Updates in Primary Aldosteronism

Transcription

1 Updates in Primary Aldosteronism Meet the Expert: AACE 2018 Anand Vaidya, MD MMSc Director, Center for Adrenal Disorders, Brigham and Women s Hospital Assistant Professor of Medicine, Harvard Medical School

2 Educational Objectives Review the physiology of Primary Aldosteronism What is Primary Aldosteronism? How Common is Primary Aldosteronism? What Causes Primary Aldosteronism? Review how to Diagnose and Localize Primary Aldosteronism When and Who to Screen? How to Confirm the Diagnosis? How to Perform and Interpret Localization Studies? Review evidence to support optimal therapies for Primary Aldosteronism

3 Resources Funder et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment. JCEM 2016 Vaidya et al. An Individualized Approach to the Evaluation and Management of Primary Aldosteronism: Endocrine Practice 2017 Vaidya et al. Genetics of Primary Aldosteronism: Endocrine Practice 2015

4 56yo man presents for evaluation of hypertension CASE 27 years ago: Diagnosed with HTN at age 33 ( BP 170/120 mmhg ) Treated initially with HCTZ. Reported to have K + =3.0 mmol/l on at least one occasion, on others Normal adrenals on MRI Now: BP 145/95 mmhg HCTZ 25mg, Verapamil 240mg ER, Enalapril 20mg, Amiloride 20mg, KCl 10 meq LABS (seated on above meds): Serum aldosterone: 49 ng/dl (high) PRA: 1.7 ng/ml/h (not suppressed) ARR: 29 ng/dl per ng/ml/h Plasma metanephrines: normal 1 mg DST: 0.9 mcg/dl

5 Question Which of the following is the most appropriate interpretation of the labs? A.Conclude that this is a positive screen for PA B.Conclude that this is a negative screen for PA C.Conclude that testing cannot be interpreted: stop enalapril for 2-4 weeks and repeat ARR D.Conclude that testing cannot be interpreted: stop HCTZ for 2-4 weeks and repeat ARR E.Conclude that testing cannot be interpreted: stop amiloride for 2-4 weeks and repeat ARR F.Conclude that testing cannot be interpreted: stop verapamil for 2-4 weeks and repeat ARR

6 Question Which of the following is the most appropriate interpretation of the labs? A.Conclude that this is a positive screen for PA B.Conclude that this is a negative screen for PA C.Conclude that testing cannot be interpreted: stop enalapril for 2-4 weeks and repeat ARR D.Conclude that testing cannot be interpreted: stop HCTZ for 2-4 weeks and repeat ARR E.Conclude that testing cannot be interpreted: stop amiloride for 2-4 weeks and repeat ARR F.Conclude that testing cannot be interpreted: stop verapamil for 2-4 weeks and repeat ARR

7 CASE He stopped his amiloride for 2.5 weeks. During this time doxazosin 4mg BID was added to his regimen to maintain a BP of /80-90 mmhg Serum aldosterone: 26 ng/dl PRA: <0.60 ng/ml/h ARR: >>27 Confirmed diagnosis of Primary Aldosteronism

8 Educational Objectives What is Primary Aldosteronism?

9 What is Primary Aldosteronism? aldosterone production inappropriately high for sodium status, relatively autonomous of the major regulators of secretion, and nonsuppressible by sodium loading. Such inappropriate production of aldosterone causes hypertension, cardiovascular damage, sodium retention, suppression of plasma renin, and increased potassium excretion that (if prolonged and severe) may lead to hypokalemia. Funder et al. JCEM 2016

10 Not All Hyperaldosteronism is the Same PHYSIOLOGY Urine/ Na + Na + Cl - HCO - Cl - Na + RENIN-DEPENDENT 3 ALDOSTERONISM Luminal Side secondary to Intravascular Volume Depletion Decreased Distal Na + Delivery K + ENaC ROMK H + Proximal Convoluted Tubule Loop of Henle & Distal Convoluted Tubule MR Principal Cell Intercalated Cell Blood/ Basolateral Side Intravascular ALDOSTERONE SUMMARY: Renin-Dependent Aldosteronism due to Volume Depletion Optimal Na + Reabsorption/Volume Expansion Decreased Distal Na ACTH AngII + Delivery Minimal K + Excretion Renin Volume Depletion Kamel et al. Kidney Int 2017; Palmer, B. CJASN 2015

