Exercise Tolerance Test Time as an Endpoint for Clinical Trials Evaluating Therapies for Refractory Angina
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# Overview
For many years, cardiac stress testing has played an important role in evaluating patients with heart disease.  The concept behind exercise stress testing is monitoring of select physiologic responses to progressively increased intensity of exercise.  The two most common physiologic responses to routine exercise testing with ECG monitoring in patients with significant impairment of coronary flow due to fixed obstructive disease are development of symptoms and ST segment abnormalities consistent with myocardial ischemia.  The advantage of standardized stress testing is that the EKG changes and symptoms are reproducible for a given workload.  If there is either medical or vascular intervention that results in reduced probability of ischemia, symptoms and EKG changes at a given workload should be less likely.  As a result, one should observe increased functional capacity manifest as the ability to do more work and measured as prolonged exercise time.  Exercise training and repeated testing, however, may also result in improved performance due to training effects on myocardial oxygen consumption as well as other unexplained placebo effects.
In the United States, the treadmill is the traditional modality of choice for exercise testing.  The great advantage of the treadmill is that the workload can be varied quickly and safely by electronically increasing the speed and grade.  There are many standardized treadmill protocols that allow for the increase in metabolic expenditure.  In the United States, the most common protocol is the Bruce which has several modified protocols.  Each stage of the Bruce protocol is 3 minutes in duration.    Depending upon which stage or fraction of the stage is completed, the metabolic expenditure can be determined. Table 1
Each MET results in the consumption of 3.5 ml/kg/min of oxygen.  At rest, the metabolic expenditure is equal to 1 MET.  All activities require a certain MET expenditure with a continuum from 1 MET to >10 METS. .  Activities from 1 to 4 METS include the ability of the patient to take care of themselves such as eating and dressing to walking at 2-3 mph and performing light housework such as dusting and washing dishes.  Recreationally, 1 to 4 METS would also include: playing the piano, leisurely canoeing, golf with a cart and slow ballroom dancing.  Activities that range from 4 to >10 METS include: climbing stairs, walking on level ground at 4 mph, running a short distance, doing heavy housework and participation in sporting activities such as cycling, tennis, golf without a cart, fast ballroom/square dancing and swimming.
If there is an intervention in a patients health that enabled them to improve their functional capacity by 60 seconds on a standardized exercise test, this would result in a 1-1.5 MET increase in their peak capacity.  This increase in functional capacity should allow the patient greater freedom to the next level of activity.  For example, the most debilitated patient may improve from only being able to sit quietly (1.5 METS) to walking about the house and daily grooming without stopping (2.5 METS).  Increases in METs and the correlation with physical activity for other hypothetical increases in exercise time are shown in Table 2.
The importance of the exercise tolerance test (ETT) as a measure of functional capacity and predictable ischemic threshold has resulted in its use as a primary efficacy endpoint in a number of clinical trials that have evaluated a variety of anti-ischemic treatments for regulatory approval.  Examples of several recent studies are included in Table 3.  The designs and results of these studies also exemplify many of the caveats that must be considered in using ETT time as an endpoint.
Firstly, as noted above, there is a tendency for study subjects to improve their exercise time simply by repeated testing.  Most of these studies, therefore, require evidence at baseline that repeat testing provides consistent exercise times, generally within 15%-25% on 2-4 baseline studies, before a subject is deemed eligible.  This potential problem is made even less likely in several of the studies by requiring exercise to be limited by physiologic evidence of ischemia, rather than, or in addition to, maximum tolerated time.  Thus, in these cases, the limit of exercise time is driven by development of typical angina of a defined severity or specified ischemic ECG change.  Since the development of these findings in patients with fixed obstructive disease is usually reproducible at a given workload, the potential for intra-subject variability is minimized.
The study design must also require the use of standardized exercise protocols at all study centers consistently at baseline and follow-up.  Finally, the design must either require a minimum level of exercise ability at baseline and/or otherwise provide for criteria that exclude patients unlikely to benefit from an intervention that may work only by reducing the myocardial ischemia threshold.  In this way, subjects whose baseline ETT times are limited by other medical conditions or inability to perform on the treadmill will not confound the results.
