 0.018); and for patients who had not performed STRT due to unstable symptoms, 8.6 (95% CI, 2.0 to 37.0; p = 0.004) [Fig 3].

[FIGURES 1-3 OMITTED]

Predictive Value of STRT for Late Hospitalizations and Revascularizations

In the intention-to-treat analysis of the TIME study, late revascularizations for refractory symptoms were needed significantly more often in patients assigned to medical treatment vs invasive treatment (48% vs 10%, respectively; p < 0.001). (15) To assess a possible predictive power of STRT results on the need for hospitalization for acute coronary syndrome or on the need for late revascularization, this was analyzed in the 142 patients assigned to optimized medical treatment. Hospitalizations were needed in 6 of 37 patients (16%) with a negative STRT result, in 11 of 42 patients (26%) with a positive STRT result, and in 13 of 63 patients (21%) who had not performed STRT (difference not significant). Similarly, the rates of late revascularization were not significantly different (46%, 26%, and 54%, respectively, for the three groups of patients; differences not significant). This suggests that STRT did not predict which patients needed late hospitalization or revascularization for refractory ischemic symptoms.

DISCUSSION

The present analysis of the prognostic power of STRT in 80-year-old patients with chronic angina despite receiving standard medical therapy shows the following several important findings. First, a symptom-limited exercise test is possible in more than half of these patients. Second, the test provides prognostic value despite concurrent antianginal drug therapy. Regarding nonfatal MI and the combined death/nonfatal MI end point, patients who could perform STRT had a better outcome than patients who were unable to do so. The best outcomes were seen in patients who had performed STRT and had no provocable ischemia while receiving drug therapy, whereas the highest rate of events was noted in patients who had been unable to perform STRT because of unstable symptoms at rest. This suggests that elderly patients with negative STRT results while receiving standard drug therapy had remarkably good prognoses (ie, a very low rate of death and nonfatal ischemic events) and may not need to undergo invasive evaluation in view of a possible revascularization.

Predictive Power of STRT in Elderly Patients

Only a few studies on STRT in the age group > 75 years of age have been published. No predictive value was found when the Duke treadmill score (16) was applied to individuals > 75 years of age. (17) One possible reason for this negative result was the fact that a high proportion of patients was not able to work long enough or to induce ischemia (eg, to induce ST depression or angina) to achieve a low-risk Duke score. As a result, the majority of patients were classified as being in the intermediate-risk group, and no prognostic value of the analysis could be shown. Another study (18) demonstrated a prognostic significance of STRT in a population [greater than or equal to] 65 years of age in terms of achieved workload. However, a positive STRT result was associated with cardiac events in persons < 65 years of age only. In the present study, the achieved exercise workload, heart rate, and BP were comparatively low, however, they were reached during symptom-limited exercise by 80-year-old patients receiving antianginal medication. Since this analysis demonstrated a strong predictive value for this type of STRT in elderly patients, conventional parameters defined in younger populations may be of limited significance in the elderly.

In younger patient populations, the prognostic value of exercise testing has repeatedly been documented) and it has been noted that patients unable to perform an exercise test have the highest risk, 4 to 9 times that of patients able to be tested. (9, 10, 12, 13) This is in agreement with the findings of the present study in elderly patients for whom the risk of death or nonfatal MI was 7.7 times that of patients who had performed STRT. The best outcomes were seen in elderly patients with no provocable ischemia during the test who had an excellent 1-year survival rate of 98.6%. In contrast to these findings in "hard" events (ie, death from any cause or MI), test results did not predict which patients would not respond to optimized medical therapy. Over the 1-year period, patients who had not performed STRT or those with documented ischemia during STRT did not have significantly higher rates of hospitalization for acute coronary syndrome or the need for revascularization than did patients without provocable ischemia during the test. Thus, although test results seemed to be predictive of outcome, they did not predict which patients would respond to optimized drug therapy and which would not.

Risk of STRT in Elderly Patients

Several smaller studies (19-21) showed that STRT is feasible in elderly patients > 60 years of age. This is in accordance with our data in a population of patients [greater than or equal to] 75 years of age in whom almost 88% of all patients selected to undergo STRT were able to perform bicycle ergometry testing despite their advanced age and a high rate of comorbidities. In only 12% of patients, a pharmacologic stress test was performed because of nondiagnostic ECG changes, chronotropic incompetence, or physical inability. Potentially, there is a higher risk of complications of STRT in elderly patients because of the higher number of comorbidities and the higher prevalence of CAD, but STRT has been described as being safe in several reports. (1,6,21,22) This is in agreement with the present experience in which no adverse events were noted during exercise testing.