11 Not All Hyperaldosteronism is the Same Urine/ Luminal Side INCREASED Na + Delivery PHYSIOLOGY Na + Na + Cl - HCO - Cl - Na RENIN-INDEPENDENT + 3 ALDOSTERONISM secondary to hyperkalemia (assuming volume replete state) ENaC K + ROMK H + Proximal Convoluted Tubule Loop of Henle & Distal Convoluted Tubule MR Principal Cell Intercalated Cell Blood/ Basolateral Side ALDOSTERONE SUMMARY: Renin-Independent Aldosteronism due to hyperkalemia Renin Optimal K + Excretion AngII K Minimal Na + Absorption/Volume Expansion + Kamel et al. Kidney Int 2017; Palmer, B. CJASN 2015

12 Not All Hyperaldosteronism is the Same Yanomami People Brazilian Pit Viper (Bothrops jararaca) Wikipedia.org;

13 Not All Hyperaldosteronism is the Same 24h Urinary K + Excretion 24h Urinary Na + Excretion (mmol/24h) (mmol/24h) Systolic Blood Pressure (mmhg) Indigenous Yanomamo Yanomamo Indigenous Industrialized Industrialized Indigenous Yanomamo Plasma Renin Activity 24h Urinary Aldosterone (ng/ml/h) (mcg) Industrialized Indigenous Yanomamo Indigenous Yanomamo Industrialized Industrialized Sun et al. Am J Clin Nut 2017 Jin et al. Hypertension 2009 Oliver et al. Circulation 1975 Brown et al. Ann Int Med 2017

14 Not All Hyperaldosteronism is the Same Brazilian Pit Viper (Bothrops jararaca) ACE inhibitor Over thousands of years, the same environmental pressures that forced Yanomamo and other terrestrial animals to evolve a hyperactive RAAS, also led Bothrops jararaca to conserve an efficient killing mechanism that targeted its enemies haemodynamic vulnerabilities. The bradykinin-potentiating peptides that would become the first ACEi s were, in essence, the viper s weapon of choice in a predator-prey arms race. Bomback et al. JRAAS 2007 Ciolek et al PNAS 2017

15 Not All Hyperaldosteronism is the Same INCREASED Na + Delivery PATHOPHYSIOLOGY Urine/ Na + Na + Cl - HCO - Cl - Na RENIN-INDEPENDENT + 3 ALDOSTERONISM Luminal Side in primary aldosteronsim (volume expanded state) ENaC K + ROMK H + Proximal Convoluted Tubule Loop of Henle & Distal Convoluted Tubule MR Principal Cell Intercalated Cell Blood/ Basolateral Side SUMMARY: Vicious Cycle Distal Na + Delivery AngII Na + Reabsorption/Volume Expansion/Blood ALDOSTERONE Pressure Renin K + /H + Excretion

16 PATHOPHYSIOLOGY Renin-Independent Aldosterone Regulation SBP (day 0) SBP (day 13) ALDO (ng/dl) When sodium loaded/volume expanded: Aldosterone-mediated 3.0 MR activation is pathologic and Myocardial Fibrosis/Necrosis Score induces CV injury via extra-renal MR (myocardial, vascular endothelial + SM) When sodium restricted/volume contracted: Aldosterone-mediated MR activation is physiologic 0.0 Dietary Na + L-NAME/AngII High - High + High + EPL Low + Rocha et al. Endocrinology 2000 Martinez et al. Hypertension 2002 McCurley et al. Nature Med 2012 Kim et al. Hypertension 2018

17 PATHOPHYSIOLOGY Renin-Independent Aldosterone Regulation Independent of Blood Pressure, MR activation in PA increases risk for: Coronary artery disease Stroke Heart failure & left ventricular hypertrophy Atrial Fibrillation Diabetes & Metabolic Syndrome Therefore, early recognition and treatment is indicated CAD Stroke CHF AFib Monticone et al. Lancet D&E 2017

