- Email: [email protected]
Current Advances in Vasodilator Pharmacological Stress Perfusion Imaging
Current Advances in Vasodilator Pharmacological Stress Perfusion Imaging Regina S. Druz, MD, FACC, FASNC*,† More than 7 million stress perfusion studies are performed in the United States annually, 44% with pharmacological vasodilator stress agents. Both adenosine and dipyridamole are nonselective coronary vasodilators that are commonly used for stress perfusion imaging. These agents are safe and provide an effective means to diagnose coronary artery disease. A newer agent, regadenoson, is an adenosine receptor agonist that is selective for coronary vasodilation. Regadenoson is noninferior to adenosine for the detection of ischemia and is better tolerated by patients. Recent trials such as INSPIRE (Adenosine Sestamibi PostInfarction Evaluation) and the COURAGE (Results from Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-driven Drug Evaluation) Nuclear Imaging Substudy have established clearly that noninvasive risk stratification with vasodilator testing is an important and appropriate step in guiding medical therapy and invasive coronary intervention. Semin Nucl Med 39:204-209 © 2009 Elsevier Inc. All rights reserved.
T
hree pharmacological radionuclide stress perfusion agents that are commonly in use are adenosine, dipyridamole, and dobutamine. Most pharmacological stress testing is accomplished with the use of coronary vasodilators such as adenosine and dipyridamole. Dobutamine is a beta-agonist that causes increased heart rate and systolic blood pressure and enhances myocardial contractility. Its effects on coronary dilation are similar to physiologic exercise. Approximately 7.5 million of stress perfusion studies are performed annually in the United States, 44% of them with vasodilators.1 Adenosine is a direct coronary vasodilator whereas dipyridamole is an adenosine reuptake inhibitor and exerts its effects by increasing endogenous levels of adenosine. Both agents result in the nonselective A2A receptor stimulation that causes the differential coronary arterial dilation required for the detection of flow heterogeneity and, thus, coronary stenoses. A new group of agents that are selective A2A adenosine receptor agonists with better side-effect profile recently have become available, with regadenoson (Lexiscan; Astellas Pharma US, Deerfield, IL) currently approved by the Food and Drug Administration for use in pharmacological perfusion imaging with single-photon emission computed tomography (SPECT). This review will focus on the basic
*Nuclear Cardiology, North Shore University Hospital, Manhasset, NY. †New York University School of Medicine, New York, NY. Address reprint requests to Regina S. Druz, MD, FACC, FASNC, Nuclear Cardiology, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. E-mail: [email protected]
204
0001-2998/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2008.12.003
principles of vasodilator stress testing, discuss new agents available, and summarize recent evidence for the vasodilator perfusion guidance in coronary intervention.
Basic Principles of Pharmacological Stress Perfusion Imaging Adenosine is infused at the rate of a 140 g/kg/min for 6 minutes, although an abbreviated 4-minute protocol has been found to be comparable with the standard 6-minute infusion.2 Intravenously administered adenosine is promptly cleared from the circulation by cellular uptake, predominately by erythrocytes and vascular endothelial cells. Once inside the cell, adenosine is quickly metabolized either via phosphorylation by adenosine kinase to adenosine monophosphate or via deamination by adenosine deaminase in the cytosol to iminase. Intravenous adenosine does not require renal function for its activation or inactivation; therefore, renal failure is not expected to alter its efficacy or side effect profile.3 Rapid clearance of adenosine results in a very short halflife (⬍10 seconds) and predictable onset of peak effect within 1 to 2 minutes of infusion. The myocardial perfusion agent is injected at 3 minutes for a 6-minute protocol or at 2 minutes for a 4-minute protocol. Multiple side-effects, such as flushing, warmth, abdominal discomfort, chest pain and dyspnea, are frequently observed. Major side-effects attributable to a
Advances in vasodilator pharmacological stress perfusion imaging slowing of atrioventricular conduction with various degrees of heart block are rare (0.7-4%).3 Adenosine and dipyridamole are contraindicated in patients with bronchospastic airways because of the potential for severe exacerbation. Xanthines (caffeine and aminophylline) directly block effects of adenosine and dipyridamole and should not be consumed for at least 12 hours before the test. Anti-ischemic cardiac medications such as beta-blockers, nitrates and calcium-channel blockers should also be withheld for at least 48 hours.4 Contraindications to coronary vasodilation include unstable angina, acute myocardial infarction with onset of less than 24 hours, critical aortic stenosis, hypertrophic obstructive cardiomyopathy, and known emphysema or asthma with ongoing bronchodilator use and/or lung examination reflective of bronchospasm. American Society of Nuclear Cardiology imaging guidelines permit adenosine perfusion imaging in patients with adequately controlled asthma after pretreatment with albuterol.4 In practice, we prefer to avoid adenosine stress in any patient with documented bronchospasm, as evidenced by prior medical history, ongoing use of inhalers, or physical examination. Dobutamine is an alternative for these patients. Although it is prudent to avoid vasodilator testing in patients with hypotension (systolic blood pressure ⬍90 mm Hg), given its short duration of action, we have successfully administered adenosine to hemodynamically stable yet hypotensive patients. Because of the short-half life of adenosine, aminophylline is rarely needed to reverse the vasodilatory effects. Dipyridamole is infused intravenously at 0.56 to 0.84 mg/kg during a 4-minute period. Unlike adenosine, maximal vasodilation occurs 3 minutes after termination of the infusion. The radioactive tracer is injected at that time, and after an additional minute of maximal hyperemic