Limitations of This Study

The data presented are based on a retrospective analysis of prospectively collected data and, therefore, are subject to inherent limitations. In addition, the patient numbers were limited. However, this is the first such study investigating the prognostic value of STRT in symptomatic patients aged [greater than or equal to] 75 years being systematically treated for ischemic symptoms. In these patients, all tests were performed while patients were receiving antianginal medication in order to test whether the patients were symptomatic despite drug therapy. This has to be taken into consideration when interpreting the data, because the maximal heart rate and maximal BP achieved were lower than might have been expected. Importantly, however, tests were symptom-limited, and the present analysis relates to this type of test. Finally, exercise ECG and pharmacologic imaging tests were analyzed together, because patient numbers for the latter were too small to warrant separate analysis. The question to be addressed was the prognostic impact of a positive STRT result and not a comparison between different tests.

CONCLUSIONS

This outcome analysis of 80-year-old patients with chronic angina despite receiving standard antianginal therapy shows that STRT is feasible in more than half of these patients and adds relevant information to their management. Patients with provocable ischemia despite receiving antianginal therapy and those unable to perform STRT due to unstable symptoms have sixfold and eightfold the risk of death/nonfatal MI, respectively, than patients without ischemia, and they may benefit particularly from evaluation for possible revascularization. In contrast, patients without inducible ischemia during STRT have a favorable 1-year outcome and do not need invasive management with its associated risks. Thus, STRT should be encouraged also in the clinical workup of elderly patients with chronic CAD because of its prognostic information in view of possible therapeutic management decisions.

ACKNOWLEDGMENTS: We gratefully acknowledge the contribution of all participating patients, and the work done by all investigators, advisors, and the critical event committee.

REFERENCES

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(13) Villella A, Maggioni AP, Villella M, et el. Prognostic significance of maximal exercise testing after myocardial infarction treated with thrombolytic agents: the GISSI-2 data-base; Gruppo Italiano per lo Studio della Sopravvivenza Nell'Infarto. Lancet 1995; 346:523-529

(14) TIME Investigators. Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial. Lancet 2001; 358:951-957

(15) Pfisterer M, Buser P, Osswald S, et al. Outcome of elderly patients with chronic symptomatic coronary artery disease with an invasive vs optimized medical treatment strategy: one-year results of the randomized TIME trial. JAMA 2003; 289:1117-1123

(16) Mark DB, Shaw L, Harrell FE Jr, et al. Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease. N Engl J Med 1991; 325:849-853

(17) Kwok JM, Miller TD, Hodge DO, et al. Prognostic value of the Duke treadmill score in the elderly. J Am Coll Cardiol 2002; 39:1475-1481

(18) Goraya TY, Jacobsen SJ, Pellikka PA, et al. Prognostic value of treadmill exercise testing in elderly persons. Ann Intern Med 2000; 132:862-870

(19) Gaul G. Stress testing in persons above the age of 65 years: applicability and diagnostic value of a standardized maximal symptom-limited testing protocol. Eur Heart J 1984; 5(suppl):51-53

(20) Glover DR, Robinson CS, Murray RG. Diagnostic exercise testing in 104 patients over 65 years of age. Eur Heart J 1984; 5(suppl):59-61

(21) Pool J, Scheffer MG, Simoons ML, et el. Clinical value of exercise testing in elderly patients. Eur Heart J 1984; 5(suppl):47-50

(22) Gill TM, DiPietro L, Krumholz HM. Role of exercise stress testing and safety monitoring for older persons starting an exercise program. JAMA 2000; 284:342-349

Raban V. Jeger, MD; Michael J. Zellweger, MD; Christoph Kaiser, MD; Leticia Grize, PhD; Stefan Osswald, MD; Peter T. Buser, MD; and Matthias E. Pfisterer, MD; for the TIME Investigators ([dagger])

* From the Division of Cardiology (Drs. Jeger, Zellweger, Kaiser, Osswald, Buser, and Pfisterer), University Hospital Basel; and Institute of Epidemiology (Dr. Grize), University of Basel, Basel, Switzerland.

([dagger]) A list of all TIME investigators is contained in reference 14. The TIME study was supported by grants from the Swiss Heart Foundation and the Adumed Foundation, Switzerland.

Manuscript received September 19, 2003; revision accepted September 23, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Matthias E. Pfisterer, MD, Principal Investigator TIME, Head, Division of Cardiology, University Hospital, CH-4031 Basel, Switzerland; e-mail: pfisterer@email.ch

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