Clinical experience with regadenoson SPECT myocardial perfusion imaging: insights into patient characteristics, safety, and impact of results on clinical management.

The Henry Ford Hospital (HFH) regadenoson (REG) registry includes patients with a variety of comorbidities allowing for the evaluation of outcomes in a large, unselected population. Using a database of electronic medical records and nuclear cardiology reports, patients aged > 18 years who underwent REG-facilitated single-photon emission computed tomography (SPECT) testing at HFH between January 2009 and August 2012 were identified. The primary objective was to describe the clinical and demographic characteristics of patients who had undergone REG only vs REG WALK (REG + low-level exercise) SPECT. A total of 2104 patients were included in the analysis (mean age 65.3 years; 50% women; 51% African American, 43% Caucasian). For the REG only (n = 1318) and REG WALK (n = 786) cohorts, SPECT was abnormal in 37% of patients (REG only, 39%; REG WALK, 34%; P < 0.01). No differences in diagnostic modalities or interventions in 90 days after SPECT were observed. Immediate safety analysis showed no deaths 48 h after REG SPECT testing. Although they guide invasive therapy, abnormal scans do not automatically lead to invasive testing. This demonstrates the focus on initial medical management, which reflects the existing evidence of initial goal-directed medical management of stable coronary disease.

Evaluating the use of pharmacological stress agents during single-photon emission computed tomography myocardial perfusion imaging tests after inadequate exercise stress test.

BACKGROUND: Past clinical trial findings suggest that the availability of regadenoson in a nuclear imaging center may affect real-world center practices related to the transition of patients from an inadequate exercise stress test (EST) to a pharmacological stress agent (PSA). METHODS AND RESULTS: This was a cross-sectional study using one-on-one telephone interviews with nuclear imaging center staff to facilitate survey development, followed by an online survey to evaluate patterns and processes around use of PSAs during single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in patients with inadequate ESTs. Of the 50 participants, 35 (70%) used only regadenoson, 3 (6%) only adenosine, 3 (6%) regadenoson and adenosine, 7 (14%) regadenoson and dipyridamole, and 2 (4%) all 3 agents for converting patients from an inadequate EST to a PSA. Nearly all centers (94%) used protocols to guide conversions. Of 12 centers using > 1 PSA, 11 reported regadenoson to be the most preferred PSA. Total staff time required from PSA transition to post-test monitoring was shortest for regadenoson. CONCLUSIONS: Compared to adenosine and dipyridamole, regadenoson is preferred by nuclear imaging center staff and associated with operational efficiencies after inadequate EST in real-world practice SPECT-MPI.

Healthcare resource utilization among patients receiving non-invasive testing for coronary artery disease in an outpatient setting: A cohort study reflecting daily practice trends.

BACKGROUND: Accurate, early diagnosis and the initiation of appropriate treatment is central to reducing the clinical burden of coronary artery disease (CAD); however, real-world evidence characterizing healthcare resource utilization (HCRU) associated with testing for CAD is lacking. METHODS AND RESULTS: Using a non-interventional, retrospective, secondary database analysis, patients aged ≥18 years who underwent outpatient non-invasive cardiac diagnostic testing were identified. The primary objective was to gain an understanding of pre- and post-assessment care pathways and the associated interventions for patients who underwent non-invasive testing for CAD in either an outpatient or emergency department setting. Overall, chest pain was the primary reason for the index visit (54.8%), followed by shortness of breath (23.7%), myocardial infarction (MI), coronary artery disease (CAD) or congestive heart failure (CHF) (3.8%), and other (46.8%); 3.0% of patients had no apparent reason for testing in the last 45 days. Single-photon emission computed tomography (SPECT) was the dominant diagnostic testing modality (40.3%). During the 90-day follow-up, 7.3% (n = 22,083) of patients were diagnosed with CAD; among these patients, 19.4% had repeat diagnostic testing, 26.0% of patients had a revascularization procedure, and 65.6% underwent cardiac catheterization. These rates varied by testing modality. CONCLUSIONS: In this study of a large real-world data sample, variability in the use of non-invasive tests and HCRU were evident. These results may assist efforts to optimize system-wide care/diagnostic pathways and value-based treatment decisions for patients.

Combination treatment of liposomal amphotericin B and isavuconazole is synergistic in treating experimental mucormycosis.

OBJECTIVES: Liposomal amphotericin B (L-AMB) and isavuconazonium sulphate are commonly used antifungal drugs to treat mucormycosis. However, the efficacy of combination therapy of L-AMB/isavuconazonium sulphate versus monotherapy is unknown. We used an immunosuppressed mouse model of pulmonary mucormycosis to compare the efficacy of L-AMB/isavuconazonium sulphate versus either drug alone. METHODS: Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with L-AMB, isavuconazonium sulphate, or a combination of both started 8 h post-infection and continued through to Day +4. Placebo mice received vehicle control. Survival to Day +21 and tissue fungal burden (by conidial equivalent using quantitative PCR) on Day +4, served as primary and secondary endpoints, respectively. RESULTS: For mice infected with R. delemar, L-AMB and isavuconazonium sulphate equally prolonged median survival time and enhanced survival versus placebo (an overall survival of 50% for either drug alone, versus 5% for placebo). Importantly, combination treatment resulted in an overall survival of 80%. Both antifungal drugs reduced tissue fungal burden of lungs and brain by ∼1.0-2.0 log versus placebo-treated mice. Treatment with combination therapy resulted in 2.0-3.5 log reduction in fungal burden of either organ versus placebo and 1.0 log reduction versus either drug alone. Similar treatment outcomes were obtained using mice infected with M. circinelloides. CONCLUSIONS: The L-AMB/isavuconazonium sulphate combination demonstrated greater activity versus monotherapy in immunosuppressed mice infected with either of the two most common causes of mucormycosis. These studies warrant further investigation of L-AMB/isavuconazonium sulphate combination therapy as an optimal therapy of human mucormycosis.

Isavuconazole Treatment of Invasive Fungal Sinusitis: A Post Hoc Analysis of the SECURE and VITAL Trials.

This post hoc analysis of international phase III isavuconazole trials identified 50 patients (90% immunocompromised or diabetic) with invasive fungal sinusitis (88% mucormycetes, Aspergillus) who received isavuconazole as primary (n = 33) or salvage (n = 17) therapy for a median of 82 days (range, 2-882). Overall survival was 82% at day 42 and 70% at day 84.

Efficacy and Associated Drug Exposures of Isavuconazole and Fluconazole in an Experimental Model of Coccidioidomycosis.

Coccidioides spp. are important pathogens in regions where they are endemic, and new treatment options are needed. Here, isavuconazonium sulfate (ISAVUSULF) and fluconazole (FLU) were evaluated in experimental disseminated coccidioidomycosis to characterize drug exposures associated with efficacy. Broth macrodilution was performed on Coccidioides isolates to measure minimal effective concentrations (MEC) and minimal fungicidal concentrations (MFC). Mice were inoculated with Coccidioides posadasii (Silveira strain). Treatment started 4 days postinoculation. In model 1, mice were treated for 19 days, followed by 30 days of off-therapy observation, measuring survival through day 49 and residual fungal burden. Treatments included ISAVUSULF (prodrug; 186, 279, or 372 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Model 2 included 7-day treatment with ISAVUSULF (prodrug; 74.4, 111.6, or 148.8 mg/kg twice daily), FLU (20 or 100 mg/kg once daily), and no treatment. Serial plasma and tissues samples were obtained for pharmacokinetics (PK) and fungal burden measurement, respectively. Fifty percent minimal effective concentration (MEC50) values were 0.39 mg/liter (isavuconazole [ISAV]) and 12.5 mg/liter (FLU). Treatment with ISAVUSULF186 or with either FLU dose resulted in higher survival compared to that in the untreated group. Treatment with ISAVUSULF186 or ISAVUSULF279 twice daily or FLU100 reduced fungal burden in all organs (model 1). In model 2, a >1 log10 CFU/organ reduction was demonstrated, with ISAV area under the concentration-time curve (AUC) values achieved with 111.6 mg/kg twice daily (56.8 mg · h/liter) in the spleen and liver. FLU AUC values of 100 and 500 mg·h/liter for 20 and 100 mg/kg doses, respectively, resulted in a >1 log10 CFU/organ mean reduction in all organs. ISAVUSULF and FLU improved survival and reduced fungal burden. Increasing plasma drug exposures resulted in decreases in fungal burden.

Factors that impact a patient's experience when undergoing single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in the US: A survey of patients, imaging center staff, and physicians.