effect, aminophylline (50-100 mg) is administered intravenously to abolish vasodilation. The principle differences between vasodilators are in their duration of action, logistics of infusion, and occurrence of side-effects, including myocardial ischemia induced by coronary flow redistribution at maximal vasodilation. Adenosine is a more potent vasodilator whereas dipyridamole, as the result of a longer half-life, is more likely to induce ischemia as evidenced by angina or ST-segment depressions or both. Consequently, the administration of aminophylline and a longer monitoring time are required for dipyridamole but not adenosine infusions. Both vasodilator agents result in a small increase in heart rate as the result of sympathetic stimulation and a decrease in systemic blood pressure. Occurrence of ST-segment depressions with normal perfusion after adenosine vasodilator testing is infrequent but is associated with female sex and greater than expected subsequent cardiac event rate.5 Pharmacologic vasodilator testing is a modality of choice for patients with orthopedic or neurologic impairments, decreased exercise tolerance, left bundle branch block, paced rhythm, Wolff-Parkinson-White syndrome, severe hypertension, or more then 24 hours after acute myocardial infarction.4 Supplemental low-level exercise is encouraged to re-
205 duce vasodilatory side-effects and increase image quality by limiting gastrointestinal uptake of the radionuclides. The latter is always an issue because of substantial dilation of the splanchnic circulation by vasodilators. It is generally accepted that adenosine and dipyridamole cause a near-maximal myocardial blood flow response that is blunted in the stenosed coronary arteries compared with normal or less severely diseased segments. The relative flow disparity is reliably detected by SPECT, and absolute flow measurements as well as coronary reserve can be determined by positron emission tomography or cardiac magnetic resonance imaging. However, only in some patients the true “coronary steal” occurs that results in detectable wall motion abnormality in addition to the perfusion defects.6 Detection of wall motion abnormalities improves specificity of vasodilator stress testing. Although it is generally believed that poststress wall motion abnormalities caused by ischemia are uncommon with adenosine vasodilator stress, such postischemic stunning has been observed in one-third of patients with severe reversible perfusion defects.7 In summary, vasodilator stress testing with adenosine and dipyridamole is a safe and effective method of reliably detecting coronary artery disease. Overall, a normal vasodilator perfusion study portends a very good prognosis with hard cardiac event rate of less than 1% per year.8 Interestingly, this rate is substantially greater than for the normal exercise perfusion study where event rate is less than or equal to 0.5% per year.9 This most likely reflects increased age and greater comorbidities of the vasodilator stress patients.
New Vasodilator Stress Agents Although adenosine and dipyridamole are the most commonly used agents for vasodilator myocardial perfusion imaging, they have a significant disadvantage of nonselective stimulation of all 4 subtypes of adenosine receptors (Table 1). Activation of receptors other than those responsible for vasodilation leads to undesirable minor and major side-effects and results in need to carefully screen and monitor vasodilator stress patients. A newer group of agents in various stages
Table 1 Types and Distribution of Adenosine Receptor Subtypes Known Effects
Receptor Subtypes
Coronary vasodilation Peripheral vasodilation Renal vasoconstriction 2 Atrioventricular nodal conduction Sympathetic surge Bronchoconstriction
A2A A2B, A2A A1 A1 A2A (carotid body) A2B, A3
Nonselective stimulation of all adenosine receptor subtypes results in coronary vasodilation and undesirable side-effects whereas a selective stimulation of A2A receptors results in coronary vasodilation with better side-effect profile.
R.S. Druz
206 of development has advantages of selective stimulation of coronary vasodilation and offers better side-effects profile.10 The 4 adenosine receptor subtypes include A1, A2A, A2B, and A3 receptors (Table 1). A2A receptors are predominantly distributed in the coronary circulation. Among the selective A2A receptor agonists, regadenoson (Lexiscan) is currently approved by the Food and Drug Administration for pharmacological stress testing using SPECT.11 Regadenoson is a selective A2A adenosine receptor blocker with low affinity for the A2A receptor. It is administered as a fixed unit bolus intravenously and increases coronary flow 2to 3-fold for 3 to 4 minutes. Its advantages over adenosine and dipyridamole include fixed unit dose not affected by central volume of distribution or body weight, good safety profile with better patient tolerance, and ease of administration. In a manufacturer-specified protocol, regadenoson is administered as 0.4 mg/5 mL intravenous injection followed by a saline flush. Radiotracer injection immediately follows with another saline flush.11 The total duration of injections is usually less than 1 minute (Fig. 1). Patients should be observed for at least 6 minutes after injection of regadenoson. Peak vasodilation is noted at 2 to 4 minutes after injection. Although the incidence of advanced heart block approaches 0% with regadenoson, it is still contraindicated in patients with second- or third-degree atrioventricular block or sinus
Adenosine at 140 mcg/kg/min (6 min infusion)
Regadenoson 0.4 mg/5 ml for 10 sec followed by saline flush and tracer injection (1 min ) Tracer at 3 min of adenosine infusion
Dipyridamole 0.142 mg/kg/min (4 min infusion)
Tracer injection “window” 5 min after dipyridamole infusion
Figure 1 Comparison of vasodilator stress perfusion protocols. Regadenoson is a selective A2A receptor agonist that is rapidly administered by intravenous injection followed by radiotracer injection whereas adenosine and dipyridamole require intravenous infusions with prespecified time point or “window” for radiotracer injection. A standard 6-minute adenosine and 4-minute dipyridamole infusion protocols are shown. (Color version of figure is available online.)
