Intravenous Regadenoson Research Articles

Resting coronary flow drives the daily pattern in coronary flow reserve in patients with chest pain without obstructive epicardial stenosis.

Ischemia with no obstructive coronary artery disease (INOCA) is a risk factor for major adverse cardiovascular events and is characterized by abnormal coronary microvascular tone. In patients with INOCA, adverse cardiovascular events most commonly occur in the morning compared to other times of the day and night. We tested whether coronary microvascular function varies diurnally with attenuation in the morning in patients with symptomatic coronary artery disease without significant (>50%) epicardial stenosis. We evaluated data from 17 patients studied in the AM (700-1159 h) and 11 patients in the PM (1200-1800 h). Coronary microvascular function was measured using perfusion contrast imaging at rest and after infusion of intravenous regadenoson. We calculated microvascular flow reserve as the ratio of hyperemic to resting flow. Along with independent sample t-tests, we performed bootstrapping procedures to test mean differences between AM and PM groups, using the bias-corrected and accelerated method with 5,000 bootstrapped samples. The AM and PM groups were matched for demographic and existing risk factors. Coronary microvascular flow reserve was ∼33% higher in the AM compared to the PM (P = 0.025, BCa 95% CI [0.25, 1.64]; Hedge's g = 0.89, 95% CI [0.11, 1.66]) as a result of significantly lower resting flow (∼50%) in the AM compared to the PM (P = 0.03, M Diff = -56.65, BCa 95% CI [-118.59, -2.12]; Hedge's g = -0.86, 95% CI [-1.60, -0.06]). Our observations are of clinical value and can influence diagnosis and treatment in the clinic based on the time of day of measurements.

Role of sex hormones in modulating myocardial perfusion and coronary flow reserve

BackgroundA growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR.MethodsRest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [18F]flurpiridaz in a total of 56 mice (7–8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [18F]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging.ResultsOrchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 ± 1.0 vs. 22.2 ± 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 ± 1.2 vs. 27.3 ± 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 ± 0.04 vs. 1.23 ± 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = −0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females.ConclusionOur experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.

Intravenous regadenoson versus intracoronary adenosine for fractional flow reserve measurement

Intravenous regadenoson versus intracoronary adenosine for fractional flow reserve measurement

Fractional flow reserve: Comparing intravenous regadenoson and intravenous adenodsine

Background and Aims: Creating an environment of maximal hyperemia is required for adequate fractional flow reserve (FFR) measurements and ultimately an effective percutaneous intervention. Currently the gold standard method is via intravenous adenosine, but it has side effects through it non-selective activation of adenosine receptors. Intravenous regadenoson has been proposed as a safe alternative, but a recent trial used regadenoson with aminophylline. The goal of this meta-analysis is to compare the previous four studies with this newly designed trial.

Feasibility, safety and effectiveness in measuring microvascular resistance with regadenoson.

AIMThe study aims to test whether simultaneous measurement of fractional flow reserve (FFR), coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) is feasible, safe and effective during regadenoson-induced hyperemia.METHODS AND RESULTSFFR, CFR and IMR were measured simultaneously during regadenoson (Rapiscan 400 μg) -induced hyperemia in 50 patients with stable coronary artery disease with a SYNTAX score of <22. Simultaneous measurement of FFR, CFR and IMR was technically feasible in all cases (50/50). No side effects occurred and even patients fulfilling classical contraindications for the use of adenosine (10/50) could be included. Regadenoson-induced hyperemia remained stable after maximal pressure drop for more than 35 sec as measured by systemic aortic and distal coronary pressure. There was a significant drop in transit mean time from baseline to hyperemia of more than 50% (1.0 ± 0.6 s vs. 0.4 ± 0.2 s, p < 0.01). Patients' mean IMR value was 23.4, and IMR values above 75th percentile significantly correlated with metformin demanding diabetes mellitus with OR 21.76 and nicotine abuse with OR 10.28.CONCLUSIONA single intravenous regadenoson bolus via peripheral line increases coronary blood flow without harmful systemic side effects enabling interventionists to simultaneously assess FFR, CFR and IMR in patients with stable coronary artery disease.

