Title: Is Metomidate PET CT superior to Adrenal venous sampling in predicting ouTCome from adrenalectomy in patients with primary Hyperaldosteronism (MATCH): a multi-centre, randomised, within-patient comparison of diagnostic techniques
Funder: Department of Health and Social Care

Abstract: Background Hypertension is a major risk factor for heart attacks and stroke. Primary hyperaldosteronism (PHA) is reported in ~10% of patients, and in 20-25% of patients with treatment resistant hypertension. In ~50% of PHA, it is caused by an aldosterone-producing adenoma (APA) in one adrenal gland, and surgery (adrenalectomy) offers a potential cure. However, <1/10 of eligible patients are diagnosed and proceed to surgery. One of the main barriers is the difficulty of proving that only one adrenal gland is the culprit. On diagnostic CT or MRI, smaller (<1 cm) adenomas may be overlooked, while conversely incidental adenomas occur in 4% of the population. Hence, guidelines recommend that most PHA patients should undergo adrenal venous sampling (AVS) if being considered for surgery. This invasive procedure is time-consuming, technically demanding and fails in 20-50% of cases. In a previous, non-randomised proof-of-concept study we found that a non-invasive alternative to AVS, 11C-metomidate PET CT, is comparable to AVS in distinguishing unilateral from bilateral PHA. If PET CT is shown in a multi-centre, randomised study to be superior to AVS, this together with greater patient preference and convenience would improve access to diagnosis, and encourage doctors to look for PHA in many more patients. Hypotheses: Our primary hypothesis is that 11C-metomidate PET CT is superior to AVS in the diagnosis of unilateral PHA. Our secondary hypothesis is that we can recognise patients in whom there is a high likelihood that hypertension, in addition to PHA will be completely cured. This is particularly important for older patients, in whom cure is currently achieved in only 50% of cases. Population The patients are those with a diagnosis of PHA, who are eligible and willing to proceed to adrenalectomy if found to have a unilateral cause of PHA. Design of study and interventions The study is a multi-centre within-patient comparison of the diagnostic accuracy of AVS and 11C-metomidate PET CT, performed in random order. Patients will be offered surgery if one or both techniques indicate unilateral disease. Outcomes and assessments The hierarchical co-primary outcomes are the proportion of patients achieving (a) cure of PHA (= normalisation of plasma renin and aldosterone), and (b) improved BP control (= home BP at least 10% lower at 6 months after adrenalectomy than prior to treatment with an aldosterone antagonist). Secondary outcomes are the proportion of patients with complete cure of hypertension, and whether this is predicted by either the BP response to spironolactone, the PET CT analyses, or pathological and molecular diagnoses of the post-surgical sample. Correlation between pre- and post- operative findings will improve future selection of patients for surgery. Sample size/recruitment rate Recruitment of 140 patients across 6 centres over 3 years (<1/centre/month), with an estimated 70 proceeding to adrenalectomy, permits 90% power at alpha=0.01 of detecting superiority of PET CT over AVS. Statistical analysis will compare the accuracy of AVS and PET CT. Economic benefit For a modest investment, if shown to be superior to AVS, then PET CT (priced equivalently to AVS in most centres) has the potential to increase at least 5-fold the numbers of patients being cured of hypertension per year, with major health and economic benefits in terms of reduction in the risk of heart attack and stroke in PHA patients.

Lay abstract: Hypertension (high blood pressure) is a major risk factor for stroke, heart attack, and kidney disease. Approximately 16 million people in the UK have hypertension and over 60,000 preventable deaths per year from stroke and heart attack are attributable to inadequate blood pressure control. Most cases of hypertension have no identifiable cause. But in some patients an underlying condition can be found. One important cause of hypertension is Conn’s syndrome in which the adrenal glands (on top of the kidneys) produce too much of the hormone, aldosterone. This hormone causes the body to retain salt, leading to the development of hypertension. Conn’s syndrome carries an even higher risk of stroke or heart attack than other forms of hypertension. It is diagnosed by measuring the hormone, aldosterone, in a blood sample. In at least half of patients with Conn’s syndrome, the condition is due to a benign nodule in one of the adrenal glands. The discovery and removal of these nodules often allows the hypertension to be cured, so avoiding the life-long need to take drugs. However the current diagnostic test for such a nodule, which involves obtaining blood from both adrenal glands, is difficult and demanding. We therefore developed a special type of CT scan, in which an adrenal nodule lights up, if present. We now wish to find out, in 140 patients with Conn’s syndrome, whether this new adrenal scan (which is quick and painless) is more accurate than the existing test for diagnosing adrenal nodules. If our study, called MATCH, proves that the scan is reliable and easy to perform, we expect that doctors will be encouraged to look for Conn’s syndrome before it has caused difficult-to-treat hypertension. The earlier an adrenal nodule is diagnosed and removed, the higher the likelihood that hypertension will be completely cured.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE