Patient- and clinician-reported satisfaction with pharmacological stress agents for single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI)

Abstract

Objective:

The objective of this study was to compare clinician and patient measures of satisfaction with two pharmacological stress agents (PSA), regadenoson and dipyridamole, used in Single Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging (MPI).

Methods:

This observational study included patients who had undergone SPECT MPI with regadenoson or dipyridamole, as well as the clinician/clinical technologist who performed the test. Mean scores for individual item and domain scores of the main outcome measures were computed as well as the effect sizes (ES) of the mean difference in scores between treatment groups. Statistical significance of the mean item and domain score differences were assessed via Mann-Whitney tests.

Main outcomes measures:

Two self-report questionnaires which had beeb previously developed and validated: Patient Satisfaction/Preference Questionnaire (PSPQ) and Clinician Satisfaction/Preference Questionnaire (CSPQ).

Results:

A total of 87 patients (68 received regadenoson, 19 received dipyridamole) and nine clinicians/clinical technologists took part in the study. Patients had a mean age of 66.8 ± 12.2 years, and 56.3% were male. Compared to dipyridamole, use of regadenoson was associated with greater clinician satisfaction on all items and domains of the CSPQ (p < 0.001 for all comparisons). Among patients, regadenoson was associated with less bother and greater satisfaction than dipyridamole for all items on the PSPQ. These patients reported less stinging at the injection site (ES = −0.66) and less nervousness during injection (ES = −0.60). The PSPQ found that regadenoson patients were more satisfied with their PSA than dipyridamole patients in all areas.

Limitations:

This study utilized a relatively small sample size of dipyridamole patients and lacked an adenosine group. A broader sampling of professionals would also help demonstrate generalizability.

Conclusion:

Both patients and clinicians reported higher satisfaction with regadenoson compared to dipyridamole for SPECT-MPI. Clinicians were particularly satisfied with the preparation and administration aspects of the drug, while patients rated it highly on convenience and reduced incidence of side-effects.

Keywords::

• Single-photon emission computer-assisted tomography
• Myocardial perfusion imaging
• Patient satisfaction
• Patient preference
• Side-effects
• Regadenoson
• Dipyridamole
• Clinician satisfaction
• Pharmacologic stress agent

Introduction

Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) stress testing is used to diagnose and monitor coronary artery disease (CAD). Dynamic exercise is the preferred method for inducing cardiac stress, as it provides information about ‘exercise tolerance, hemodynamic response, heart rate recovery, and electrocardiographic changes’1, but it requires that patients achieve at least 85% of age-adjusted maximal predicted heart rate and five metabolic equivalents2. The use of pharmacologic stress agents (PSA) is an alternative for patients who have reduced mobility or tolerability for exercise-induced stress testing. In the US, vasodilator PSA accounts for 40–50% of all stress MPI studies performed3. PSAs have the advantages of speed, reliability, and reproducibility; but patients must abstain from caffeinated beverages for at least 12 h before PSA administration, and the test itself is time-consuming.

Currently, there are three primary vasodilator PSAs available in the US: dipyridamole, adenosine, and regadenoson, which was approved by the Food and Drug Administration (FDA) in 2008. A secondary PSA, dobutamine, is also used off-label, primarily in patients with contraindications to the three primary PSAs2. Despite demonstrated safety, adenosine and dipyridamole require continuous, weight-based infusion over 4–6 min2,4. The selective A_2A agonist, regadenoson, has been shown to be well-tolerated with generally mild side-effects (e.g., chest discomfort, flushing, dyspnea) that are transient. Regadenoson is administered in a single rapid infusion (10 s), without the need for an infusion pump or weight-based dosing. Unlike adenosine or dipyridamole, regadenoson is not contraindicated in bronchoconstrictive or bronchospastic lung disease (e.g., asthma, chronic obstructive pulmonary disease)5. Further, among patients with body mass indices greater than 25 kg/m², Reyes et al.6 found that regadenoson may be better tolerated than adenosine.