18 Educational Objectives How Common is Primary Aldosteronism? What Causes Primary Aldosteronism?

19 The Prevalence of Primary Aldosteronism PA Screen IV Saline Confirmation or Captopril Challenge 1672 consecutive Italian primary care HTNives on NO medications ARR>30 Aldo>10 ng/dl 232 with positive PA screen Aldo>5 ng/dl ARR>30 99 with confirmed PA Unrecognized Yet Biochemically Overt PA Overt PA >180/110 >160/100 >140/90 Monticone et al. JACC 2017

20 The Prevalence of Primary Aldosteronism Prevalence of PA in Resistant HTN: 10-25% PATHWAY-2: Resistant HTN (3 drugs) Williams et al. Lancet 2015

21 Subclinical Primary Aldosteronism 1) Best 4 th Drug: MR antagonist 2) Works best when Renin lowest Williams et al. Lancet 2015

22 Milder Primary Aldosteronism 3) Works best when there is renin-independent aldosteronism (aka:???) A substantial proportion of Resistant essential HTNives appear to have mild primary aldosteronism: Aldosterone-MR mediated HTN Williams et al. Lancet 2015 & Lancet D&E 2018

23 The Prevalence of Primary Aldosteronism Vasan et al. NEJM 2004

24 The Prevalence of Primary Aldosteronism Incidence Rate of Hypertension (incident cases per 1,000 person-years) context of this renin suppression, associated with increased risk for hypertension via 80.6 inappropriate Aldo-MR 70.7 interactions the inference to be drawn is that the strict definition of primary PRA 0.50 ng/dl/h Suppressed Renin Phenotype PRA ng/dl/h Indeterminate Phenotype Agenda Item Q1 for Q2 next Q3 Q4 5 years: Q1 Recognize Q2 Q3 Q4 the true Q1 prevalence Q2 Q3 Q4 of 140 aldosteronism is no longer tenable. 20 PRA 1.0 ng/dl/h EXPANDING SPECTRUM OF PRIMARY ALDOSTERONISM: Unsuppressed Renin Phenotype Renin suppression, and higher aldosterone concentrations in the N=136 N=111 N=88 N=57 N=60 N=75 primary aldosteronism to include dysregulated N=72 N=64 N=19 N=25 N=53 N=90 Aldosterone (ng/dl) aldosterone Aldosterone (ng/dl) secretion Aldosterone (ng/dl) and inappropriate aldosterone production. *Models Adjusted for age, sex, race/ethnicity (Caucasian-, Chinese-, African-, Hispanic-American), BMI, cigarette smoking status (never former, current), weekly physical activity (MET*min/week), alcohol use (Y/N), education level (no school to grade 11, high school to some college, Associate s degree or Bachelor s degree or other professional degree), annual income (<$30,000, $30,000-75,000, >$75,000), health insurance status (Y/N), oral estrogen use (Y/N), nonsteroidal anti-inflammatory medication use (Y/N), fasting blood glucose, low-density lipoprotein cholesterol, systolic blood pressure, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio (normal, microalbuminuria, macroalbuminuria) John Funder, Horm Metab Res 2017 Brown et al. Annals of Internal Medicine 2017

25 Update: Aldosterone Producing Cell Clusters 1. APCC s are not tumors, and are common in morphologically normal adrenals: ~45% of morphologically normal adrenals have APCCs % of APCC s harbor mutations known to cause autonomous aldosterone secretion: CACNA1D, ATP1A1, ATP2B3 somatic mutations 3. APCC s generally do not express CYP11B1 or CYP17A1 (necessary for cortisol synthesis) 4. APCC s found in morphologically normal adrenal tissue adjacent to APA s, despite suppressed PRA/AngII 5. APCC s can be found in normotension, and increase with AGE 6. APCC s may be a precursor to neoplastic and overt PA? Contribute to age-related aldosteronism? Nanba & Vaidya et al., Circulation 2017 Nanba,Vaidya, Rainey Hypertension 2017 Nishimoto et al. JCEM 2010 Nishimoto et al. PNAS 2015 Omata et al. Journal of the Endocrine Society 2017