Of course, a major concern that is evident by reviewing the outcomes of these prior studies is the previously described placebo effect as it relates to ETT time.  It is not the intent of this paper to develop the possible physiologic mechanisms for this effect, but it is clear from review of the data that improvements of 60 seconds or more in ETT time have been noted in patients receiving placebo therapies.  It is of critical importance and reassuring to note, however, that careful masking of treatment assignment to subjects and evaluators provides for validation of ETT time as an endpoint.  Perhaps the best example is in the evaluation of transmyocardial revascularization (TMR) for refractory angina.  Prior studies of surgical and percutaneous TMR had shown overwhelming evidence for benefit based on the ETT time endpoint, with statistically significant improvements of 89 and 111 seconds in the two largest studies.  Theories for the physiologic effect of therapy were quickly adapted to account for the benefit even as a previous theory was disproved.  In the end no reasonable histologic or physiologic explanation was found.  Ultimately, the only double-blinded, placebo controlled study (DIRECT) showed no evidence for a benefit in ETT time, and the therapy is no longer regarded as having an anti-ischemic or other beneficial effect.  As noted in Table 3, among the double blind, placebo controlled biologic and pharmacologic studies, only the ranolazine studies were positive for the ETT time endpoint, suggesting again that in appropriately controlled studies ETT time remains a valid endpoint with ability to discriminate among effective and likely ineffective therapies.
The importance of the ETT time endpoint as a measure of improved functional capacity must be weighed against the more critical clinical endpoints of death, myocardial infarction, and cardiac re-hospitalization.  Review of the studies in Table 3 that provide at least one-year outcomes for these endpoints in patients with Canadian Cardiovascular Society (CCS) class III or IV demonstrates mortality of 5-11%, MI rates of 7-14%, and cardiac re-hospitalizaton in approximately 50% of subjects. There are many reasons why therapies that provide clear benefit for reducing ischemia as measured by ETT time in patients with refractory angina may have little or no impact on these other clinical endpoints.  Mortality in these patients is multi-factorial.  Most patients have had prior MI and thus are at risk for sudden death due to arrhythmia or death due to progressive congestive heart failure.  There is also a poor correlation between lesions responsible for severe fixed obstructive disease and the development of acute unstable coronary syndromes that are likely to result in death, MI, and many of the cardiac re-hospitalizations.  Indeed, studies have now shown that most of these acute coronary syndromes are caused by mild or moderate lesions rather than the severely stenotic lesions that are histologically stable but cause symptomatic demand ischemia.  It should be expected, however, that therapies providing global reductions in ischemic burden as assessed by improved ETT time may allow some patients to better tolerate other acute ischemic events and lessen their impact.  While it is unlikely this will be measurable as a mortality reduction for the reasons noted, a decrease in MI size or frequency and/or cardiac re-hospitalization is a potential.  Validated clinically significant improvements in ETT time may thus serve as a surrogate for improvements in these more serious clinical endpoints.  This potential notwithstanding, the daily incapacitating angina and limited functional capacity remains as a most serious morbidity for these patients, and true improvements in ETT time reflect measurable benefit.  Of course, as with any efficacy measure, the benefit must be evaluated against overall safety of the therapy, such that there are at least no associated increases in clinical endpoints, such as death or MI, as a result of the therapeutic benefit measured by ETT time.
It would be ideal to confirm the presumed reduction in ischemic burden or improved myocardial perfusion by a validated imaging modality.  Single Photon Emission Computerized Tomography (SPECT) has been one modality proposed for this correlation.  Unfortunately, there are a number of theoretical reasons why this may not be a reliable measure in patients with refractory angina who have undergone a non-revascularization intervention.  These interventions may not measurably improve myocardial perfusion as rest, so rest imaging would not necessarily detect potentially significant improvements in perfusion during work.  Likewise, since the goal of repeat ETT time is to achieve ischemia albeit at a higher workload (i.e. longer time) imaging during stress would be expected to still show ischemic areas similar to baseline.  Rest and exercise imaging are both further limited in their assessment of most non-revascularization therapies by the fact that changes may be global rather than regional and thus not detectable by SPECT.  For these reasons, SPECT imaging has not been validated as a measure of change in myocardial ischemic threshold or perfusion in response to non-revascularization therapies.

# Conclusion
ETT time is a valid measure of ischemic threshold and is a reproducible measure for a given level of work.  Clinical trials using ETT time as a primary endpoint require careful design and must be fully blinded to protect against the placebo effect.  Clinically significant improvements in ETT time resulting from mechanical or pharmacologic interventions represent improved functional capacity for treated patients.  While improved ETT time may be a surrogate for reduced size or frequency of MI or fewer cardiac hospitalizations, it is unlikely to be associated with reductions in mortality in the refractory angina population.  Imaging modalities such as SPECT for measuring the presumed reduction in ischemic burden have not yet been validated in this treatment population.

# Tables
Table 1. Metabolic Equivalents (METs) for Bruce Protocol Exercise Tolerance Test
Table 1a. Modified Bruce Protocol: Added initial stages at lower workload
Table 2. Correlation of Change in ETT time with Estimated MET equivalents and Activity Examples
Modified from Reference 1 and 2.
Table 3. Recent Studies with ETT Time as Primary Efficacy Endpoint