Table 2 Common Adverse Reactions to Regadenoson (Lexiscan) and Adenosine (Adenoscan) Adverse Events Dyspnea Headache Flushing Chest pain Angina or ST-segment depression Nausea Abdominal discomfort Rhythm or conduction abnormalities First-degree AV block (PR > 220 ms) Second-degree AV block Ventricular conduction abnormalities Premature atrial/ventricular complexes
Regadenoson Adenosine (%) (%) 28 26 16 7 12
26 17 25 10 18
6 5 26
6 2 30
3
7
0.1 6
1 5
7/14
9/12
More headache and abdominal discomfort were observed with regadenoson while the occurrence of AV nodal block was substantially less than with adenosine. AV, atrioventricular; PR, P wave to R wave ECG interval.
node dysfunction without a functioning pacemaker (Table 2). It should also be used with caution in patients with asthma or chronic obstructive pulmonary disease. No randomized trial data exists with regard to caffeine use; thus, there is still a requirement to hold all xanthines before stress. The ADVANCE-MPI (Adenoscan Versus Regadenoson Comparative Evaluations for Myocardial Perfusion Imaging) trials have demonstrated noninferiority of regadenoson to adenosine for detection of reversible perfusion defects and better tolerability of the regadenoson regardless of age, sex, body habitus and diabetes.12 A total of 1871 patients had a baseline adenosine study and were subsequently randomized in the 2:1 ratio to a repeat stress study with regadenoson (n ⫽ 1240) or adenosine (n ⫽ 631). Three experts independently scored the blinded images by using a 17-segment model on a 5-point scale from 0 ⫽ normal to 4 ⫽ no activity.13 Summed stress perfusion scores were used to categorize ischemia as none to minimal (0-1), small to moderate (2-4), and large (ⱖ5). The overall average ischemia agreement rates between adenosine-adenosine and adenosine-regadenoson were 0.62 ⫾ 0.03 and 0.63 ⫾ 0.02 with an agreement difference of 0% (95% confidence interval ⫺6.2% to 6.8%), respectively. Agreement rates were greatest in the no ischemic category (80%) and lowest in the moderate-to-large ischemia extent categories (50%). Regadenoson was noninferior to adenosine for detection of ischemia (noninferiority margin ⫽ 13.3% was greater than 95% confidence interval of ⫺6.2% to 6.8%). Patients receiving regadenoson had reduced incidence of chest pain and flushing but experienced more headaches and gastrointestinal discomfort. Unlike adenosine, regadenoson has a different pharmacodynamic profile. The injection induces an initial phase of a 2-
Advances in vasodilator pharmacological stress perfusion imaging to 3-fold increase in myocardial blood flow with a half-life of 2 to 4 minutes. A second phase ensues, with a half-life on average of 30 minutes with a gradual loss of the pharmacodynamic effect. The final phase consists of a decrease in the plasma concentration with a half-life of approximately 2 hours.11 In contrast to regadenoson, intravenously administered adenosine is promptly cleared from the circulation by cellular uptake, predominately by erythrocytes and vascular endothelial cells. Once inside the cell, adenosine is quickly metabolized either via phosphorylation by adenosine kinase to adenosine monophosphate, or via deamination by adenosine deaminase in the cytosol to iminase.3 We have recently reported that these differences in pharmacodynamic profiles may be relevant to patients with endstage renal disease.14 A 38-year-old woman with end-stage renal disease requiring hemodialysis underwent a regadenoson perfusion testing preoperatively. She developed ST-segment depressions and chest pain that lasted for 30 minutes after termination of regadenoson infusion and were abolished with intravenous aminophylline. Perfusion images were abnormal, revealing reversible defect in the lateral wall suggestive of ischemia (Fig. 2). Subsequent angiogram confirmed
207 high-grade in-stent restenosis in the left circumflex coronary artery. Intravenous adenosine does not require renal function for its activation or inactivation, so renal failure is not expected to alter its efficacy or side effect profile. In contrast, in patients with increasing renal impairment, the fraction of regadenoson excreted unchanged in urine and the renal clearance decreases, resulting in increased elimination half-lives compared with healthy subjects.15 Regadenoson clearance decreases in parallel with a reduction in creatinine clearance. Results from patients with renal dysfunction have suggested that dose adjustments are not necessary. However, the pharmacokinetics of regadenoson in patients on dialysis have not been assessed. It is possible that these differences in pharmacodynamic profiles of adenosine and regadenoson accounted for a prolonged effect and persistence of ischemia in our patient. In summary, selective A2A receptor agonists such as regadenoson are noninferior to adenosine for detection of ischemia and offer improved safety profile and ease of administration. Regadenoson has a different pharmacodynamic profile than adenosine, and its effects in certain patient pop-
Figure 2 Regadenoson myocardial perfusion images in patient with end-stage renal disease. A reversible perfusion defect is present in the lateral wall suggestive of ischemia. Subsequent invasive angiogram confirmed a high-grade in-stent restenosis in the left circumflex coronary artery.
208
Figure 3 INSPIRE study. Stable patients after acute myocardial infarction were assigned into low-, intermediate-, and high risk groups based on the perfusion defect size (PDS), ischemic perfusion defect size (IPDS), and left ventricular ejection fraction (LVEF). (Reprinted with permission from Mahmarian et al.16) (Color version of figure is available online.)
ulations such as those with end-stage renal disease need to be evaluated.
