Xofigo

Pharmacotherapeutic group: diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticals for the cardiovascular system, ATC code: V09GX04 Mechanism of action Rubidium-82 (Rb-82) is analogous to potassium ion (K+) in its biochemical behaviour and is rapidly extracted by the myocardium proportional to the blood flow.‍‍‍‍‍‍​​​‍​​​​​​ Rb-82 participates in the sodium-potassium (Na+/K+) ion exchange pumps that are present in cell membranes. The intracellular uptake of Rb-82 requires maintenance of an ionic gradient across cell membranes. Rb-82 radioactivity is increased in viable myocardium reflecting intracellular retention, while the tracer is cleared rapidly from necrotic or infarcted tissue. No pharmacological activity has been observed in the dose levels of Rb-82 administered for diagnostic purposes. The use of Cardiogen-82 in medical diagnostics is based on the biodistribution properties of Rb-82. Pharmacodynamic effects At the chemical concentrations and activities recommended for diagnostic examinations, rubidium-82 (Rb-82) chloride does not appear to have any pharmacodynamic activity. In human studies, myocardial activity was noted within the first minute after peripheral intravenous infusion of Rb-82. When areas of infarction or ischaemia are present in the myocardium, these appear as photon-deficient areas within 2-7 minutes after infusion. In patients with reduced cardiac function (LVEF < 50%), it may take longer for the rubidium (Rb-82) to reach and be taken up by the myocardium, and uptake may also be diminished (see section 4.4). As the blood flow carries Rb-82 to all parts of the body during the first circulation, uptake of the tracer is also observed in other tissues such as the kidneys, liver, spleen and lungs. Clinical efficacy and safety Hyafil et al. ( J Nucl Cardiol 2020) conducted a prospective intra-individual comparison in a population of 169 men with BMI ≥ 25 kg/m 2 and 144 women referred for clinically indicated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), and with an intermediate prevalence of coronary artery disease (CAD) pre-test (> 30% with Diamond and Forrester clinical score or > 3 cardiovascular risk factors). Patients were not eligible if they had known CAD or cardiomyopathy, or had undergone coronary angiography (CA) in the previous 2 years. All individuals underwent Rb-82 positron emission tomography (PET) MPI with 3D PET/CT, and 99mTc-sestamibi SPECT MPI with a cadmium-zinc-telluride (CZT) gamma camera, performed within 90 days of each other. Experienced nuclear cardiologists analysed the MPI studies separately, and were blinded to the results of each other's analyses; automated methods were used to obtain summed stress, rest and difference scores. Myocardial blood flow (MBF) and flow reserve (MFR) were quantified on PET using data from dynamic acquisitions. Subjects who were negative for significant CAD on both scans were followed up for 1 year for the development of coronary events. Subjects who were positive for significant CAD on either or both MPI scans underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurements. Positivity on CA was defined as significant stenosis as follows: coronary stenosis ≥ 50% and FFR ≤ 0.8; coronary stenosis ≥ 50% for the left main artery; coronary stenosis ≥ 70% or occlusion for other vessels. In the absence of CA, positivity was defined as an occurrence of an acute coronary event during the following year. Five patients were excluded (uninterpretable scans / inflammatory arteritis) and 14 declined CA or follow-up, leaving 294 patients. Thirty-seven (37) patients had myocardial ischaemia. Overall, Rb-82 PET MPI was found to have a sensitivity of 83.8% and a specificity of 93.8%, while 99mTc-sestamibi SPECT MPI with a modern CZT camera had a sensitivity of 56.8% and a specificity of 96.1%. Receiver operating characteristic (ROC) curve analysis showed Rb-82 PET MPI to possess the highest area under the curve (AUC, 0.94, vs. 0.86 for 99mTc-sestamibi SPECT MPI). It was suggested that the greater sensitivity of Rb-82 PET MPI was due to more accurate detection of balanced myocardial ischemia, potentiated by the ability with PET to obtain myocardial flow and flow reserve data. In a systematic review and meta-analysis of 15 published Rb-82 PET MPI clinical studies including 1,344 patients, and 8 published 99mTc SPECT MPI studies including 1,755 patients (McArdle et al. J Am Coll Cardiol 2012), pooled accuracy using weighted averages according to the size of the patient populations was determined for PET and SPECT. Inclusion criteria were publication in peer-reviewed journals, patient populations with ischemic heart disease, MPI performed with either Rb-82 PET or 99mTc SPECT with both ECG gating and attenuation correction (AC) with either CT or transmission sources, the use of ICA as a reference standard for the diagnosis of obstructive CAD, and diagnostic performance being reported on a per-patient basis. For the PET compared to the SPECT studies, a higher proportion of patients were male (63.5% vs. 55%), with a higher baseline CAD prevalence (63% vs 50%), fewer patients with a low likelihood of CAD (13% vs 30%) and more patients with previous MI (30% vs 3.4%) and prior coronary intervention (32% vs. 3.2%). The overall pooled sensitivity and specificity of Rb-82 PET MPI for the detection of obstructive CAD were 90% (95% CI: 0.88 to 0.92) and 88% (95% CI: 0.85 to 0.91), respectively. Comparison of studies where >50% stenosis on ICA was used as a reference with >70% showed no significant difference in diagnostic accuracy (AUC: 0.948 vs. 0.954, respectively). The overall pooled sensitivity and specificity for 99mTc SPECT MPI with ECG-gating and AC were 85% (95% CI: 0.82 to 0.87) and 85% (95% CI: 0.82 to 0.87), respectively. Subgroup analysis showed that accuracy for a >50% stenosis on ICA was superior to >70% (AUC: 0.91 and 0.87, respectively). Analysis of SPECT studies where patients with known CAD or previous myocardial infarction were excluded did not alter diagnostic accuracy significantly. However, when patients with a low likelihood of CAD were excluded, there was a marked decrease in the specificity of SPECT, to 70% (95% CI: 0.66 to 0.75) with an AUC of 0.86. For PET, when patients with a low likelihood of CAD were excluded, diagnostic accuracy was unchanged (AUC 0.94), with a small decrease in specificity to 86% (95% CI: 0.82 to 0.90).