J of Technology, first published online April 13, 2017 as doi:10.2967/jnmt.116.188938

Accuracy of Rb-82 PET/CT MPI With Regadenoson Stress Including Three Year Clinical Outcomes Reporting PRESENT: PET/CT Regadenoson Stress Experience at the VA North Texas

Authors- Michael D. Brophey, MD Irfan M. Farukhi, MD Rosinda Castanon, MD Rosinda DeLaPena, BS Ledjona Bradshaw, MPH Subhash Banerjee, MD

Affiliations- All authors are staff members at the VANTHCS, Dallas VA Medical Center as designated below: M. Brophey- Nuclear Medicine Service, Staff Physician I. Farukhi- Nuclear Medicine Service, Chief R. Castanon- Nuclear Medicine Service, Staff Physician R. DeLaPena- Nuclear Medicine Service, Research L. Bradshaw- Research S. Banerjee- Section, Chief

Disclaimer- This work was supported by the Dallas VA Research Corporation and with resources and the use of facilities at the VA North Texas Health Care System, Dallas VA Medical Center

Corresponding Author- Michael D. Brophey, MD Nuclear Medicine Service, Mail Slot 115 4500 S. Lancaster Road Dallas, TX 75216 214-857-0130 telephone 214-857-0129 fax [email protected]

Word Count: 3380

Short running foot line: Regadenoson Cardiac PET Outcomes

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Accuracy of Rb-82 PET/CT MPI With Regadenoson Stress Including Three Year Clinical Outcomes Reporting PRESENT: PET/CT Regadenoson Stress Experience at the VA North Texas

ABSTRACT- The purpose of this study was to determine the clinical accuracy of Rb-82 PET/CT MPI when performed with regadenoson stress in a VA population of patients. Methods- The initial cohort of 480 patients undergoing vasodilator PET MPI with regadenoson stress at our institution from September 2009 through July 2010 were closely tracked for short term outcomes based on correlation with invasive . Long term outcomes were determined by major adverse cardiac event rates (MACE) based on data extraction from the electronic medical record and grouped by SSS for a three year period. Results- At three year follow up there were 31 patient deaths, 5 of which were cardiac related. Twenty-four (24) patients had documented myocardial infarctions. Event rates and cardiac death rates were highly predicted by the results of PET MPI. Seventy (70) patients underwent invasive within 60 days of the PET MPI. Patients were increasingly likely to undergo catheterization as their SSS increased. Cath correlation demonstrated a sensitivity of 95%, PPV 88.4% for significant CAD, and an overall accuracy rate of 86% for PET MPI with regadenoson when compared to invasive catheterization. Conclusion- Cardiac PET MPI with regadenoson stress demonstrates high accuracy when correlated with invasive catheterization and clinical outcomes. The SSS is highly predictive of cardiac events and patient survival in a VA population over a three year period of clinical follow up.

BACKGROUND- Myocardial perfusion imaging (MPI) with SPECT and PET has earned a strong reputation for providing accurate clinical information to guide decision making for patients with known or suspected coronary disease (CAD). Its utilization continues to be endorsed by practice guidelines and refined by published appropriate use criteria.1-3 The clinical superiority of myocardial perfusion PET has also been recently recognized in a joint statement of the American Society of Nuclear Cardiology and the Society of Nuclear Medicine and (ASNC/SNMMI) to encourage its continued appropriate use.4 PET MPI has been increasingly utilized in recent years as the availability of a generator produced radiotracer (Rb-82) and the proliferation of hybrid PET/CT cameras across the community has brought the technically superior PET modality within the realm of the wider clinical community lacking direct access to a cyclotron. These developments have also coincided with the availability of regadenoson, a new

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FDA approved cardioselective vasodilator. Regadenoson stress has been found to be accurate when used with SPECT-MPI (ADVANCE Trial) where it produced results comparable to adenosine stress.5 However, questions have persisted about its accuracy for cardiac PET MPI because of its quick onset, shorter duration of action, and lower degree of vasodilation compared to other vasodilators historically used for cardiac PET protocols.6 While regadenoson is FDA approved for SPECT MPI applications it’s use for PET MPI would technically considered off label. Early reports from single center sites involving small numbers of patients have found that PET MPI with pharmacological stress with regadenoson is comparable to dipyridamole in regards to image quality and the size and severity of any stress induced abnormality.7 Other investigators have performed similar quantitative comparisons of the two stressors including utilizing coronary flow reserve analysis and found they were not significantly different with respect to the measurement of absolute myocardial blood flow and myocardial flow reserve.8 More recently the accuracy of the modality emphasizing the importance of systolic reserve has also been reported.9 The purpose of this study is to report on the clinical outcomes of the initial cohort of 480 patients undergoing cardiac PET MPI with regadenoson stress performed at our institution. To our knowledge, this is the first study to document clinical outcomes for thirty-six (36) months following the reference PET MPI study when performed with regadenoson stress.