Despite the above-mentioned characteristics of regadenoson, there is little research available to address the patient and provider experiences and preferences for PSA use in MPI. To address this gap, two self-report measures were previously developed and validated to understand the impact of MPI pharmacological stress testing: the Patient Satisfaction and Preference Questionnaire (PSPQ) (8-items); and the Clinician Satisfaction and Preference Questionnaire (CSPQ) (8-items)7. The questionnaires measure satisfaction with and preference for pharmacological stress agents used in the SPECT MPI procedure from the perspective of the patients and the nuclear cardiologists or nuclear technologists, thereafter referred to as ‘clinicians’. The content validity of the questionnaires (i.e., its ability to capture concepts that are important and comprehensive for the respondent) was ensured by respondents’ participation in the item generation and item modification phases7,8.

The objectives of this study were to: (1) evaluate the univariate distribution of items and domain scores of the two questionnaires (clinician and patient); and (2) explore whether differences in preference and satisfaction exist between patients who receive either regadenoson or dipyridamole, as well as clinicians who administered the agents.

Patients and methods

This 12-month, non-interventional, observational study recruited 90 patients (in- and outpatient), between the ages of 31–95, who underwent SPECT MPI with a PSA. The study included 13 cardiologists or clinical technologists who administered or aided in PSA administration. To be eligible for the study, patients had to be referred for a pharmacological stress SPECT MPI; at least 18 years old; and fluent in US English. Patients were excluded if they had been hospitalized for any reason within the past 6 weeks, or if they had a significant physical or mental illness that would prevent completing the questionnaire. Eligible clinicians had at least 2 years’ experience performing, aiding, or monitoring pharmacological stress for SPECT MPI, were fluent in US English, and were affiliated with a medical facility that reported use of more than one PSA. The study was approved by a central institutional review board (Copernicus IRB) prior to any recruitment procedures, and all patients gave written informed consent prior to enrollment.

Patients were recruited by nuclear cardiologists/technologists at the time of their scheduled visit for the SPECT MPI procedure. The PSPQ was completed by patients following their SPECT MPI procedure with a PSA. The CSPQ was completed by nuclear cardiologists and/or technologists for each of their study patients the same day that they administered a PSA to the patient.

Instruments

The PSPQ is a Patient Reported Outcomes (PRO) instrument containing eight items (Figure 1). It assesses convenience of and preference for PSAs used in SPECT MPI. It contains three items addressing ‘bother’ associated with preparing for the procedure (i.e., the need to fast, and to avoid caffeine or medication), two items assessing discomfort with the procedure itself (stinging and nervousness during the injection), and three items about satisfaction with the procedure (length of time, side-effects, and overall experience). The scales for the satisfaction items on the PSPQ range from −5 to 5, with higher scores representing greater satisfaction. The scales for items related to preparation and reaction to agent range from 0–10, with higher scores indicating greater levels of bother or discomfort. Scoring of the PSPQ divides the items into the following four domains: Preparation, Reaction to Agent (i.e., nervousness, stinging at the injection site), Administration, and Side Effects. Previous results have found the test–re-test reliability for each domain was ≥0.70, with intra-class correlation coefficients (ICCs) ranging from 0.73–0.86 7.

Figure 1. Patient satisfaction/preference questionnaire.

The CSPQ is a Clinician Reported Outcomes (CRO) instrument measuring clinicians’ satisfaction with and preference for PSAs used for SPECT MPI (Figure 2). It contains eight items assessing the clinician’s satisfaction with administering a PSA and includes the following domains: Preparation, Administration, Monitoring, Side Effects, and Image Quality. Each item scale ranges from −5 to 5, with higher scores representing greater satisfaction. The CSPQ and its domains have been shown to demonstrate strong internal consistency (α > 0.90)7.