Use of Vasodilator Perfusion Imaging to Guide Therapeutic Intervention: Lessons from INSPIRE and the COURAGE Imaging Substudy Two recently completed trials, INSPIRE and COURAGE Imaging Substudy, have evaluated vasodilator stress myocardial perfusion imaging in guiding therapeutic interventions. The INSPIRE (Adenosine Sestamibi Post-Infarction Evaluation) trial was a prospective multicenter trial that enrolled 728 stable patients after acute myocardial infarction to assess the role of noninvasive imaging in risk stratification.16 All patients underwent nitrate-enhanced rest-stress adenosine perfusion protocol to maximize detection of ischemia. Subsequently, patients were assigned into risk categories based on total perfusion defect size as well as ischemic perfusion defect size (Fig. 3). Importantly, those patients in the highest risk category (defined as total perfusion defect greater than or equal to 20% and ischemic perfusion defect greater than or equal to 10%) were further stratified based on the left ventricular ejection fraction: those with less than 35% proceeded to invasive angiogram whereas those with greater or equal than 35% were randomized to intensive medical therapy or medical therapy with revascularization. All patients in the highest risk category underwent a second adenosine stress study after randomization. Patient follow-up was 98% complete at 1 year for all patient risk groups for sudden cardiac death, nonfatal reinfarction, admission for heart failure, or acute coronary syndrome. Overall cardiac and death/reinfarction event rates increased significantly across risk groups from low (5.4% and 1.8%) to intermediate (14% and 9.2%) to high (18.6 and
R.S. Druz 11.6%), respectively. These differences were observed despite a high initial rate of revascularization in the highest risk group (50%) and were still significant after adjustment by Thrombolysis in Myocardial Infarction (TIMI) scores. In fact, INSPIRE assessment of risk based on scan variables outperformed TIMI risk score for the event prediction. Each 10% absolute increment in total or ischemic perfusion defect size increased the unadjusted relative risk for any event by 37% and 64%, respectively. Revascularization impacted event rates in the high risk group with decreased ejection fraction whereas in patients with ischemia and preserved function medical therapy was as effective as coronary revascularization.17 Results were significant irrespective of age, sex, or type or location of an infarct. The INSPIRE trial was unique in several regards. All patients were assigned to a conservative imaging strategy and subsequently triaged to invasive procedures based on quantitative imaging results with extent of ischemia as the primary focus of stratification. Adenosine stress was performed expeditiously (with more than half the patients in the United States undergoing the procedure within 2 days) and safely with no cardiac events occurring before noninvasive testing.16 Sequential adenosine imaging not only allowed to track risk but also identified specifically subgroups of patients who may benefit from early revascularization as well as those who can be discharged safely. Thus, noninvasive risk stratification with vasodilator stress emerged as safe and cost-effective way of guiding therapeutic interventions. These findings were further extended in the COURAGE (Results from Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-driven Drug Evaluation) Imaging Substudy.18 The COURAGE trial evaluated outcomes in stable patients with chronic coronary artery disease treated with optimal medical therapy with or without percutaneous intervention. The main trial found no difference by treatment strategy in the primary endpoint of death or myocardial infarction.19 Of the 2287 COURAGE patients, 314 were enrolled in the imaging substudy, with most undergoing vasodilator stress (230 patients). All patients underwent serial imaging before and 6 to 18 months later after randomization into optimal medical therapy or optimal medical therapy with revascularization groups. Moderate-to-severe ischemia was defined as greater than or equal to 10% of the ventricular myocardium, and the primary endpoint was at least 5% reduction in ischemia. Revascularization was more effective than medical therapy alone in reducing ischemia (33% versus 19%, respectively), especially in patients with moderate-tosevere pretreatment ischemia (78% improvement versus 52% with mild ischemia). Patients with ischemia reduction had lower unadjusted risk for death or myocardial infarction particularly if pretreatment ischemia was severe. The main results from the COURAGE trial were controversial in that no difference was shown in the long-term outcomes for patient with stable coronary artery disease among those receiving optimal medical therapy and the those receiving medical therapy with revascularization. The nuclear substudy provides an important refinement to that finding by quantitatively assessing ischemia, and using this parameter to
Advances in vasodilator pharmacological stress perfusion imaging guide application of invasive strategy as well as to assess its effectiveness. In summary, INSPIRE and the COURAGE Imaging Substudy were pivotal trials that clearly established significant role of vasodilator stress perfusion imaging in risk stratification of stable patients with coronary artery disease and guidance of therapeutic interventions.
Conclusion Vasodilator stress perfusion imaging is safe and effective in identifying prognostically significant coronary artery disease. Newer agents allow better tolerance, ease of administration, and improved side-effect profile. Recent trials have firmly established a pivotal role of vasodilator stress perfusion imaging in risk stratification and therapeutic guidance of patients with stable coronary artery disease.
209
10.
11. 12.
13.
14.
References 1. Astellas Pharma Internal Reports. Deerfield, IL, Astellas Pharma US, 2008 2. Bokhari S, Ficaro EP, McCallister BD Jr: Adenosine stress protocols for myocardial perfusion imaging. J Nucl Cardiol 14:415-416, 2007 3. Adenoscan (adenosine injection) package insert. Deerfield, IL, Astellas Pharma, US, Inc, 2005 4. Henzlova MJ, Cerqueira MD, Mahmarian JJ, et al: Stress protocols and tracers. J Nucl Cardiol 13:e80-90, 2006 5. Klodas E, Miller TD, Christian TF, et al: Prognostic significance of ischemic electrocardiographic changes during vasodilator stress testing in patients with normal SPECT images. J Nucl Cardiol 10:4-8, 2003 6. Kaufmann PA: Differential effects of pharmacological stressors: More than meets the eye. J Nucl Cardiol 13:311-312, 2006 7. Druz RS, Akinboboye OA, Grimson R, et al: Postischemic stunning after adenosine vasodilator stress. J Nucl Cardiol 11:534-541, 2004 8. Hachamovitch R, Berman DS, Kiat H, et al: Incremental prognostic value of adenosine stress myocardial perfusion single-photon emission computed tomography and impact on subsequent management in patients with or suspected of having myocardial ischemia. Am J Cardiol 80:426-433, 1997 9. Hachamovitch R, Berman DS, Shaw LJ, et al: Incremental prognostic value of myocardial perfusion single photon emission computed to-
15.