METHODS- All patients who underwent a clinically indicated PET MPI from January 2009 through July 2010 were included in an IRB approved retrospective database and their clinical outcomes were carefully tracked. Short term outcomes are reported based on correlation with invasive cardiac catheterization when performed within 60 days of the noninvasive study. Long term outcomes are reported by the incidence of major adverse cardiac events (MACE) determined by history of MI extracted through encounter ICD9 codes occurring after the patient date of enrollment in the study. The outcomes of three specific patient subpopulations were evaluated and reported separately including patients unable to augment LVEF from rest to stress, patients with an ischemic ECG response to regadenoson stress, and female patients. This study was approved by the Institutional Review Board and the need for informed consent was waived.

Regadenoson PET Imaging Protocol- All subjects were imaged with a Gemini TOF PET/CT (Philips Medical) in 3D mode before and after pharmacological stress with regadenoson 0.4 mg administered as a rapid IV bolus followed immediately by a 10 ml saline flush and stress tracer

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administration. Stress and rest imaging were both performed with 30 mCi Rb-82 Cl and a low dose CT scan was performed for CTAC purposes at rest and stress (patients weighing more than 300 lbs received 40 mCi of Rb-82 Cl for both rest and stress imaging). The imaging protocol is illustrated in Figure 1. Patients were continuously monitored throughout the procedure for rate, , and ECG changes until recovery and stress imaging was completed. Data acquisition was performed from the initial time of injection in list mode and perfusion data was processed following a 60-90 second delay as appropriate to allow for clearance of blood pool activity.

Image Processing and Reconstruction- Perfusion images were iteratively processed (MLEM Butterworth 0.6, cut off 10, 12 iterations) on a Philips EBW workstation and exported to a separate workstation for semi-quantitative review using Emory Cardiac Toolbox (Version 3.0). Alignment of emission and transmission images was manually performed initially by the technologist staff and confirmed by the interpreting physician by viewing fused images in the axial, coronal, and sagittal planes for both rest and stress datasets. Misregistration was corrected by manually shifting the fused datasets with special attention given to exclude cardiac activity from the field to avoid artifact. CTAC images were also carefully reviewed for the presence of clinically relevant incidental findings. Non-attenuation correction (NAC) images were also carefully inspected for concordance with the CTAC imaging findings. Any discrepancies were again scrutinized for correct alignment of the transmission and emission datasets.

Interpretation of Perfusion & Gated Images- Perfusion images were independently interpreted by four experienced observers board certified in Nuclear Medicine using a standard 17-segment cardiac model without knowledge of catheterization results. Images were semi-quantitatively analyzed using a 5 point scoring system (0=normal, 1=equivocal reduction of counts, 2=mild reduction of counts, 3=moderate reduction of counts, and 4=absence of counts or background equivalence). Studies were evaluated for transient dilation (TID) based on concordance of the visual qualitative assessment and a quantitative threshold of greater than 1.19 as indicative of clinically significant transient dilation and possible critical or multivessel . A summed stress score of less than four was considered normal; 4-8 mildly abnormal; 9- 13 moderately abnormal, and >13 severely abnormal. Eight frame gating was performed for

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assessment of global and regional systolic function. Image review and semi-quantitative analysis was performed with the use of Emory Cardiac Toolbox (ver 3.0).

Coronary - Cineangiograms were obtained in multiple projections using an Integris FD20 angiographic system (Philips Medical). Coronary cine angiograms were considered positive for significant coronary artery disease if the visually determined of the left main was > 50% or the left anterior descending, circumflex, or right coronary or their major branches had > 70% stenosis.

Demographics- 480 patients presenting for a clinically indicated cardiac PET examination between January 2009 through July 2010 are reported in this study. Ninety-seven percent (97%) where male, the average age was 61 years old and 38.9% had an established diagnosis of coronary artery disease at the time of the cardiac PET examination. Most patients were evaluated for chest pain, dyspnea, or atypical clinical symptoms suspicious for or an anginal equivalent. Additional patient characteristics are listed in Table 1.