26 2-Hit Hypothesis for the Primary Aldosteronism Syndrome (Uncoupled Secretion and Proliferation) PROPOSAL: Overt Neoplastic PA may be the uncommon result of the collision of two more common abnormalities: 1. SECRETORY: Autonomous aldosetrone secretion (APCC) ZR 2. PROLIFERATIVE: Adrenal neoplasia (benign nonfunctional adrenal tumors). However, these abnormalities are likely to co-exist across a broad spectrum of ZG permutations, and manifest Secretory Abnormality: with heterogeneous APCC histologic and genetic CACNA1D phenotypes that ultimately ATP1A1 => determine the biochemical and clinical ATP2B3 KCNJ5/CLCN2phenotype ZF Proliferative Abnormality?: Wnt/ -catenin mutations? PKA mutations? APC mutations? AFF3 mutations? ARMC5 mutations? Marx. JCEM 2014; Zennaro et al. Endocrine Rev 2017; Nishimoto et al. JCEM 2016

27 Educational Objectives When/Who to Screen for Primary Aldosteronism? How to Confirm Primary Aldosteronism?

28 Case Question Patient with 30y history of (resistant) HTN and hypokalemia Amiloride HCTZ Verapmail Hydralazine Enalapril Serum aldosterone: 49 ng/dl PRA: 1.7 ng/ml/h ARR: 29 Which of the following is the most appropriate interpretation of the labs? A.Conclude that this is a positive screen for PA B.Conclude that this is a negative screen for PA C.Conclude that testing cannot be interpreted: stop enalapril for 2-4 weeks and repeat ARR D.Conclude that testing cannot be interpreted: stop HCTZ for 2-4 weeks and repeat ARR E.Conclude that testing cannot be interpreted: stop amiloride for 2-4 weeks and repeat ARR F.Conclude that testing cannot be interpreted: stop verapamil for 2-4 weeks and repeat ARR

29 When/Who to Screen for Primary Aldosteronism? Severe or Resistant Hypertension BP>150/100 mmhg x3; or >140/90 mmhg on 3 medications; or <140/90 mmhg on 4+ medications HTN + spontaneous or diuretic-induced hypokalemia HTN + adrenal mass HTN + sleep apnea HTN and family member with PA HTN + Family history of early-onset HTN or cerebrovascular accident (<40yrs) TES: Funder et al. JCEM 2016 AACE: Vaidya et al. Endocr Pract 2017

30 When/Who to Screen for Primary Aldosteronism? Severe or Resistant Hypertension BP>150/100 mmhg x3; or >140/90 mmhg on 3 medications; or <140/90 mmhg on 4+ medications HTN + spontaneous or diuretic-induced hypokalemia HTN + adrenal mass HTN + sleep apnea HTN and family member with PA HTN + Family history of early-onset HTN or cerebrovascular accident (<40yrs) TES: Funder et al. JCEM 2016 AACE: Vaidya et al. Endocr Pract 2017

31 How to Screen for Primary Aldosteronism? **There is no histopathologic gold standard for diagnosis** SCREENING TEST: ARR=aldosterone-to-renin ratio Positive Screen: o ARR that is >20 or >30 ng/dl per ng/ml/h o Sufficiently elevated aldosterone (>10, >15 ng/dl); Autonomous and Renin-Independent Aldosteronism 1. Suppressed PRA (<0.50? <0.60? ng/ml/h) 2. Inappropriately/Dysregulated aldosterone secretion (?) TES: Funder et al. JCEM 2016 AACE: Vaidya et al. Endocr Pract 2017

32 How to Screen for Primary Aldosteronism? PROBLEMS WITH ARR: First Test! If renin suppressed, aldosterone and ARR values are likely interpretable. If not, consider false negatives that may need to be addressed FALSE NEGATIVE: Raise PRA (denominator): o MR antagonist, ENaC Inhibitor o Acute administration of ACEi/ARB o Dietary sodium restriction (>AHA diet) o Volume contraction (ie very aggressive/acute diuresis) o Pregnancy FALSE POSITIVE: Lower PRA (denomiator): o β-blocker o α 2 -agonists