16.
17.
18.
19.
mography for the prediction of cardiac death: Differential stratification for risk of cardiac death and myocardial infarction. Circulation 97: 535-543, 1998 Gao Z, Li Z, Baker SP, et al: Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship between affinity and duration of action of A2A agonists. J Pharmacol Exp Ther 298:209218, 2001 Lexiscan (regadenoson injection) package insert. Deerfield, IL, Astellas Pharma, US, Inc, 2008 Cerqueira MC, Nguyen P, et al: Effects of age, gender, obesity, and diabetes on the efficacy and safety of the selective a2a agonist regadenoson versus adenosine in myocardial perfusion imaging: Integrated ADVANCE-MPI Trial Results. JACC Cardiovascular Imaging 1:307316, 2008 Cerqueira MD, Weissman NJ, Dilsizian V, et al: Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation 105:539-542, 2002 Laighold S, Druz R: Initial clinical experience with a selective A2A receptor agonist, Regadenoson, in a patient with end-stage renal disease on hemodialysis. J Nucl Cardiol (in press) Gordi T, Blackburn B, Lieu H: Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function. J Clin Pharmacol 47:825-833, 2007 Mahmarian JJ, Shaw LJ, Filipchuk NG, et al: A multinational study to establish the value of early adenosine technetium-99m sestamibi myocardial perfusion imaging in identifying a low-risk group for early hospital discharge after acute myocardial infarction. J Am Coll Cardiol 48:2448-2457, 2006 Mahmarian JJ, Dakik HA, Filipchuk NG, et al: An initial strategy of intensive medical therapy is comparable to that of coronary revascularization for suppression of scintigraphic ischemia in high-risk but stable survivors of acute myocardial infarction. J Am Coll Cardiol 48:24582467, 2006 Shaw LJ, Berman DS, Maron DJ, et al: Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: Results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 117:1283-1291, 2008 Boden WE, O’Rourke RA, Teo KK, et al: Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 356:15031516, 2007
T
hree pharmacological radionuclide stress perfusion agents that are commonly in use are adenosine, dipyridamole, and dobutamine. Most pharmacological stress testing is accomplished with the use of coronary vasodilators such as adenosine and dipyridamole. Dobutamine is a beta-agonist that causes increased heart rate and systolic blood pressure and enhances myocardial contractility. Its effects on coronary dilation are similar to physiologic exercise. Approximately 7.5 million of stress perfusion studies are performed annually in the United States, 44% of them with vasodilators.1 Adenosine is a direct coronary vasodilator whereas dipyridamole is an adenosine reuptake inhibitor and exerts its effects by increasing endogenous levels of adenosine. Both agents result in the nonselective A2A receptor stimulation that causes the differential coronary arterial dilation required for the detection of flow heterogeneity and, thus, coronary stenoses. A new group of agents that are selective A2A adenosine receptor agonists with better side-effect profile recently have become available, with regadenoson (Lexiscan; Astellas Pharma US, Deerfield, IL) currently approved by the Food and Drug Administration for use in pharmacological perfusion imaging with single-photon emission computed tomography (SPECT). This review will focus on the basic
*Nuclear Cardiology, North Shore University Hospital, Manhasset, NY. †New York University School of Medicine, New York, NY. Address reprint requests to Regina S. Druz, MD, FACC, FASNC, Nuclear Cardiology, North Shore University Hospital, 300 Community Drive, Manhasset, NY 11030. E-mail: [email protected]
204
0001-2998/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.semnuclmed.2008.12.003
principles of vasodilator stress testing, discuss new agents available, and summarize recent evidence for the vasodilator perfusion guidance in coronary intervention.
Basic Principles of Pharmacological Stress Perfusion Imaging Adenosine is infused at the rate of a 140 g/kg/min for 6 minutes, although an abbreviated 4-minute protocol has been found to be comparable with the standard 6-minute infusion.2 Intravenously administered adenosine is promptly cleared from the circulation by cellular uptake, predominately by erythrocytes and vascular endothelial cells. Once inside the cell, adenosine is quickly metabolized either via phosphorylation by adenosine kinase to adenosine monophosphate or via deamination by adenosine deaminase in the cytosol to iminase. Intravenous adenosine does not require renal function for its activation or inactivation; therefore, renal failure is not expected to alter its efficacy or side effect profile.3 Rapid clearance of adenosine results in a very short halflife (⬍10 seconds) and predictable onset of peak effect within 1 to 2 minutes of infusion. The myocardial perfusion agent is injected at 3 minutes for a 6-minute protocol or at 2 minutes for a 4-minute protocol. Multiple side-effects, such as flushing, warmth, abdominal discomfort, chest pain and dyspnea, are frequently observed. Major side-effects attributable to a
Advances in vasodilator pharmacological stress perfusion imaging slowing of atrioventricular conduction with various degrees of heart block are rare (0.7-4%).3 Adenosine and dipyridamole are contraindicated in patients with bronchospastic airways because of the potential for severe exacerbation. Xanthines (caffeine and aminophylline) directly block effects of adenosine and dipyridamole and should not be consumed for at least 12 hours before the test. Anti-ischemic cardiac medications such as beta-blockers, nitrates and calcium-channel blockers should also be withheld for at least 48 hours.4 Contraindications to coronary vasodilation include unstable angina, acute myocardial infarction with onset of less than 24 hours, critical aortic stenosis, hypertrophic obstructive cardiomyopathy, and known emphysema or asthma with ongoing bronchodilator use and/or lung examination reflective of bronchospasm. American Society of Nuclear Cardiology imaging guidelines permit adenosine perfusion imaging in patients with adequately controlled asthma after pretreatment with albuterol.4 In practice, we prefer to avoid adenosine stress in any patient with documented bronchospasm, as evidenced by prior medical history, ongoing use of inhalers, or physical examination. Dobutamine is an alternative for these patients. Although it is prudent to avoid vasodilator testing in patients with hypotension (systolic blood pressure ⬍90 mm Hg), given its short duration of action, we have successfully administered adenosine to hemodynamically stable yet hypotensive