Figure 2. Clinician satisfaction/preference questionnaire.

Analyses

Univariate descriptive analyses of the PSPQ and CSPQ were obtained and stratified by PSA (regadenoson or dipyridamole). Continuous variables were described presenting the frequency, mean, standard deviation (SD), median, minimum, maximum, and amount of missing data. The mean differences in PSPQ and CSPQ total and domain scores between the two PSAs were tested at a significance level of α = 0.05. In addition, effect sizes (ES) for these comparisons were calculated as the difference in group means divided by the pooled standard deviation of the two groups.

Results

The PSPQ and CSPQ questionnaires were completed by 90 patients and nine clinicians. Two patients who had missing data were excluded from the analysis along with the one patient who received adenosine, giving a final sample size of 87 patients. Sixty-eight patients received regadenoson (78.2%); 19 received dipyridamole (21.8%). The average age of patients was 66.8 (SD = 12.2 years old) and 56.3% of patients were male (Table 1).

Table 1. Demographic characteristics of patient population, by PSA group.

	Regadenoson (n = 68)	Dipyridamole (n = 19)	Total (n = 87)
	n (%)	n (%)	n (%)
Age (years)
Mean ± SD	66.3 ± 12.1	75.0 ± 10.8	66.8 ± 12.2
Median	67.0	77.5	67.0
Range	31–95	60–85	31–95
Missing/No response	0	15 (78.9%)	15 (17.2%)
Sex
Female	26 (38.2)	11 (57.9)	37 (42.5)
Male	41 (60.3)	8 (42.1)	49 (56.3)
Missing/No response	1 (1.5)	0 (0.0)	1 (1.1)
Highest level of education
Some high school	10 (14.7)	6 (31.6)	16 (18.4)
High school diploma/GED	15 (22.1)	5 (26.3)	20 (23.0)
Some college	16 (23.5)	5 (26.3)	21 (24.1)
Certificate program	3 (4.4)	0 (0.0)	3 (3.4)
College/university degree	14 (20.6)	1 (5.3)	15 (17.2)
Graduate/professional degree	9 (13.2)	1 (5.3)	10 (11.5)
Other	1 (1.5)	1 (5.3)	2 (2.3)
Employment status
Working full- or part-time	21 (30.9)	3 (15.8)	24 (27.6)
Full- or part-time homemaker	7 (10.3)	1 (5.3)	8 (9.2)
Unemployed	3 (4.4)	4 (21.1)	7 (8.0)
Retired	35 (51.5)	11 (57.9)	46 (52.9)
Other	2 (2.9)	0 (0.0)	2 (2.3)
Living situation
Alone	19 (27.9)	8 (42.1)	27 (31.0)
With a significant other (SO)/spouse	32 (47.1)	4 (21.1)	36 (41.4)
With children	5 (7.4)	0 (0.0)	5 (5.7)
With both SO and children	9 (13.2)	4 (21.1)	13 (14.9)
With relative (other than SO/children)	2 (2.9)	2 (10.5)	4 (4.6)
With friends	1 (1.5)	1 (5.3)	2 (2.3)

PSPQ

Regadenoson was associated with lower ‘bother’ scores on the PSPQ than dipyridamole (Table 2). Regadenoson was also associated with higher satisfaction scores on all domains of the PSPQ (Convenience, Effectiveness, Global Satisfaction, Side Effects) than dipyridamole. Across the PSPQ items and domains, effect size estimates were very high for the mean differences between regadenoson and dipyridamole, as the majority of patients answered ‘extremely satisfied’ for most questions. Apart from item 1 (‘bothered to avoid caffeine’), all mean differences were not significant at the p < 0.05 threshold.

Table 2. PSPQ item and domain results, by PSA group.