33 How to Screen for Primary Aldosteronism? My General Advice for Screening: 1. Be aware of potential causes of false negatives (and positives), but then GO ahead and screen in the clinic if you think about PA: If renin is suppressed, results are likely to be interpretable and useful Washing out/changing BP medications can be risky/dangerous, cumbersome, laborious, resource heavy, requires compliance, and can take days-to-weeks.usually unnecessary 2. If renin unsuppressed, or results not convincing, consider: Medication washout until renin suppressed: o MR antagonist, ENaC inhibitors (2-6 weeks) o Rarely is ACEi/ARB washout needed Ensure liberalized sodium intake (or at least ensure not severely sodium restricted) Alternative diagnoses (renin-dependent aldosteronism: renal artery stenosis, reninoma, etc)

34 How to Screen for Primary Aldosteronism? NEUTRAL BP Medications to Use During Washout: o α 1 -antagonists (ie-doxazosin) o Hydralazine o verapamil

35 Case Question Patient with 30y history of (resistant) HTN and hypokalemia Amiloride HCTZ Verapmail Hydralazine Enalapril Serum aldosterone: 49 ng/dl PRA: 1.7 ng/ml/h ARR: 29 Plasma metanephrines: WNL 1 mg DST: 0.9 mcg/dl Which of the following is the most appropriate interpretation of the labs? A.Conclude that this is a positive screen for PA B.Conclude that this is a negative screen for PA C.Conclude that testing cannot be interpreted: stop enalapril for 2-4 weeks and repeat ARR D.Conclude that testing cannot be interpreted: stop HCTZ for 2-4 weeks and repeat ARR E.Conclude that testing cannot be interpreted: stop amiloride for 2-4 weeks and repeat ARR F.Conclude that testing cannot be interpreted: stop verapamil for 2-4 weeks and repeat ARR

36 How to Confirm Primary Aldosteronism? CONFIRMATORY TESTS: Confirm screening results suggestive of autonomous and renin- and sodium-independent aldosterone secretion Huge variability in practice and use of confirmatory tests ***Most confirmatory tests involve sodium/volume expansion (increase distal sodium delivery), and therefore increase the risk for hypertensive urgency and profound hypokalemia THERE IS NO GOLD STANDARD 1. If PRA suppressed, Aldosterone>20 ng/dl, HTN & hypokalemia 2. Oral Sodium Suppression Test (>200 mmol Na/24h, AER>10-12mcg/24h) 3. Intravenous Saline Suppression Test 4. Fludrocortisone Suppression Test 5. Captopril Challenge Test

37 Educational Objectives How to Perform and Interpret Localization Studies?

38 Localization Localization should follow biochemical confirmation Imaging (CT/MRI) and Adrenal Venous Sampling are localization procedures (not for confirmation) that are generally recommend for all patients who are surgical candidates AVS is recommended by almost all societies/experts, when reasonably available, for almost every scenario PRO: Better classification, surgical cure optimal to lifelong medical therapy CON: requires expertise, not always available, costly For younger patients (<35-45y), with hypokalemia and very high ARR, and unilateral adrenal abnormalities on CT, AVS may be unnecessary

39 CASE Confirmed to have Primary Aldosteronism Abdominal CT scan: No obvious masses. Left adrenal diffusely thickened. Right adrenal possibly thickened.