patients. Because of the short-half life of adenosine, aminophylline is rarely needed to reverse the vasodilatory effects. Dipyridamole is infused intravenously at 0.56 to 0.84 mg/kg during a 4-minute period. Unlike adenosine, maximal vasodilation occurs 3 minutes after termination of the infusion. The radioactive tracer is injected at that time, and after an additional minute of maximal hyperemic effect, aminophylline (50-100 mg) is administered intravenously to abolish vasodilation. The principle differences between vasodilators are in their duration of action, logistics of infusion, and occurrence of side-effects, including myocardial ischemia induced by coronary flow redistribution at maximal vasodilation. Adenosine is a more potent vasodilator whereas dipyridamole, as the result of a longer half-life, is more likely to induce ischemia as evidenced by angina or ST-segment depressions or both. Consequently, the administration of aminophylline and a longer monitoring time are required for dipyridamole but not adenosine infusions. Both vasodilator agents result in a small increase in heart rate as the result of sympathetic stimulation and a decrease in systemic blood pressure. Occurrence of ST-segment depressions with normal perfusion after adenosine vasodilator testing is infrequent but is associated with female sex and greater than expected subsequent cardiac event rate.5 Pharmacologic vasodilator testing is a modality of choice for patients with orthopedic or neurologic impairments, decreased exercise tolerance, left bundle branch block, paced rhythm, Wolff-Parkinson-White syndrome, severe hypertension, or more then 24 hours after acute myocardial infarction.4 Supplemental low-level exercise is encouraged to re-
205 duce vasodilatory side-effects and increase image quality by limiting gastrointestinal uptake of the radionuclides. The latter is always an issue because of substantial dilation of the splanchnic circulation by vasodilators. It is generally accepted that adenosine and dipyridamole cause a near-maximal myocardial blood flow response that is blunted in the stenosed coronary arteries compared with normal or less severely diseased segments. The relative flow disparity is reliably detected by SPECT, and absolute flow measurements as well as coronary reserve can be determined by positron emission tomography or cardiac magnetic resonance imaging. However, only in some patients the true “coronary steal” occurs that results in detectable wall motion abnormality in addition to the perfusion defects.6 Detection of wall motion abnormalities improves specificity of vasodilator stress testing. Although it is generally believed that poststress wall motion abnormalities caused by ischemia are uncommon with adenosine vasodilator stress, such postischemic stunning has been observed in one-third of patients with severe reversible perfusion defects.7 In summary, vasodilator stress testing with adenosine and dipyridamole is a safe and effective method of reliably detecting coronary artery disease. Overall, a normal vasodilator perfusion study portends a very good prognosis with hard cardiac event rate of less than 1% per year.8 Interestingly, this rate is substantially greater than for the normal exercise perfusion study where event rate is less than or equal to 0.5% per year.9 This most likely reflects increased age and greater comorbidities of the vasodilator stress patients.
New Vasodilator Stress Agents Although adenosine and dipyridamole are the most commonly used agents for vasodilator myocardial perfusion imaging, they have a significant disadvantage of nonselective stimulation of all 4 subtypes of adenosine receptors (Table 1). Activation of receptors other than those responsible for vasodilation leads to undesirable minor and major side-effects and results in need to carefully screen and monitor vasodilator stress patients. A newer group of agents in various stages
Table 1 Types and Distribution of Adenosine Receptor Subtypes Known Effects
Receptor Subtypes
Coronary vasodilation Peripheral vasodilation Renal vasoconstriction 2 Atrioventricular nodal conduction Sympathetic surge Bronchoconstriction
A2A A2B, A2A A1 A1 A2A (carotid body) A2B, A3
Nonselective stimulation of all adenosine receptor subtypes results in coronary vasodilation and undesirable side-effects whereas a selective stimulation of A2A receptors results in coronary vasodilation with better side-effect profile.
R.S. Druz
206 of development has advantages of selective stimulation of coronary vasodilation and offers better side-effects profile.10 The 4 adenosine receptor subtypes include A1, A2A, A2B, and A3 receptors (Table 1). A2A receptors are predominantly distributed in the coronary circulation. Among the selective A2A receptor agonists, regadenoson (Lexiscan) is currently approved by the Food and Drug Administration for pharmacological stress testing using SPECT.11 Regadenoson is a selective A2A adenosine receptor blocker with low affinity for the A2A receptor. It is administered as a fixed unit bolus intravenously and increases coronary flow 2to 3-fold for 3 to 4 minutes. Its advantages over adenosine and dipyridamole include fixed unit dose not affected by central volume of distribution or body weight, good safety profile with better patient tolerance, and ease of administration. In a manufacturer-specified protocol, regadenoson is administered as 0.4 mg/5 mL intravenous injection followed by a saline flush. Radiotracer injection immediately follows with another saline flush.11 The total duration of injections is usually less than 1 minute (Fig. 1). Patients should be observed for at least 6 minutes after injection of regadenoson. Peak vasodilation is noted at 2 to 4 minutes after injection. Although the incidence of advanced heart block approaches 0% with regadenoson, it is still contraindicated in patients with second- or third-degree atrioventricular block or sinus
Adenosine at 140 mcg/kg/min (6 min infusion)
Regadenoson 0.4 mg/5 ml for 10 sec followed by saline flush and tracer injection (1 min ) Tracer at 3 min of adenosine infusion
Dipyridamole 0.142 mg/kg/min (4 min infusion)
Tracer injection “window” 5 min after dipyridamole infusion
Figure 1 Comparison of vasodilator stress perfusion protocols. Regadenoson is a selective A2A receptor agonist that is rapidly administered by intravenous injection followed by radiotracer injection whereas adenosine and dipyridamole require intravenous infusions with prespecified time point or “window” for radiotracer injection. A standard 6-minute adenosine and 4-minute dipyridamole infusion protocols are shown. (Color version of figure is available online.)