BACKGROUND: Single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) is commonly used for coronary artery disease diagnosis/assessment in the United States (US); however, the factors that most significantly affect patients' experience when undergoing SPECT-MPI are not well known. METHODS: In this US-based cross-sectional study, an online questionnaire was used to identify and quantify attributes of the SPECT-MPI process that impact patients' experience, according to adults who underwent SPECT-MPI in the prior month, cardiac imaging center staff, and referring physicians. Participants were asked to rate the importance of 32 factors using an 11-point scale; congruence between groups (physicians vs patients, patients vs imaging center staff, and physicians vs imaging center staff) was assessed. RESULTS: The survey was completed by 101 patients, 101 center staff, and 100 physicians, who gave similar ratings for the highest-rated factors (high-quality results/decreasing likelihood of having to retest, highly skilled and knowledgeable staff, and compassionate and respectful staff). Congruence was higher between patients and imaging center staff compared with physicians and patients, and was notably low between imaging center staff and physicians. CONCLUSIONS: We identified areas for improvement in the patient SPECT-MPI experience that could translate into improved quality and value.

Use of Antifungals and Outcomes Among Inpatients at Risk of Invasive Aspergillosis or Mucormycosis in the USA: A Retrospective Cohort Study.

INTRODUCTION: Prophylaxis and treatment of invasive aspergillosis (IA) and mucormycosis (IM) within a real-world US inpatient setting is undocumented since the introduction of isavuconazole. This retrospective medical record review aimed to describe characteristics, triazole use, and outcomes among inpatients across the USA who initiated antifungal monotherapy (AFMT) as prophylaxis or treatment of IA/IM. METHODS: A convenience sample of US physicians abstracted data from randomly selected records of hospitalized patients aged ≥ 18 years initiating AFMT (amphotericin B, isavuconazole, voriconazole, or posaconazole) as prophylaxis or treatment of IA/IM between 2013 and 2017. Retrieved data included background characteristics, dosage and duration of AFMT, healthcare resource use, and survival. Characteristics and outcomes were compared (prophylaxis vs treatment) using Fisher's exact and one-way analysis of variance tests where applicable. Exploratory Kaplan-Meier analyses described overall and inpatient survival. RESULTS: Physicians (n = 23) retrieved 124 patient records (43 prophylaxis; 81 treatment). Median duration of first-line AFMT was 14 days (range 1-603 days) and 19 days (range 3-351 days) in the prophylaxis and treatment groups, respectively. One patient received second-line therapy. Median duration of hospitalization was 29 days (range 4-259 days) and 31 days (range 6-980 days) in the prophylaxis and treatment groups, respectively. Admission to intensive care occurred in 14% and 52% of patients in the prophylaxis and treatment groups, respectively. At the time of data retrieval, overall and inpatient survival rates in the prophylaxis group were 88% and 87%, respectively, and in the treatment group were 66% and 76%, respectively. CONCLUSIONS: This study documented real-world prophylactic and therapeutic AFMT use for IA/IM and associated outcomes among hospitalized patients in the USA since approval of isavuconazole. IA/IM were associated with lengthy hospital stays commonly requiring intensive care. Prophylactic and therapeutic AFMT dosages and duration generally followed recommendations and switching between agents was rare. FUNDING: Astellas Pharma Global Development, Inc., Northbrook, IL, USA.

Use of Initial Noninvasive Cardiac Testing and Association with Downstream Healthcare Resource: A Retrospective Review of Resources Used Across a 12-Month Window for Probable Type I Myocardial Infarction Patients.

BACKGROUND: Clinical guidelines provide clinicians with substantial discretion in the use of noninvasive cardiac testing for patients with suspected coronary artery disease. Repeat testing, frequent emergency department (ED) visits, and increases in other cardiac-related procedures can be a burden on patients and payers and can complicate treatment planning. We assessed downstream healthcare resource utilization (HCRU) for patients undergoing initial single-photon emission computed tomography (SPECT), myocardial perfusion imaging (MPI), stress echocardiography (ECHO), or exercise treadmill testing (ETT) with probable type I myocardial infarction (MI). METHODS: Electronic medical records data from 12,130 patients with probable type I MI presenting to EDs within a large healthcare system comprised of 11 adult hospitals were retrospectively analyzed. Logistic and linear regression determined the individual contribution of SPECT-MPI, ETT, and ECHO on repeat cardiovascular (CV) testing, inpatient visits, outpatient visits, and cardiac-related costs within 12 months of the index visit. RESULTS: The majority of patients received SPECT-MPI for the index-testing event (56.5%), followed by ETT (29.2%) and ECHO (14.3%). Patients who had SPECT-MPI at the index visit were less likely to have a repeat CV testing visit (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62‒0.96; p = 0.020) or an inpatient visit (OR 0.70, 95% CI 0.49‒0.98; p = 0.039) than those who underwent ETT or ECHO. ETT and ECHO were not predictive of any outcome. CONCLUSIONS: SPECT-MPI does not result in more downstream HCRU than ETT or ECHO and is associated with a lower likelihood of repeat non-invasive CV testing and inpatient visits.