RESULTS- Patients generally tolerated regadenoson well. The agent was very safe for use as a pharmacological stress agent in this study population. Minimal side effects were reported by 38% of patients undergoing testing. The most frequent side effects listed in the package insert are dyspnea, headache, flushing and chest pain. Only 6 patients (1.2%) experienced side effects severe enough to require aminophylline reversal. Cardiac PET imaging results found that 223/480 (46.5%) had normal results (SSS<4), 134/480 (27.9%) had mildly abnormal stress test results (SSS 4-8), 55/480 (11.5%) had moderately abnormal (SSS 9-13), and 68/480 (14.2%) had severely abnormal stress test results (SSS > 13, TID, drop in LVSF) based on SSS, TID, and systolic function evaluation.

At three year follow up there were 31 patient deaths, 5 of which were cardiac related. Twenty- four (24) patients had documented myocardial infarctions during the follow up period. Event rates and cardiac death rates were highly predicted by the results of PET MPI (See Figure2). Fifty (50) patients without prior CABG underwent invasive cardiac catheterization within 60 days of the PET MPI. Patients were increasingly likely to undergo catheterization as their SSS

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increased (See Figure3). Correlation demonstrated a sensitivity of 95%, PPV 88.4%, and an overall cath correlation or accuracy rate (TP+TN/TP+TN+FP+FN) of 86% for PET MPI with regadenoson when compared to invasive catheterization.

Special Patient Populations-

LVEF reserve- LVEF reserve, the ability of the heart to increase its systolic function in response to stress has been previously reported to be an important factor in predicting future events.9 Sixty-five patients (65/480, 13.5%) completing cardiac PET MPI with regadenoson stress in the study population were found to have a decrease in systolic function after stress testing. The range of fall in EF in the study group was from 1 to 25% (mean -5.5%). None of these patients had a cardiac death during the three year follow up period. Six (6/65, 9.2%) patients unable to augment their EF had an MI, none of these patients had a delta EF less than 2%. The average fall in EF among patients with a documented hard event following stress testing was 9.5% (range of 2-25% fall in EF). Of these 65 patients with EFs that fell post stress testing, 5 also concurrently manifested an ischemic ECG response to vasodilator stress defined as greater than or equal to 1 mm of ST depression during pharmacological stress. Their SSS ranged from 0 to 36 (average of 9.4).

Abnormal ECG response- Ten patients (10/480, 2.1%) in the study group developed an ischemic ECG response to pharmacological stress with regadenoson defined as greater than or equal to 1 mm ST depression. Their average SSS was 12.5 (range from 0-29) and these patients were 2.7 times more likely to undergo invasive cardiac catheterization then patients without an ischemic electrocardiographic response to pharmacological stress. Three patients with discordant ECG and imaging findings (abnormal ECG response to pharmacological stress but SSS < 4) did not undergo invasive catheterization. None of these patients had a documented hard event during the follow up period. All patients with an ischemic response concordant with imaging results had invasive cardiac catheterization and were found to have significant, multivessel CAD. Five (5/6, 83%) of these patients were revascularized (3 CABG, 2 PCI) and 1 patient died of pancreatic CA during the follow up period without undergoing revascularization despite multivessel CAD because of the comorbid malignancy.

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Females- Fourteen (14/480, 2.9%) patients in the study group were female. All had a normal PET MPI except for one patient who had a mildly abnormal study (SSS 8) indicating inferior ischemia. This patient was treated medically with a good clinical outcome and no hard event documented during the study follow up period. No female patient underwent cardiac catheterization. No female patient had an MI or cardiac death during the three years following testing. No female patient demonstrated an ischemic response to vasodilator stress or developed stress induced systolic dysfunction.

DISCUSSION- Coronary artery disease (CAD) continues to be the leading killer of Americans, both men and women. The Center for Disease Control (CDC) reports that recent changes in the mortality trends related to heart disease and cancer suggest that cancer is poised to become the leading cause of death in the US in this decade if those trends are sustained (See Figure 4). There are several states in the US where this is already the case. 10 The noninvasive assessment of CAD has relied heavily on gated SPECT MPI in the past because of its powerful ability to risk stratify patients, predict prognosis, and direct patient management decisions to allocate healthcare systems resources appropriately while improving patient outcomes. In recent years, use of cardiac PET/CT has led to an even better sensitivity and specificity as a result of its greater spatial resolution, inherent, high quality attenuation correction and flow quantification.

Cardiac PET/CT MPI offers technically superior, CT attenuation corrected perfusion images for clinically challenging patients with known or suspected CAD compared to conventional SPECT MPI. For the subset of patients who are not able to achieve adequate treadmill exercise or for other reasons are obligated to undergo pharmacological stress (such as LBBB) and do not have severe, limiting claustrophobia, cardiac PET MPI offers a superior clinical protocol that can be completed in approximately 30 minutes. This is reflected in the recent joint statement by ASNC/SNMMI recognizing the superiority of cardiac PET for these patients.4 This also greatly improves the clinical efficiency of the department and lessens the patient’s required time commitment compared to a standard 3 hour conventional pharmacological SPECT MPI protocol.