Table 2 Common Adverse Reactions to Regadenoson (Lexiscan) and Adenosine (Adenoscan) Adverse Events Dyspnea Headache Flushing Chest pain Angina or ST-segment depression Nausea Abdominal discomfort Rhythm or conduction abnormalities First-degree AV block (PR > 220 ms) Second-degree AV block Ventricular conduction abnormalities Premature atrial/ventricular complexes
Regadenoson Adenosine (%) (%) 28 26 16 7 12
26 17 25 10 18
6 5 26
6 2 30
3
7
0.1 6
1 5
7/14
9/12
More headache and abdominal discomfort were observed with regadenoson while the occurrence of AV nodal block was substantially less than with adenosine. AV, atrioventricular; PR, P wave to R wave ECG interval.
node dysfunction without a functioning pacemaker (Table 2). It should also be used with caution in patients with asthma or chronic obstructive pulmonary disease. No randomized trial data exists with regard to caffeine use; thus, there is still a requirement to hold all xanthines before stress. The ADVANCE-MPI (Adenoscan Versus Regadenoson Comparative Evaluations for Myocardial Perfusion Imaging) trials have demonstrated noninferiority of regadenoson to adenosine for detection of reversible perfusion defects and better tolerability of the regadenoson regardless of age, sex, body habitus and diabetes.12 A total of 1871 patients had a baseline adenosine study and were subsequently randomized in the 2:1 ratio to a repeat stress study with regadenoson (n ⫽ 1240) or adenosine (n ⫽ 631). Three experts independently scored the blinded images by using a 17-segment model on a 5-point scale from 0 ⫽ normal to 4 ⫽ no activity.13 Summed stress perfusion scores were used to categorize ischemia as none to minimal (0-1), small to moderate (2-4), and large (ⱖ5). The overall average ischemia agreement rates between adenosine-adenosine and adenosine-regadenoson were 0.62 ⫾ 0.03 and 0.63 ⫾ 0.02 with an agreement difference of 0% (95% confidence interval ⫺6.2% to 6.8%), respectively. Agreement rates were greatest in the no ischemic category (80%) and lowest in the moderate-to-large ischemia extent categories (50%). Regadenoson was noninferior to adenosine for detection of ischemia (noninferiority margin ⫽ 13.3% was greater than 95% confidence interval of ⫺6.2% to 6.8%). Patients receiving regadenoson had reduced incidence of chest pain and flushing but experienced more headaches and gastrointestinal discomfort. Unlike adenosine, regadenoson has a different pharmacodynamic profile. The injection induces an initial phase of a 2-
Advances in vasodilator pharmacological stress perfusion imaging to 3-fold increase in myocardial blood flow with a half-life of 2 to 4 minutes. A second phase ensues, with a half-life on average of 30 minutes with a gradual loss of the pharmacodynamic effect. The final phase consists of a decrease in the plasma concentration with a half-life of approximately 2 hours.11 In contrast to regadenoson, intravenously administered adenosine is promptly cleared from the circulation by cellular uptake, predominately by erythrocytes and vascular endothelial cells. Once inside the cell, adenosine is quickly metabolized either via phosphorylation by adenosine kinase to adenosine monophosphate, or via deamination by adenosine deaminase in the cytosol to iminase.3 We have recently reported that these differences in pharmacodynamic profiles may be relevant to patients with endstage renal disease.14 A 38-year-old woman with end-stage renal disease requiring hemodialysis underwent a regadenoson perfusion testing preoperatively. She developed ST-segment depressions and chest pain that lasted for 30 minutes after termination of regadenoson infusion and were abolished with intravenous aminophylline. Perfusion images were abnormal, revealing reversible defect in the lateral wall suggestive of ischemia (Fig. 2). Subsequent angiogram confirmed
207 high-grade in-stent restenosis in the left circumflex coronary artery. Intravenous adenosine does not require renal function for its activation or inactivation, so renal failure is not expected to alter its efficacy or side effect profile. In contrast, in patients with increasing renal impairment, the fraction of regadenoson excreted unchanged in urine and the renal clearance decreases, resulting in increased elimination half-lives compared with healthy subjects.15 Regadenoson clearance decreases in parallel with a reduction in creatinine clearance. Results from patients with renal dysfunction have suggested that dose adjustments are not necessary. However, the pharmacokinetics of regadenoson in patients on dialysis have not been assessed. It is possible that these differences in pharmacodynamic profiles of adenosine and regadenoson accounted for a prolonged effect and persistence of ischemia in our patient. In summary, selective A2A receptor agonists such as regadenoson are noninferior to adenosine for detection of ischemia and offer improved safety profile and ease of administration. Regadenoson has a different pharmacodynamic profile than adenosine, and its effects in certain patient pop-
Figure 2 Regadenoson myocardial perfusion images in patient with end-stage renal disease. A reversible perfusion defect is present in the lateral wall suggestive of ischemia. Subsequent invasive angiogram confirmed a high-grade in-stent restenosis in the left circumflex coronary artery.