	Descriptive statistics, Mean ± SD (Range), Missing		Between-group comparison,
	Regadenoson (n = 68)	Dipyridamole (n = 19)	Absolute effect size (d), p-value
Avoid caffeine	0.59 ± 1.53 (0–7), 2	3.26 ± 4.72 (0–10), 0	1.03, p = 0.0289
Avoid eating	0.82 ± 1.80 (0–10), 0	2.26 ± 4.00 (0–10), 0	0.592, p > 0.5
Avoid medication	0.80 ± 1.81 (0–7), 8	3.26 ± 4.53 (0–10), 0	0.911, p > 0.5
Stinging at injection site	0.88 ± 1.77 (0–10), 0	2.37 ± 3.47 (0–10), 0	0.663, p > 0.5
Nervousness while receiving injection	1.59 ± 2.41 (0–10), 0	3.32 ± 4.22 (0–10), 0	0.598, p > 0.5
Length of time for injection to be administered	3.91 ± 2.29 (−5–5), 2	2.53 ± 3.58 (−5–5), 0	0.527, p > 0.5
Satisfaction with injection side effects	2.86 ± 2.48 (−3–5), 3	2.37 ± 3.70 (−5–5), 0	0.176, p > 0.5
Overall satisfaction	3.43 ± 2.11 (−2–5), 1	2.95 ± 3.31 (−5–5), 0	0.201, p > 0.5
Sub-scale: Preparation domain	0.66 ± 1.16 (0–5), 8	2.93 ± 4.23 (0–10), 0	0.993, p > 0.5
Sub-scale: Reaction to agent domain	1.24 ± 1.89 (0–10), 0	2.84 ± 3.70 (0–9.5), 0	0.672, p > 0.5

CSPQ

Regadenoson was associated with higher satisfaction scores on the CSPQ than dipyridamole (Table 3). All items and domains of the CSPQ showed significant (p < 0.001) differences between regadenoson and dipyridamole.

Table 3. CSPQ item and domain results, by PSA group.

	Descriptive statistics, Mean ± SD (Range), Missing		Between-group comparison,
	Regadenoson (n = 68)	Dipyridamole (n = 19)	Absolute effect size (d), p-value
Time required to prepare agent	5.00 ± 0.00 (5–5), 0	−0.32 ± 1.42 (−5–2), 0	8.16, p < 0.001
Ease of preparing agent	5.00 ± 0.00 (5–5), 0	−0.84 ± 1.46 (−5–2), 0	8.68, p < 0.001
Time required to administer agent	5.00 ± 0.00 (5–5), 0	−1.42 ± 1.17 (−5–0), 0	11.9, p < 0.0001
Ease of administering agent	4.99 ± 0.12 (4–5), 0	−1.68 ± 1.45 (−5–1), 0	9.83, p < 0.0001
Time required to monitor patient	5.00 ± 0.00 (5–5), 0	−1.63 ± 1.95 (−5–2), 0	7.39, p < 0.0001
Side-effects	4.63 ± 1.30 (−2–5), 0	−2.53 ± 1.74 (−5–3), 0	5.08, p < 0.0001
Image quality/accuracy	4.31 ± 1.73 (0–5), 0	3.37 ± 0.90 (2–5), 0	0.599, p < 0.0001
Overall satisfaction	4.90 ± 0.85 (−2–5), 0	1.58 ± 2.04 (−2–4), 0	2.76, p < 0.0001
Sub-scale: Preparation domain	5.00 ± 0.00 (5–5), 0	−0.58 ± 1.36 (−5–2), 0	8.94, p < 0.0001
Sub-scale: Administration domain	4.99 ± 0.06 (4.5–5), 0	−1.55 ± 1.25 (−5–0.5), 0	11.4, p < 0.0001

Discussion

Patient and clinician satisfaction has an impact on treatment preference in many clinical settings, particularly when the treatment induces, or is correlated to, a stressful outcome or situation. Regadenoson was developed as a short acting PSA with the potential to selectively increase coronary blood flow while minimizing some of the side-effects due to its selectivity for the A2A adenosine receptor9. Regadenoson presented a favorable safety profile in a Phase IV study that evaluated 999 subjects with stable asthma (n = 532) or cardiac obstructive pulmonary disease (COPD; n = 467). Dyspnea was one of the most common adverse events reported among subjects with asthma (10.7%) and COPD (18.0%). However, for both patient groups, a short-acting bronchodilator (SABA) was used at the time of an adverse event in less than 1% of subjects10.