Regadenoson is an agent that is more efficient to use than the other clinically available vasodilators because of its fixed dosing (0.4 mg for all patients) and simple IV bolus

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administration. While no infusion system is required there has been clinical concern regarding the lower level and shorter duration of maximal vasodilation compared to the other commercially available vasodilators dipyridamole and adenosine. While previous reports have documented equivalent defect detectability and similar quantitative myocardial flow and flow reserve results compared to dipyridamole this is the first report we are aware of in which the incidence of MACE (major adverse cardiac events) is reported out to three years following the reference cardiac PET MPI when performed with regadenoson MPI.

The temporal efficiency of vasodilator PET MPI also allows the assessment of global systolic function and regional wall motion to be made more contemporaneously with the evaluation of myocardial perfusion, increasing the modalities ability to detect myocardial stunning in response to pharmacological stress. Other authors have proposed that failure of the stress EF to augment at least one percentage point compared to rest may be a poor prognostic predictor.9 While the magnitude threshold of rest and stress EF changes may be debatable the temporal proximity of wall motion assessment to the stress test event should increase the sensitivity of the test to detect this ischemic manifestation of CAD.

Cardiac PET MPI performed well as a modality in our cohort of patients. The spectrum of disease findings in patients with known or suspected CAD can range from normal to severely abnormal. A representative normal case from the study cohort demonstrates a patient with normal myocardial perfusion and function at stress and rest and denotes a patient with a low risk of MI or cardiac death (See Figure 5). The next case presents a patient with single vessel disease involving the inferior wall (See Figure 6). PET/CT is particularly helpful in this situation because of the likelihood of interfering diaphragmatic attenuation artifact, especially in large male patients commonly seen in our VA population. This patient can be treated with maximal medical therapy while revascularization would be reserved for refractory symptoms. A final representative case from our study cohort shows a patient with extremely high risk features (See Figure 7). The triad of multiple vascular territory ischemia, TID, and hemodynamic instability identified from rest and stress gating, is coupled with the development of acute ECG changes following vasodilator stress. This constellation of findings predicts that catheterization will show that surgical revascularization may be likely to be the most appropriate management option for

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this patient. Subsequent cardiac catheterization demonstrated critical disease of the proximal circumflex and moderate disease of the left anterior descending artery. Unfortunately this patient was not a candidate for revascularization due to comorbid malignancy and died of non-cardiac causes 6 months after the examination.

Although conventional SPECT cameras are more available in the community setting, hybrid PET/CT scanners are growing in availability. PET/CT is being increasingly performed to assess and risk stratify patients with known or suspected coronary artery disease. Cardiac PET/CT with its more efficient imaging protocols result in higher quality clinical results, lower radiation exposure to patients and a significant decrease in time to complete the procedure. The attenuation correction inherent in all cardiac PET imaging makes it better suited for patients prone to attenuation artifacts. Although PET/CT requires a large capital investment and operational footprint, studies have shown that the decreased downstream costs that come with its increased accuracy make the modality more than cost effective.11 Particularly when already deployed for oncology imaging in a busy clinical environment like the VA health care system, cardiac PET can maximize utilization and improve patient care to the advantage of both patient care and healthcare system efficiencies through improved workflows. The availability of a generator produced myocardial perfusion tracer, although costly, obviates the need for a cyclotron. If a facility has access to a cyclotron other agents may be more cost effective (eg NH- 13).

While our results are limited by their retrospective design and are from a single center site it is reassuring to know that both short term correlation when cardiac catheterization is performed within 60 days of the cardiac PET MPI or long term outcomes to thirty-six months show that cardiac PET MPI performed with regadenoson stress is highly predictive of obstructive coronary artery disease and subsequent cardiac events. These findings, when taken in context with other recent published series documenting similar lesion detectability and absolute flow quantification further support the continued clinical use of regadenoson for cardiac PET MPI. Absolute quantification of myocardial blood flow and coronary flow reserve is another powerful tool that can be used to further increase the sensitivity and specificity of cardiac PET MPI studies.

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Validated software was only available for N-13H3 when our initial patient cohort was studied and hardware limitations also precluded its use at our center. Computer modeling is now available for Rb-82 and needs to be further validated for regadenoson as the vasodilator compared to dipyridamole. The addition of this assessment to cardiac PET would be expected to further strengthen the modalities ability to successfully identify patients with CAD and at risk for future adverse events. The study population is almost exclusively male as reflected by the patient demographic served by the VA healthcare system. Female patients are increasingly cared for in the VA but are underrepresented in the study cohort. PET MPI performed well in the study population for the limited number of females in the cohort. The normalcy rate in this group successfully predicted low cardiac event rates in these patients. It will be important to continue to verify the modalities accuracy when performed for women with regadenoson stress.