Comparison of regadenoson and nitroprusside to adenosine for measurement of fractional flow reserve: A systematic review and meta-analysis.

FFR is useful in defining the physiological significance of intermediate coronary stenosis and requires induction of maximal hyperemia and measurement of pressure proximal and distal to the stenosis. Hyperemia normally is induced by either IV or IC adenosine, a medication associated with short-term side effects. IV regadenoson and IC nitroprusside have been suggested as viable alternatives. This meta-analysis aims to identify all studies comparing use of intravenous (IV) regadenoson or intracoronary (IC) nitroprusside with IV adenosine to determine differences related to the agent utilized for assessment of fractional flow reserve (FFR). We searched PubMed, EMBASE, Web of Science, SCOPUS, ClinicalTrials.gov and the Cochrane Library databases for studies comparing IV regadenoson or IC nitroprusside to IV adenosine for FFR assessment. The main outcome was difference in mean FFR measurement. The main secondary outcomes were composite side-effect profile and reclassification of lesions. Seven studies were included in the analysis, with a total of 375 patients. Compared to IV adenosine, there was no difference in the mean FFR derived from IV regadenoson (p=1.0) or IC nitroprusside (p=0.48). IV regadenoson was associated with 53% lower risk of pooled side effects compared to IV adenosine (p=0.05). IC nitroprusside was associated with 97% lower risk of pooled side effects compared to IV adenosine (p<0.001). IV regadenoson and IC nitroprusside produce similar pressure-derived FFR measurements compared to IV adenosine and have a favorable side effect profile. Both can be considered as alternative agents to IV adenosine for FFR measurement. Further clinical validation is warranted.

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

BackgroundRegadenoson 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 ResultsHealthy 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. ConclusionRepeated doses of regadenoson appeared to be safe and well tolerated in healthy subjects.

Quantitation of left ventricular ejection fraction reserve from early gated regadenoson stress Tc-99m high-efficiency SPECT

BackgroundEjection fraction (EF) reserve has been found to be a useful adjunct for identifying high risk coronary artery disease in cardiac positron emission tomography (PET). We aimed to evaluate EF reserve obtained from technetium-99m sestamibi (Tc-99m) high-efficiency (HE) SPECT. MethodsFifty patients (mean age 69 years) undergoing regadenoson same-day rest (8-11 mCi)/stress (32-42 mCi) Tc-99m gated HE SPECT were enrolled. Stress imaging was started 1 minute after sequential intravenous regadenoson .4 mg and Tc-99m injections, and was composed of five 2 minutes supine gated acquisitions followed by two 4 minutes supine and upright images. Ischemic total perfusion deficit (ITPD) ≥5 % was considered as significant ischemia. ResultsSignificantly lower mean EF reserve was obtained in the 5th and 9th minute after regadenoson bolus in patients with significant ischemia vs patients without (5th minute: −4.2 ± 4.6% vs 1.3 ± 6.6%, P = .006; 9th minute: −2.7 ± 4.8% vs 2.0 ± 6.6%, P = .03). ConclusionsNegative EF reserve obtained between 5th and 9th minutes of regadenoson stress demonstrated best concordance with significant ischemia and may be a promising tool for detection of transient ischemic functional changes with Tc-99m HE-SPECT.

The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.