The present study found that regadenoson was associated with lower ‘bother’ scores on the PSPQ than dipyridamole, and higher satisfaction scores on all domains of the PSPQ. Across the PSPQ items and domains, effect size estimates were very high for the mean differences between regadenoson and dipyridamole. Among clinicians, regadenoson was associated with higher satisfaction scores than was dipyridamole, and all items and domains of the CSPQ differed significantly between the regadenoson and dipyridamole groups.

Results of this study are consistent with those reported in a large multi-center, double-blinded phase 3 trial (n = 784) in which patients received an MPI test with adenosine that was randomly followed by a test with either adenosine (again) or regadenoson. A summed symptom score of side-effects (flushing, chest pain, and dyspnea) was found to be lower with regadenoson than adenosine (p < 0.013), while the degree of diagnostic information provided by both methods was comparable11. This study also administered a questionnaire that asked how the patients felt after each test, and about how the second (randomized) test compared to the first (adenosine) test. The researchers found that patients favored regadenoson over adenosine in both cases.

The advantages of regadenoson in the clinical setting include its efficiency and relatively simple protocol for use, as the agent has a rapid onset of action, is administered as a weight-unadjusted fixed dose even in patients with renal insufficiency (excluding those on dialysis), a short duration of action, and any side-effects can be quickly reversed by aminophylline, if necessary12. Because of the fixed dosing, the pharmacologic stress testing procedure is faster and simpler with regadenoson compared to other agents, is less likely to result in dose calculation errors, and doesn’t require the resources or materials needed for constant infusion3. From the patient perspective, studies have shown regadenoson is better tolerated and has fewer side-effects, such as discomfort, compared to adenosine6.

Limitations of this study include the relatively small sample size of patients administered dipyridamole and the lack of an adenosine group, which would be a worthwhile comparison. Further, only nine clinicians or clinical technologists were surveyed in this study, three of whom accounted for almost three-quarters of all completed CSPQs. A broader sampling of professionals would help demonstrate generalizability of these findings. On the other hand, the patient population reflected a diverse clinical and demographic profile: approximately half the sample (n = 42) had previously undergone an MPI procedure; just over half were male and the sample ranged in age from young adulthood to elderly, with representation across a number of educational and employment strata.

Conclusions

This observational study provides research addressing the patient and provider experiences and preferences for PSA use in MPI, and included both patients with past MPIs and those who were undergoing the procedure for the first time. Using two self-report measures that were previously developed and validated, both patients and clinicians reported higher satisfaction with regadenoson compared to dipyridamole for SPECT-MPI. The domains of Preparation and Administration of agent are key considerations for physician support, and the results of this analysis show large differences favoring regadenoson. However, due to the small sample size of this study, a larger scale, multi-site, observational study should be conducted, with larger numbers of both patients and clinicians, as well as representation of all three primary vasodilator PSAs available in the US: dipyridamole, adenosine, and regadenoson.

Transparency

Declaration of funding

This study was funded by Astellas Scientific and Medical Affairs, Inc.

Declaration of financial/other relationships

James Spalding has disclosed that he is an employee of Astellas Scientific and Medical Affairs, Inc. Stacie Hudgens and Janis Breeze have disclosed that they are employees of Adelphi Values, a company that received funding from Astellas Scientific and Medical Affairs, Inc. to assist with the data analysis and writing of this manuscript. JME Peer Reviewers on this manuscript have no relevant financial relationships to disclose.