CONCLUSION- Cardiac PET MPI with regadenoson stress demonstrates high sensitivity, positive and negative predictive values, and overall accuracy rates when compared to invasive catheterization. The SSS is highly predictive of cardiac events and survival in the initial cohort of 480 patients undergoing the procedure at our facility. The combination of a reversible perfusion abnormality and an ischemic ECG response to regadenoson stress was highly predictive of severe CAD and the need for subsequent revascularization. The results of regadenoson stress are accurate and clinically relevant demonstrating noninferiority to conventional SPECT MPI performed at our facility based on historical comparisons with active cath correlations that have been documented since 2008 at the study facility. Interesting areas of future research include evaluation of the quantitation of PET MPI when performed with Rb-82 PET and regadenoson stress in regards to CFR. The conventional SPECT derived break points for SSS, TID and delta EF may also bear reexamination in the PET era. The modalities ability to successfully detect and risk stratify female patients for CAD is also important to establish with regadenoson stress. These investigations will require larger patient populations and are currently underway at our facility.

Acknowledgments- The authors thank all of the patients who contributed to this study, E. Tajalle and S. Faith, the CNMTs who cared for them while performing the examination and to M. Shuler for her excellent technical, data analysis and statistical support. This work was

Brophey 10 supported by the Dallas VA Research Corporation and with resources and the use of facilities at the VA North Texas Health Care System, Dallas VA Medical Center.

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Figure Section-

Figure 1 Legend-Rest Stress 82Rb PET/CT protocol- CTAC (120 kVp, 10 mA, pitch 0.704) was acquired slowly over one minute to simulate volume averaged emission data from the 7 minute rest and stress perfusion data. Pharmacologic stress was performed with 0.4 mg regadenoson followed by 10 ml saline flush followed immediately by a second 30 mCi (1110 MBq) infusion of rubidium. A final CTAC to apply to the stress emission data concludes the protocol which can be completed in approximately 30 minutes.

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Figure 2 Legend- Cardiac events including MI and death by SSS (Normal < 4, Mildly Abnormal 4-8, Moderately abnormal 8-13 and Severely Abnormal > 13)

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Figure 3 Legend- The rate of cardiac catheterization increased as the SSS increased.

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Figure 4 Legend- US Mortality trends for Heart disease and Cancer, NOTES: Leading cause is based on number of deaths. SOURCE: NCHS, National Vital Statistics System, Mortality. NCHS Data Brief 254, August 2016

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Figure 5 Legend- Normal Rb-82 PET Myocardial Perfusion Imaging- 56 year old male with history of DM, HTN, and morbid obesity with complains of exertional dyspnea and atypical chest pain. Panel (A) shows normal myocardial perfusion at stress and rest. Semi-quantitative Bull’s Eye (B) and Gated (C) images are also normal. The presence of normal regional myocardial perfusion and LV systolic function identifies this patient as being at low risk for MI or cardiac death. This patient has done well with no cardiac related events in the 36 months since the examination.

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Figure 6 Legend- Rb-82 PET MPI shows abnormal myocardial perfusion in a 50 year old male with history of chronic chest pain, risk factors for CAD, and an abnormal baseline EKG. Perfusion images (A) demonstrate a severe, non-reversible perfusion defect in the distal inferior wall and apex consistent with an old . Semi-quantitative Bulls Eye (B) and Gated (C) images confirm a fixed defect and associated regional wall motion abnormality.

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Figure 7 Legend-Rb-82 PET scan of a 59 year old male with known CAD, s/p PCI of the LAD with complaints of exertional arm and jaw pain. Perfusion images show a large territory of severe inferolateral ischemia in an expected circumflex distribution (A). The semi-quantitative Bulls Eye images (B) show that the SSS was 15. Gated Images (C) revealed a normal LVEF of 61% at rest which fell to 29% at stress. Transient dilatation (TID 1.3, normal <1.19) was also present. The patient developed 1.5 mm ST depression seen in the inferior leads II, III, and AVF (circled) during pharmacological stress which resolved after administration of Aminophylline administered IV. A subsequent left heart catheterization (D) showed 60% stenosis of Proximal LAD (thick arrow) and 99% stenosis of the proximal circumflex (thin arrow) confirming the Rb-82 PET findings. The patient was not a candidate for due to comorbid disease and died of noncardiac causes 6 months after the examination.

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