Attributes of nuclear imaging centers impacting physician referrals for single-photon emission computed tomography myocardial perfusion imaging tests.

AIM: To evaluate nuclear imaging center attributes that cardiologists and primary care physicians (PCPs) consider when referring patients for single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) tests, and how these attributes impact physician referral decisions in the United States. METHODS: A targeted literature review and seven one-to-one interviews with physicians and imaging center directors were conducted to identify attributes that could impact physicians' referral decisions. The impact of the identified attributes was assessed via an online discrete choice survey among eligible PCPs and cardiologists randomly selected from a nationally representative panel, and quantified with an odds ratio (OR) scale estimated with a multivariable logistic regression. RESULTS: Nine two-level attributes were identified: ease of the referral process, waiting time for tests, insurance preauthorization assistance, time to receive results, conclusive test reports, patient satisfaction, a protocol for rapid conversion from an exercise to a pharmacological stress test, patient communication, and assistance with parking/wheelchair access. A total of 410 physicians, including 208 (50.7%) cardiologists and 202 (49.3%) PCPs completed the survey. Among all physicians, a protocol that allows for a rapid conversion from an exercise to a pharmacological stress test (OR = 2.9) and preauthorization assistance (OR = 2.6) were the most impactful attributes. Additionally, cardiologists preferred imaging centers that provide an easy referral process (OR = 2.7), while PCPs favored centers offering a conclusive test report (OR = 2.4). LIMITATIONS: Some center features that might impact physician referral decision were not evaluated in this study, if they were not easily changeable from an imaging center's perspective. CONCLUSIONS: The availability of a protocol for rapid conversion from an exercise to a pharmacological stress test and preauthorization assistance had the most significant impact on physician referral decisions for SPECT-MPI. Additionally, cardiologists preferred centers providing an easy referral process, while PCPs favored those offering a concluding statement and actionable steps in test reports.

The EXERRT trial: "EXErcise to Regadenoson in Recovery Trial": A phase 3b, open-label, parallel group, randomized, multicenter study to assess regadenoson administration following an inadequate exercise stress test as compared to regadenoson without exercise for myocardial perfusion imaging using a SPECT protocol.

BACKGROUND: This study assessed the non-inferiority and safety of regadenoson administration during recovery from inadequate exercise compared with administration without exercise. METHODS: Patients unable to achieve adequate exercise stress were randomized to regadenoson 0.4 mg either during recovery (Ex-Reg) or 1 hour after inadequate exercise (Regadenoson) (MPI1). All patients also underwent non-exercise regadenoson MPI 1-14 days later (MPI2). The number of segments with reversible perfusion defects (RPDs) detected using single photon emission computerized tomography imaging was categorized. The primary analysis evaluated the majority agreement rate between Ex-Reg and Regadenoson groups. RESULTS: 1,147 patients were randomized. The lower bound of the 95% confidence interval of the difference in agreement rates (-6%) was above the -7.5% non-inferiority margin, demonstrating non-inferiority of Ex-Reg to Regadenoson. Adverse events were numerically less with Ex-Reg (MPI1). In the Ex-Reg group, one patient developed an acute coronary syndrome and another had a myocardial infarction following regadenoson after exercise. Upon review, both had electrocardiographic changes consistent with ischemia prior to regadenoson. CONCLUSIONS: Administering regadenoson during recovery from inadequate exercise results in comparable categorization of segments with RPDs and with careful monitoring appears to be well tolerated in patients without signs/symptoms of ischemia during exercise and recovery.

Safety and tolerability of intravenous regadenoson in healthy subjects: A randomized, repeat-dose, placebo-controlled study.

BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist indicated for radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress. However, the safety, tolerability, and plasma concentrations associated with repeated doses have not previously been assessed. METHOD AND RESULTS: Healthy males and females were randomized to receive intravenous regadenoson [100 µg (3 doses), 200 µg (3 doses), or 400 µg (2 doses)], or placebo (2 or 3 doses; 0.9% sodium chloride); all doses 10 minutes apart. The primary endpoint was vital sign measurements (blood pressure and heart rate). Secondary endpoints included 12-lead electrocardiogram measurements, clinical laboratory evaluations (hematology, chemistry, and urinalysis), and adverse events. Thirty-six subjects were randomized and completed the study. Plasma concentrations of regadenoson increased in a dose-related manner and with successive doses. No consistent effect was observed for systolic blood pressure, although diastolic blood pressure was slightly lower than placebo for all regadenoson groups. Transient, dose-dependent increases in heart rate were observed in all regadenoson groups. There were no serious adverse events; 27 adverse events occurred in 14 regadenoson-treated subjects vs two events in two placebo-treated subjects. CONCLUSION: Repeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

A randomized, multicenter, multivendor study of myocardial perfusion imaging with regadenoson CT perfusion vs single photon emission CT.

BACKGROUND: Myocardial CT perfusion (CTP) is a promising tool for the detection of myocardial ischemia. We hypothesize that regadenoson CTP is noninferior to regadenoson single photon emission CT (SPECT) for detecting or excluding myocardial ischemia. METHODS: Patients (men ≥ 45 years; women ≥ 50 years) with known or suspected coronary artery disease (n = 124) were randomized to 1 of 2 diagnostic sequences: rest and regadenoson SPECT on day 1, then regadenoson CTP and rest CTP (and coronary CT angiography [CTA]) (CTA; same acquisition) on day 2 or regadenoson CTP and rest CTP (and CTA) on Day 1, then rest and regadenoson SPECT on day 2. Scanning platforms included 64-, 128-, 256-, and 320-slice systems. The primary analysis examined the agreement rate between CTP and SPECT for detecting or excluding reversible ischemia in ≥ 2 myocardial segments as assessed by independent, blinded readers. RESULTS: Complete and interpretable CTP and SPECT scans were obtained for 110 patients. Regadenoson CTP was noninferior to SPECT for detecting or excluding reversible ischemia with an agreement rate of 0.87 (95% confidence interval [CI], 0.77-0.97) and sensitivity and specificity of 0.90 (95% CI, 0.71-1.00) and 0.84 (95% CI, 0.77-0.91), respectively. The agreement rate for detecting or excluding ≥ 1 fixed defects by regadenoson CTP and SPECT was 0.86 (95% CI, 0.74-0.98). With SPECT as the reference standard, the diagnostic accuracies for detecting or excluding ischemia by regadenoson CTP and CTA alone were 0.85 (95% CI, 0.78-0.91) and 0.69 (95% CI, 0.60-0.77), respectively. CONCLUSIONS: This study establishes the noninferiority of regadenoson CTP to SPECT for detecting or excluding myocardial ischemia.

Regadenoson-stress myocardial CT perfusion and single-photon emission CT: rationale, design, and acquisition methods of a prospective, multicenter, multivendor comparison.

Pharmacologic stress myocardial CT perfusion (CTP) has been reported to be a viable imaging modality for detection of myocardial ischemia compared with single-photon emission CT (SPECT) in several single-center studies. However, regadenoson-stress CTP has not previously been compared with SPECT in a multicenter, multivendor study. The rationale and design of a phase 2, randomized, cross-over study of regadenoson-stress myocardial perfusion imaging by CTP compared with SPECT are described herein. The study will be conducted at approximately 25 sites by using 6 different CT scanner models, including 64-, 128-, 256-, and 320-slice systems. Subjects with known/suspected coronary artery disease will be randomly assigned to 1 of 2 imaging procedure sequences; rest and regadenoson-stress SPECT on day 1, then regadenoson-stress CTP and rest CTP/coronary CT angiography (same acquisition) on day 2; or regadenoson-stress CTP and rest CTP/CT angiography on day 1, then rest and regadenoson-stress SPECT on day 2. The prespecified primary analysis examines the agreement rate between CTP and SPECT for detecting or excluding ischemia (≥2 or 0-1 reversible defects, respectively), as assessed by 3 independent blinded readers for each modality. Non-inferiority will be indicated if the lower boundary of the 95% CI for the agreement rate is within 0.15 of 0.78 (the observed agreement rate in the regadenoson pivotal trials). The protocol described herein will support the first evaluation of regadenoson-stress CTP by using multiple scanner types compared with SPECT.