208
Figure 3 INSPIRE study. Stable patients after acute myocardial infarction were assigned into low-, intermediate-, and high risk groups based on the perfusion defect size (PDS), ischemic perfusion defect size (IPDS), and left ventricular ejection fraction (LVEF). (Reprinted with permission from Mahmarian et al.16) (Color version of figure is available online.)
ulations such as those with end-stage renal disease need to be evaluated.
Use of Vasodilator Perfusion Imaging to Guide Therapeutic Intervention: Lessons from INSPIRE and the COURAGE Imaging Substudy Two recently completed trials, INSPIRE and COURAGE Imaging Substudy, have evaluated vasodilator stress myocardial perfusion imaging in guiding therapeutic interventions. The INSPIRE (Adenosine Sestamibi Post-Infarction Evaluation) trial was a prospective multicenter trial that enrolled 728 stable patients after acute myocardial infarction to assess the role of noninvasive imaging in risk stratification.16 All patients underwent nitrate-enhanced rest-stress adenosine perfusion protocol to maximize detection of ischemia. Subsequently, patients were assigned into risk categories based on total perfusion defect size as well as ischemic perfusion defect size (Fig. 3). Importantly, those patients in the highest risk category (defined as total perfusion defect greater than or equal to 20% and ischemic perfusion defect greater than or equal to 10%) were further stratified based on the left ventricular ejection fraction: those with less than 35% proceeded to invasive angiogram whereas those with greater or equal than 35% were randomized to intensive medical therapy or medical therapy with revascularization. All patients in the highest risk category underwent a second adenosine stress study after randomization. Patient follow-up was 98% complete at 1 year for all patient risk groups for sudden cardiac death, nonfatal reinfarction, admission for heart failure, or acute coronary syndrome. Overall cardiac and death/reinfarction event rates increased significantly across risk groups from low (5.4% and 1.8%) to intermediate (14% and 9.2%) to high (18.6 and
R.S. Druz 11.6%), respectively. These differences were observed despite a high initial rate of revascularization in the highest risk group (50%) and were still significant after adjustment by Thrombolysis in Myocardial Infarction (TIMI) scores. In fact, INSPIRE assessment of risk based on scan variables outperformed TIMI risk score for the event prediction. Each 10% absolute increment in total or ischemic perfusion defect size increased the unadjusted relative risk for any event by 37% and 64%, respectively. Revascularization impacted event rates in the high risk group with decreased ejection fraction whereas in patients with ischemia and preserved function medical therapy was as effective as coronary revascularization.17 Results were significant irrespective of age, sex, or type or location of an infarct. The INSPIRE trial was unique in several regards. All patients were assigned to a conservative imaging strategy and subsequently triaged to invasive procedures based on quantitative imaging results with extent of ischemia as the primary focus of stratification. Adenosine stress was performed expeditiously (with more than half the patients in the United States undergoing the procedure within 2 days) and safely with no cardiac events occurring before noninvasive testing.16 Sequential adenosine imaging not only allowed to track risk but also identified specifically subgroups of patients who may benefit from early revascularization as well as those who can be discharged safely. Thus, noninvasive risk stratification with vasodilator stress emerged as safe and cost-effective way of guiding therapeutic interventions. These findings were further extended in the COURAGE (Results from Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-driven Drug Evaluation) Imaging Substudy.18 The COURAGE trial evaluated outcomes in stable patients with chronic coronary artery disease treated with optimal medical therapy with or without percutaneous intervention. The main trial found no difference by treatment strategy in the primary endpoint of death or myocardial infarction.19 Of the 2287 COURAGE patients, 314 were enrolled in the imaging substudy, with most undergoing vasodilator stress (230 patients). All patients underwent serial imaging before and 6 to 18 months later after randomization into optimal medical therapy or optimal medical therapy with revascularization groups. Moderate-to-severe ischemia was defined as greater than or equal to 10% of the ventricular myocardium, and the primary endpoint was at least 5% reduction in ischemia. Revascularization was more effective than medical therapy alone in reducing ischemia (33% versus 19%, respectively), especially in patients with moderate-tosevere pretreatment ischemia (78% improvement versus 52% with mild ischemia). Patients with ischemia reduction had lower unadjusted risk for death or myocardial infarction particularly if pretreatment ischemia was severe. The main results from the COURAGE trial were controversial in that no difference was shown in the long-term outcomes for patient with stable coronary artery disease among those receiving optimal medical therapy and the those receiving medical therapy with revascularization. The nuclear substudy provides an important refinement to that finding by quantitatively assessing ischemia, and using this parameter to
Advances in vasodilator pharmacological stress perfusion imaging guide application of invasive strategy as well as to assess its effectiveness. In summary, INSPIRE and the COURAGE Imaging Substudy were pivotal trials that clearly established significant role of vasodilator stress perfusion imaging in risk stratification of stable patients with coronary artery disease and guidance of therapeutic interventions.
Conclusion Vasodilator stress perfusion imaging is safe and effective in identifying prognostically significant coronary artery disease. Newer agents allow better tolerance, ease of administration, and improved side-effect profile. Recent trials have firmly established a pivotal role of vasodilator stress perfusion imaging in risk stratification and therapeutic guidance of patients with stable coronary artery disease.
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