The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P < 0.05). A similar trend was noted in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). Brain concentrations and brain:plasma ratios were not significantly different 360 min after temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

TR-09 * THE EFFECT OF REGADENOSON-INDUCED TRANSIENT DISRUPTION OF THE BLOOD BRAIN BARRIER ON TEMOZOLOMIDE DELIVERY TO RAT BRAIN PARENCHYMA

PURPOSE: The blood-brain barrier (BBB) poses a serious challenge to effective delivery of systemically administered agents to the central nervous system. Temozolomide is the only systemically delivered chemotherapeutic agent to significantly improve survival in patients with glioblastoma. Brain temozolomide concentrations are only 20% of that in blood. Regadenoson is an FDA approved adenosine receptor agonist that transiently disrupts rodent's BBB allowing dextran (70 kD) brain entry. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brains. METHODS: Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing female F344 rats. Sixty to 90 minutes later two-thirds of the animals received a single dose of intravenous regadenoson. The animals were sacrificed 120 or 360 minutes after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. RESULTS: At 120 minutes, brain temozolomide concentrations were significantly higher when given with regadenoson vs. alone (8.1 ± 2.7 µg/g and 5.1 ± 3.5 µg/g, P < 0.05), with a similar trend in brain:plasma ratios (0.45 ± 0.08 and 0.29 ± 0.09, P < 0.05). 360 minutes after temozolomide administration brain and brain:plasma were increased without statistical significance. There was no difference in plasma temozolomide concentration with or without regadenoson. CONCLUSION: These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without changing plasma temozolomide concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents can potentially improve the efficacy of therapeutic agents used in patients with brain tumors and other neurologic disorders.

Abstract 17138: Intravenous Regadenoson with Aminophylline Reversal is Safe and Equivalent to Intracoronary Adenosine Infusion for Fractional Flow Reserve Measurements

Background: Small studies have shown that Adenosine is equivalent to Regadenoson when obtaining Fractional Flow Reserve (FFR) measurements. A larger study that also evaluates time and safety of aminophylline reversal was yet to be presented. Methods: After IRB approved consent was obtained, 46 consecutive patients with clinically indicated FFRs were enrolled between 4/2012 and 5/2014. Each patient had FFR measured with adenosine 140 mcg/kg/min IV then allowed to return to baseline. FFR was repeated with Regadenoson 140 mcg IV bolus than reversed with aminophylline 150 mg IV and time to baseline hemodynamics were measured. Tests were compared using linear regression. Reversal time recorded in seconds. Results: As demonstrated in Figure1 FFR results were similar with both agents, R2 = 0.935, p&lt;0.0001. Also, using the 0.80 cutoff, there was no divergence regarding studies significance. After aminophylline, hemodynamics returned to baseline in 112+/- 72 secs. There were no side-effects reported. Conclusion: The use of regadenoson for FFR measurements provides results consistent with the ones obtained with adenosine infusion. Aminophilline reversal for regadenoson was fast, well tolerated and safe. Regadenoson with aminophylline reversal may be considered as an alternative for FFR measurements.

Comparison of intravenous adenosine and intravenous regadenoson for the measurement of pressure-derived coronary fractional flow reserve

Defining the clinical and physiologic significance of an intermediate coronary artery stenosis is aided by measurement of fractional flow reserve (FFR). Adenosine is the most common agent used in the cardiac catheterisation laboratory for the measurement of FFR. Regadenoson, a selective adenosine receptor agonist, with fewer side effects than adenosine has been used extensively in stress testing to induce hyperaemia. We postulated that FFR measurements would be equivalent following administration of regadenoson and adenosine. Twenty patients with an angiographic intermediate coronary artery stenosis (50% to 80%) were included in the study. FFR was measured during three minutes of intravenous (IV) adenosine infusion and for five minutes after an injection of regadenoson. The mean difference between the FFR measured by IV adenosine and IV regadenoson was 0.0040 (min -0.04, max +0.04, standard deviation [SD] 0.025). There was a strong linear correlation between the FFR measured by IV adenosine and IV regadenoson (R2 linear=0.933). The FFR at maximum hyperaemia was achieved earlier using regadenoson than adenosine (59±24.5 sec vs. 93±44.5 sec, p=0.01). Regadenoson produces similar pressure-derived FFR compared to IV adenosine infusion.