Advanced hybrid stress testing: A potential new paradigm combining exercise and pharmacologic stress

Gregory S. Thomas 0 FACC 0 FASNC 0 1 2 Harkawal S. Hundal 0 1 2 Myrvin H. Ellestad 0 FACC 0 1 2 0 From the MemorialCare Heart & Vascular Center, Long Beach Memorial Medical Center and Miller Children's Hospital of Long Beach 1 University of California , Irvine, Irvine, CA . Reprint requests: Gregory S. Thomas, MD , MPH, FACC, FASNC, MemorialCare Heart & Vascular Center, Long Beach Memorial Medical Center and Miller Children's Hospital of Long Beach , 2801 Atlantic Ave, Long Beach, CA 90806 2 Long Beach, CA ; and Division of Cardiology - hybrid fashion with low level exercise combined with pharmacological stress. Partington and colleagues seized upon the specific advantages of regadenoson (bolus administration over 10 seconds and one dose for all patients) to evaluate maximal vasodilation stress with regadenoson injected at near-peak exercise in 211 relatively low-risk patients who could not achieve [85% of maximum heart rate (220 - age). Beginning with 2,237 patients undergoing MPI and able to exercise in their observational trial, 1,522 (68%) achieved [85% of maximum heart rate and, therefore, did not require regadenoson. The remaining 715 patients received either (a) radiotracer despite a heart rate \85% maximum (ETT-Submax, n = 504, 23%) or (b) a novel protocol of regadenoson injected 1 minute prior to exercise termination, with radiotracer (Tc-99 sestamibi) injected 30 seconds following regadenoson (n = 211, 9%). They labeled this new test ETT-Reg. Patients who underwent regadenoson stress MPI while supine (SupineReg, n = 239) during the same time period served as another comparison group. Patients who had ischemic ECG changes or symptoms of ischemia during exercise stress received radiotracer when this occurred so were part of the ETTSubmax group. Patients were excluded from the ETT-Reg group a priori if, prior to the initiation of stress testing, they had (a) undergone past coronary revascularization, (b) a Q wave myocardial infarction on their resting ECG, (c) known CAD and were being evaluated for ischemia at the workload achieved, even if exercise was submaximal, (d) CAD and were undergoing MPI for symptoms suggestive of ischemia. The decision to exclude patients from ETT-Reg during the test included the clinicians belief that adding regadenoson to maximal exercise, albeit submaximal by heart rate, was unsafe in a particular patient based on signs or symptoms exhibited during exercise. Such exclusions resulted in the ETT-Reg group patients comprising a low-risk group compared to the comparison groups. Acknowledging this, the investigators found ETT-Reg to be feasible, safe, and significantly better tolerated than regadenoson administered supine. Vasodilator-related adverse events: flushing, dizziness, light-headedness, and gastrointestinal symptoms, occurred in 49% of patients in the ETT-Reg group compared to 6% in the Supine-Reg group. Similarly, aminophylline was required in 8.1% of Supine-Reg patients compared to only 0.5% of the ETT-Reg patients. Initiating regadenoson selectively by allowing patients to attempt maximal exercise has important implications. Cost could lessen with fewer patients requiring pharmacologic stress, prognosis could potentially be better evaluated using exercise duration and exercise-induced symptoms could be evaluated.11 What are the potential downsides of a stress testing strategy that includes an ETT-Reg option? In a preliminary report, Thompson et al12 found excessive hypertension or hypotension to occur not infrequently in their early report of the use of regadenoson given at near-peak, but submaximal exercise. Excessive hypertension or hypotension was infrequently observed by Partington and colleagues. This may have been secondary to methodological differences; however, as blood measure was measured several times within first 2 minutes of regadenoson administration in Thompsons report while measured at the 2-minute mark post-regadenoson in Partingtons. In the resting state, the response of systolic blood pressure to regadenoson is variable, increasing in some and decreasing in others.13 While the hypotensive response is likely related to vascular A2a receptor activation, the hypertensive response is likely elicited by stimulation of the A2A receptors in the carotid body. Stimulation of these latter receptors results not in vasodilation but in norepinephrine release.14 Dhalla et al15 demonstrated a doubling of plasma norepinephrine levels in the rat model by 2 minutes following regadenoson administration. Further evaluation of blood pressure response with regadenoson at near-peak exercise is warranted. Another challenge with ETT-Reg is the co-morbidities of patients undergoing exercise testing. Individuals in whom exercise MPI testing is performed with some trepidation are likely poor candidates for the double stress of ETT-Reg. Table 1 of the 2002 societal guidelines lists those with relative contraindications to exercise.16 Excluded patients with these contraindications would be prudent at this early juncture in the evaluation of ETT-Reg. Such contraindications include moderate to severe asymptomatic aortic stenosis, hypertrophic cardiomyopathy, very recent myocardial infarction and symptoms likely representing unstable angina. The use of nontraditional electrocardiographic changes to evaluate for ischemia and potential injection of radiotracer should not be ignored. Increasing p-wave duration17 and ST elevation in AVR18 have significant potential as measures of ischemia and merit further evaluation. An alternative approach using regadenoson at nearpeak exercise in patients not achieving 85% maximum predicted heart rate is continuing exercise to the maximum tolerated and injecting regadenoson during a walking recovery period (Ex2Reg). This approach is logistically easier than injecting regadenoson and radiotracer prior to exercise test completion. More importantly, it provides the opportunity to evaluate the ECG during recovery. Rywik et al19 evaluated 216 asymptomatic patients who developed ischemic ECG changes during exercise testing and found that changes occurred only during recovery in 27%. Injecting regadenoson at near-peak exercise with ETT-Reg creates a potential hazard if substantial ischemic ECG changes were to develop in recovery resulting in a clinician regretting the double stress created with the injection of regadenoson to a patient who was likely already ischemic at near-peak exercise. The use of regadenoson during recovery may also be friendlier from a hemodynamic standpoint. Excessive hypertension or hypotension would be expected to occur less frequently if regadenoson were injected during low level recovery exercise compared to maximum exercise. A large randomized clinical trial of regadenoson injected during a walking recovery period is now underway.20 If further studies demonstrate the safety of regadenoson at near-peak exercise or during recovery, hybrid testing could be more deeply in (...truncated)