40 The most appropriate treatment for this patient is: A.Left-sided adrenalectomy CASE B.Right-sided adrenalectomy C.Mineralocorticoid receptor antagonist therapy Adrenal Venous Sampling Aldosterone (ng/dl) Cortisol (mcg/dl) A/C Ratio IVC Right Adrenal Vein Left Adrenal Vein R Selectivity Index = 156/9.4 = 16.6 L Selectivity Index = 47.4/9.4 = 5.0 Lateralization Index = 11.5/7.2 = 1.6 Adrenal Venous aldosterone >>> IVC aldosterone

41 The most appropriate treatment for this patient is: A.Left-sided adrenalectomy CASE B.Right-sided adrenalectomy C.Mineralocorticoid receptor antagonist therapy Adrenal Venous Sampling Aldosterone (ng/dl) Cortisol (mcg/dl) A/C Ratio IVC Right Adrenal Vein Left Adrenal Vein R Selectivity Index = 156/9.4 = 16.6 L Selectivity Index = 47.4/9.4 = 5.0 Lateralization Index = 11.5/7.2 = 1.6 Adrenal Venous aldosterone > IVC aldosterone

42 Traditional Treatment Dogma UNILATERAL PA Adenoma (Conn s Tumor), nodular, hyperplasia Treatment Surgery for Cure Normal BILATERAL PA Macro or micro nodular, hyperplasia Treatment Lifelong Mineralocorticoid Receptor Antagonist

43 CASE Is medical treatment optimized? AVS: bilateral autonomous aldosterone secretion Diagnosed with bilateral PA and treated with MR antagonist What is the goal of MR antagonist therapy in PA? Medictions weaned to: Eplerenone, amlodipine. A. BP normalization B. K + normalization K=3.7 C. Increase meq/l renin Aldosterone=22 D. Cardiovascular ng/dl, PRA<0.6 Risk Reduction ng/ml/h E. All of the above BP= 131/82 mmhg on eplerenone 150mg daily, amlodipine 10mg daily

44 Risk for Incident Composite Cardiovascular Events Incident Composite Cardiovascular Events (%) No. at risk Primary Aldosteronism Essential Hypertension Years ,853 34,423 25,870 18,261 12,453 8,279 5,090 Hundemer et al, The Lancet D&E 2018

45 Risk for Incident Composite Cardiovascular Events Incident Composite Cardiovascular Events (%) HR=1.91 (1.63, 2.25) 15 year Incidence Difference: 16.5 excess events/100 persons Components of the Composite: MI or Coronary Revasc: HR= 1.81 ( ) CHF Hospitalization: HR= 1.61 (1.17, 2.22) Stroke: HR= 2.38 (1.83, 3.08) PA on MRA Essential HTN 56.3 events/1,000 py 26.6 events/1,000 py No. at risk Primary Aldosteronism Essential Hypertension Years ,853 34,423 25,870 18,261 12,453 8,279 5,090 Hundemer et al, The Lancet D&E 2018

46 Other Secondary Outcomes Mortality (%) Mortality (%) HR= 1.34 (1.06, 1.71) 15.4 events/1,000 py 14.6 events/1,000 py Atrial Fibrillation (%) 100 HR= 1.93 (1.54, 2.42) events/1,000 py events/1,000 py Diabetes Mellitus (%) HR= 1.26 (1.01, 1.57) 32.2 events/1,000 py 26.1 events/1,000 py Hundemer et al, The Lancet D&E 2018

47 Blood Pressure (mmhg) PA on MRA Essential HTN Systolic BP Diastolic BP # of non-mra anti-htn meds: 2.9 (1.4) # of non-mra anti-htn meds: 2.7 (1.4) (18) 134 (17) 76 (10) 76 (11) -1-6 mos Study Entry Years Hundemer et al, The Lancet D&E 2018

48 Biomarkers of MR Antagonism Urine/ Na + Cl - HCO - 3 Na + Cl - Luminal Side DECREASED INCREASED Na + Delivery Na + K + H + ENaC ROMK Proximal Convoluted Tubule Loop of Henle & Distal Convoluted Tubule MR Principal Cell Intercalated Cell Blood/ Basolateral Side Volume Expansion Volume Contraction AngII Renin AngII Renin SUMMARY: Optimal MRA Therapy in PA ENaC-Mediated Na + Reabsorption ALDOSTERONE K + and H + Excretion Volume Contraction Increase in Renin

