Safety of Regadenoson in Patients with End-Stage Renal Disease
Article Outline
Regadenoson is a selective A2A receptor agonist that was recently approved by the Food and Drug Administration for vasodilator stress myocardial perfusion imaging. Because the drug is cleared by renal excretion, its safety in patients with end-stage renal disease (ESRD) needs to be determined. We studied 277 consecutive patients with ESRD who had undergone regadenoson stress gated single photon emission computed tomography myocardial perfusion imaging and compared their side effect profile and safety outcome to those of 134 patients with normal kidney function. The ESRD group included 164 men (59%) and the control group included 73 men (54%; p = NS). The patients with ESRD were younger than the controls (52 ± 11 years vs 61 ± 12 years; p <0.001). The myocardial perfusion imaging findings were abnormal in 53 patients (19%) with ESRD and in 24 patients in the control group (18%; p = NS). The left ventricular ejection fraction was 57 ± 12% in the ESRD group and 64 ± 12% in the control group (p <0.001). The changes in heart rate and systolic blood pressure (from baseline to peak stress) were 20 ± 12 beats/min versus 22 ± 13 beats/min and −11 ± 24 mm Hg versus −12 ± 23 mm Hg in the ESRD and control groups, respectively (p = NS for both). Very few patients in either group reported symptoms during the stress test. No medication-related hospitalizations, serious events, or death occurred in either group within 30 days of the study. In conclusion, this is the first study to document the safety of regadenoson in a large number of patients with ESRD. The drug was well tolerated, and the hemodynamic and side effect profiles were similar to those of patients with normal renal function.
Myocardial perfusion imaging (MPI) is widely used for the detection of coronary artery disease and risk stratification, with >50% of the studies using vasodilator stress agents.1, 2 Regadenoson, a selective A2A receptor agonist, was approved by the Food and Drug Administration in 2008 for use with stress MPI. The properties of this molecule have recently been reviewed.3 Unlike adenosine, which is intracellularly cleared within a few seconds, regadenoson is cleared renally. Although Gordi et al4 showed in a small trial that regadenoson is well tolerated in patients with chronic kidney disease, no safety data for the drug are available regarding patients with end-stage renal disease (ESRD) who are dependent on dialysis. Such safety data are important, because many of these patients undergo vasodilator MPI for clinical indications or before renal transplantation.5 The purpose of the present study was to examine the hemodynamic changes, safety, and tolerability of regadenoson in patients with ESRD who required dialysis.
Methods
We identified 277 consecutive patients with ESRD and 134 control patients with normal kidney function from our database, who had undergone regadenoson stress gated MPI for clinical indications during the same period. The patients' records were reviewed for age, gender, race, co-morbidities, medications at the time of the study, the electrocardiographic findings, and the changes in heart rate (HR) and blood pressure (BP).
The changes in HR and systolic and diastolic BP are expressed as the absolute changes (peak − at rest) and percentage of changes (peak − at rest/at rest × 100).
The patients' reported symptoms during the stress test and any adverse effects that might have led to hospitalization or were associated with significant morbidity or mortality within 30 days of the study were also recorded. Our institutional review board approved the protocol.
Gated single photon emission computed tomography MPI was obtained after stress (intravenous bolus administration of 400 μg regadenoson) using technetium-99m sestamibi according to American Society of Nuclear Cardiology guidelines and as previously described.6 The perfusion pattern was assessed as normal or showing reversible or fixed defects (or both). The left ventricular ejection fraction was determined using the method described by Germano et al,7 and the perfusion defect size was measured by a well-validated, automated program (MDSPECT, Ann Arbor, Michigan).8, 9
The data are presented as percentages for categorical variables and as the mean ± SD for continuous variables. The patients with ESRD and the control patients with normal renal function were compared using Student's t test or the chi-square test, as appropriate. All p values are 2-tailed. A p value <0.05 was considered statistically significant. The 95% confidence intervals were also computed.
Results
The baseline characteristics of the patients are listed in Table 1. The patients with ESRD were younger than those in the control group and included more African-Americans and more patients with left ventricular hypertrophy on the electrocardiogram. Both groups had a similar proportion of patients with diabetes mellitus and a history of cardiac revascularization.
Table 1. Baseline variables
| Variable | ESRD (n = 277) | Control (n = 134) | p Value |
|---|---|---|---|
| Age (years) | 52 ±11 | 61±12 | <0.001 |
| Men | 164(59%) | 73(54%) | NS |
| White | 88(32%) | 84(63%) | <0.001 |
| Previous revascularization | 48(17%) | 32(24%) | NS |
| Diabetes mellitus | 133(48%) | 51(38%) | NS |
| Hypertension | 259(94%) | 113(84%) | NS |
| Heart failure | 31(11%) | 12(9%) | NS |
| Atrial fibrillation | 8(3%) | 12(9%) | 0.007 |
| Peripheral vascular disease | 40(14%) | 20(15%) | NS |
| Left ventricular hypertrophy | 49(18%) | 9(7%) | 0.004 |
| Left bundle branch block | 4(1.4%) | 2(1.5%) | NS |
| Smoking history | 170(61%) | 76(57%) | NS |
| Chronic obstructive sleep apnea/asthma | 21(7%) | 8(6%) | NS |
| Medications | |||
| β Blockers | 171(61%) | 66(49%) | 0.02 |
| Statins | 92(33%) | 60(44%) | 0.03 |
| ACE inhibitor/angiotensin receptor blocker | 140(51%) | 86(65%) | 0.02 |
| Aspirin | 66(24%) | 49(37%) | 0.009 |
| Diuretics | 58(21%) | 77(57%) | <0.001 |
| Hypoglycemic agents | 97(35%) | 44(33%) | NS |
| Calcium channel blockers | 124(44%) | 47(35%) | NS |
| Inhalers and/or steroids | 25(9%) | 21(16%) | NS |
The results of gated-single photon emission computed tomography MPI are listed in Table 2. Patients with ESRD had a lower left ventricular ejection fraction than did patients with normal renal function. The percentage of patients with an abnormal perfusion pattern and the perfusion defect size in patients with an abnormal perfusion pattern were similar in the 2 groups.
Table 2. Stress technetium-99m sestamibi results
| Variable | ESRD (n = 277) | Control (n = 134) | p Value |
|---|---|---|---|
| Left ventricular ejection fraction (%) | 57±12% | 64±12% | <0.0001 |
| Normal perfusion | 224(81%) | 110(82%) | NS |
| Scar and/or ischemia | 53(19%) | 24(18%) | NS |
| Mean perfusion defect size in patients with abnormal images | 22±14% | 23±19% | NS |
Regadenoson was associated with a comparable increase in HR and a decrease in systolic and diastolic BP in both groups (Table 3).
Table 3. Hemodynamic changes and safety of regadenoson
| Variable | ESRD | Control |
|---|---|---|
| At rest heart rate (beats/min) | 73±12 | 69±12 |
| Δ Heart rate (beats/min) | 20±12 | 22±13 |
| Change heart rate (%) | 32±22% | 34±22% |
| Resting systolic blood pressure (mm Hg) | 138±24 | 135±23 |
| Δ Change systolic blood pressure (mm Hg) | −11±24 | −12±23 |
| Change systolic blood pressure (%) | −7±11% | −8±11% |
| Resting diastolic blood pressure (mm Hg) | 78±13 | 82±13 |
| Δ Change diastolic blood pressure (mm Hg) | −7±13 | −13±13 |
| Change diastolic blood pressure (%) | −8±11% | −9±14% |
| Chest pain | 2(0.7%) | 0 |
| Dyspnea and/or bronchospasm | 1(0.4%) | 0 |
| Gastrointestinal symptoms | 5(1.8%) | 1(0.7%) |
| Symptomatic hypotension/dizziness | 0 | 1(0.7%) |
| High-degree atrioventricular block | 1(0.4%) | 0 |
| Use of aminophylline | 2(0.7%) | 0 |
| Positive electrocardiographic response | 7(2.5%) | 3(2.2%) |
| 30-Day hospitalization and/or mortality | 0 | 0 |
Very few symptoms were reported by either group, and no serious events leading to hospitalization or death within 30 days of the study were reported (p = NS for all variables; Table 3). Aminophylline was used in 2 patients in the ESRD group because of chest pain or shortness of breath. Finally, 1 patient in the control group had nausea/vomiting that necessitated a brief visit to the emergency department for antiemetics and was discharged home.
Discussion
This is the largest study to document the safety of regadenoson in patients with ESRD. The changes in HR and BP (absolute or relative) were similar in these patients just as they were in the patients with normal renal function. Remarkably few side effects were reported in either group, certainly much less than what was reported in the pivotal phase III trials. This was not unlike the case with adenosine, which had many more side effects in the phase III trials than in clinical practice.1
Regadenoson is a new selective A2A receptor agonist that is administered intravenously as a bolus at a constant dose of 400 μg with no weight adjustment.3 Unlike adenosine, regadenoson is cleared renally (58% of elimination route) with a volume of distribution at steady state of 78 L, estimated clearance of 37.8 L/hour, and terminal half-life of 33 to 108 minutes.10 It binds to the A2A receptor on the coronary arterial bed and promotes vasodilation. Peak hyperemia (>2.5 increase in coronary blood flow from baseline) is achieved within 30 seconds of the bolus injection, and lasts 2 to 3 minutes (mean 2.3).11 Regadenoson remains in the circulation at low concentrations that are clinically irrelevant, even in patients with moderate chronic kidney disease.4
Although we did not measure the serum concentration of regadenoson or its clearance in patients with ESRD, our results have clearly shown hemodynamic responses and tolerability similar to those seen in patients with normal renal function. The hemodynamic changes were almost identical to those in the control group and to that of the entire cohort of patients who were enrolled in the adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging, phase III trial12, 13, 14 (ADVANCE MPI; p = NS; Fig 1). No serious side effects were seen such as bronchospasm, symptomatic hypotension, or severe ischemia, and no long-term related complications were seen for ≤30 days of the study.
Figure 1.
Hemodynamic changes associated with regadenoson. (Left) Bars represent percent changes with SDs. (Right) Bars represent absolute changes with SDs. ADVANCE MPI, Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Phase 3 trial; bmp, beats per minute; DBP, diastolic blood pressure; SBP, systolic blood pressure.
No data are yet available to clarify whether regadenoson is dialyzable or whether marked differences exist in clearance in patients receiving dialysis versus those with severe renal impairment (stages 3 and 4). According to unpublished data (data on file at CV Therapeutics, Paolo Alto, California), regadenoson, because it is a small molecule, should be permeable through the dialysis membrane. Furthermore, the combined effects of a low glomerular filtration rate and inhibition of possible tubular secretion as seen in ESRD would not result in a clinically meaningful increase in regadenoson exposure compared to a low glomerular filtration rate only because the nonrenal clearance remains constant and greatly exceeds the renal clearance in subjects with severe renal impairment.
The retrospective nature of the present study and that it was from a single tertiary center are obvious limitations. Larger prospective studies with pharmacokinetics are needed and have been planned for the near future.
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Dr. Iskandrian is a consultant to Gilead Sciences, Inc., Foster City, California, and to Astellas Pharma Global Development, Inc., Deerfield, Illinois.
PII: S0002-9149(09)02228-0
doi:10.1016/j.amjcard.2009.08.663
© 2010 Elsevier Inc. All rights reserved.