49 Risk for Incident Composite Cardiovascular Events Incident Composite Cardiovascular Events (%) HR= 2.83 (2.11, 3.80) for Suppressed PRA vs Essential HTN HR= 1.09 (0.56, 2.10) for Unsuppressed PRA vs Essential HTN HR= 0.58 (0.35, 0.97) for Adrenalectomy vs Essential HTN MRA Therapy PRA< 1.0 ng/ml/h MRA Therapy PRA 1.0 ng/ml/h Essential HTN Surgery Years Hundemer et al, The Lancet D&E 2018

50 Other Secondary Outcomes Cumulative Incidence of AFib (%) HR= 2.53 (1.74, 3.69) for Suppressed PRA vs. Essential HTN HR= 1.27 (0.66, 2.46) for Unsuppressed PRA vs. Essential HTN HR= 0.72 (0.40, 1.32) for Adrenalectomy vs. Essential HTN MRA Therapy PRA < 1 ng/ml/h MRA Therapy PRA 1 ng/ml/h Essential HTN Surgery Years Hundemer et al

51 Other Secondary Outcomes 50 HR= 1.63 (95% CI 1.03, 2.59) for Suppressed PRA vs Essential HTN HR= 0.88 (95% CI 0.91, 2.11) for Unsuppressed PRA vs Essential HTN 40 Mortality (%) MRA Therapy PRA < 1 ng/ml/h 10 Essential HTN MRA Therapy PRA 1 ng/ml/h Year Hundemer et al, The Lancet D&E 2018

52 Treatment Summary The current (recommended) practice of lifelong MR antagonist therapy in PA: Associated with a significantly higher risk for incident cardiovascular events & death, independent of blood pressure control Intensification of MR antagonist therapy to raise renin, as a proxy for optimal MR antagonism, may mitigate this risk. o Not always possible!! (adverse effects of MRA, CKD/hyperkalemia) Surgical therapy, to cure primary aldosteronism, appears to mitigate these risks MORE QUESTIONS: How to candidly counsel PA patients who receive lifelong MR antagonist therapy about the efficacy and future risk associated with this decision? Is the current treatment dogma still appropriate?? Should surgical adrenalectomy should be considered more frequently?

53 Adapted from Funder et al. JCEM 2016 Suspicion for PA Screen: Assess aldosterone and renin (ARR) Positive Screen: Suppressed Renin and Inappropriate Aldosterone such that ARR>20-30 Patient Unable to Proceed or Not Interested in Surgery Confirmatory Testing Localization: Imaging (CT/MRI) No Need for Confirmatory Testing if: Renin suppressed Aldosterone>20 ng/dl HTN & hypokalemia Severe PA, Young Age, clear unilateral adenoma Surgery Desired Adrenal Venous Sampling Unilateral Bilateral Surgical Adrenalectomy (laparascopic adrenalectomy) Cure aldosterone excess Improve/Cure HTN and K + Lower cardiovascular Risk??? Grossly Asymmetric Disease Inability to control BP/K + CKD limiting MRA therapy High CV risk Lifelong MR Antagonist Therapy Normalize BP and K + Lower cardiovascular risk Attempt to raise renin?

54 Educational Objectives/Take Home Points Review the physiology of Primary Aldosteronism o o Review how to Diagnose and Localize Primary Aldosteronism o o o Review evidence to support optimal therapies for Primary Aldosteronism o o Primary aldosteronism is aldosterone secretion that is independent of renin/angii and sodium status. Prevalence is much higher than classically recognized. Diagnostic studies should support a renin-independent aldosteronism that is not suppressible. Beware of factors that may result in false negative screening (namely, medications that increase renin) Localization studies (imaging and AVS) should be considered once a biochemical confirmation is made, and if there is interest in potential surgical therapy. Surgical therapy to cure or attenuate aldosterone excess is associated with reduction in excess cardiovascular risk. MR antagonist therapy is associated with cardiovascular risk reduction when optimized.

55 Updates in Primary Aldosteronism Meet the Expert: AACE 2018 Anand Vaidya, MD MMSc Director, Center for Adrenal Disorders, Brigham and Women s Hospital Assistant Professor of Medicine, Harvard Medical School