What is the Role of Plasma Renin Activity Levels in the Management of Hypertension? Ilya Danelich, PharmD, BCPS Cardiology Clinical Pharmacist Pharmacy Grand Rounds Mayo Clinic Hospital ‐ Rochester July 19, 2016
Objectives • Describe the role of PRA levels in the management of hypertension • Review the differences between using PRA levels and traditional methods of managing hypertension • Outline a treatment care plan using PRA levels to manage hypertension PRA ‐ plasma renin activity
Epidemiology of Hypertension • Affects nearly 78 million people ≥ 20 years in the US • 47.5% have uncontrolled hypertension • Hypertension related mortality: 18.5% • Estimated Cost: $51 billion Percent of patients with hypertension at first event Myocardial Infarction 69% Heart Failure 74% Stroke 77% Circulation. 2013;127:e6 ‐ e245.
JNC 8 Guidelines Implement Lifestyle Interventions General Population Diabetes or CKD present (no diabetes or CKD) All ages All ages Select a drug treatment titration strategy Age ≥ 60 years Age < 60 years CKD Present +/ ‐ Diabetes Present A. Maximize first medication before adding second or Diabetes No CKD B. Add second medication before reaching maximum dose of first medication or BP Goal BP Goal BP Goal BP Goal C. Start with 2 medication classes separately or as fixed ‐ dose combination < 150/90 mm Hg < 140/90 mm Hg < 140/90 mm Hg < 140/90 mm Hg Black Nonblack All Races Thiazide ‐ type diuretic or Thiazide ‐ type diuretic or ACEI or ARB, alone ACEI or ARB or CCB, alone CCB, alone or in or in combination with or in combination combination other drug class ACEI ‐ angiotensin ‐ converting enzyme inhibitor CCB ‐ calcium channel blocker ARB ‐ angiotensin receptor blocker CKD ‐ chronic kidney disease JAMA. 2014;311:507 ‐ 20. BP ‐ blood pressure JNC 8 ‐ Eighth Joint National Committee
PRA Levels: Laragh Method John H. Laragh, MD Jean E. Sealey, D.Sc. http://www.laraghmethod.org/
Volume –Vasoconstriction Concep to Blood Pressure Control Blood Pressure is sustained by: Body sodium ‐ volume content (V) Plasma renin ‐ angiotensin vasoconstrictor activity (R) The V and R interacting control system sustains all normotension and all forms of hypertension Am J Hypertens. 2011;24:1164 ‐ 80.
Interaction between Body Sodium and Circulating Renin ‐ Angiotensin | Blood Pressure | | Feedback suppression BP = V x R | of renin | secretion | Arterial Volume (V) Vasoconstriction (R) | | ‐‐‐‐‐‐‐ > ARB | | Angiotensin II | Renal Sodium | ‐ blocker ACEI ‐‐‐‐‐‐ > Retention | | | | Angiotensin I > Diuretic ‐‐‐‐‐‐ > ‐‐‐‐‐‐ > DRI RENIN Sodium Angiotensinogen Am J Hypertens. 2011;24:1164 ‐ 80. DRI ‐ direct renin inhibitor
PRA Definitions For Patients Not Taking ACEI or ARB PRA Level Type of (ng/mL/hr) Hypertension Low renin < 0.65 V Medium renin 0.65 ‐ 6.5 R High Renin > 6.5 R For PatientsTaking ACEI or ARB PRA Level ePRA Level Type of (ng/mL/hr) (ng/mL/hr) Hypertension Low renin < 6.5 < 0.65 V Medium renin 6.5 ‐ 65 0.65 ‐ 6.5 R High Renin > 65 > 6.5 R ePRA = 0.1 x PRA Am J Hypertens. 2011;24:1164 ‐ 80. ePRA = effective PRA
Drug Types Anti ‐ V Drugs Anti ‐ R Drugs Diuretics ACEI Aldosterone receptor ARB antagonists Direct renin inhibitors Calcium channel blockers Beta ‐ blockers Alpha ‐ 1 blockers Central α 2 ‐ agonists Am J Hypertens. 2011;24:1164 ‐ 80.
Untreated Hypertensive Patient Step 1 : Measure PRA | | Low PRA: < 0.65 Medium to high PRA: ≥ 0.65 | V Patient R Patient | | | | Steps 2 & 3 : Give anti ‐ V drug Steps 2 & 3 : Give anti ‐ R drug | Step 4: If BP elevated, measure PRA | | | Steps 5 & 6 : If PRA Steps 5 & 6 : If PRA Steps 5 & 6 : If PRA Steps 5 & 6 : If PRA | (or ePRA) < 0.65 (or ePRA) ≥ 0.65 < 0.65 = V+ V patient ≥ 0.65 = V+ R patient | = R + V patient = R + R patient Add 2 nd anti ‐ V Drug Add anti ‐ R Drug Add 2 nd anti ‐ R drug | Add anti ‐ V drug | | Am J Hypertens. 2011;24:1164 ‐ 80.
Treated Hypertensive Patient BP not controlled on full doses of 1 anti ‐ V & 1 anti ‐ R drug (ACEI or ARB) Step 1: Measure PRA Step 2: If PRA < 0.65, Step 2: If PRA >6.5 Steps 2 & 3: there is no renin to (ePRA > 0.65) patient If PRA 0.65 ‐ 6.5 block. Anti ‐ R drug may be volume (ePRA < 0.65), renin is may be pressor. depleted effectively blocked. Add 2 nd anti ‐ V drug Subtract anti ‐ R drug Subtract anti ‐ V drug Steps 3 & 4: If BP not Steps 3 & 4: If BP not Steps 4: If BP controlled on controlled on controlled, monotherapy, monotherapy, Test subtracting Add 2 nd anti ‐ R drug Add 2 nd anti ‐ V drug anti ‐ R drug Am J Hypertens. 2011;24:1164 ‐ 80.
Audience Response #1 Using PRA levels in the management of hypertension helps determine which of the following? a. Whether the patient would benefit most from ACE inhibitor vs. beta ‐ blocker b. Whether the patient has R mediated hypertension vs. V mediated hypertension, thereby guiding treatment c. Which blood pressure goal to target d. Whether the patient would benefit most from spironolactone vs. amlodipine
Audience Response #2 Which of the following statements between using PRA levels and traditional methods of managing hypertension is true? a. JNC8 recommends thiazide ‐ type diuretic as initial therapy for all patients whereas using PRA levels allows for individualized care b. JNC8 provides the ability to individualize the pharmacotherapy plan whereas using PRA levels consists of stepped care with progressive addition of medications c. JNC8 recommends stepped care with progressive addition of medications whereas using PRA levels focuses on individualizing the pharmacotherapy plan d. JNC8 provides guidance for patients with treated and untreated hypertension whereas PRA levels only provide guidance for untreated hypertension
Plasma Renin Test–Guided Drug Treatment Algorithm for Correcting Patients With Treated but Uncontrolled Hypertension: A Randomized Controlled Trial Egan BM, Basile JN, Rehman SU, et al. Am J Hypertens. 2009;22:792 ‐ 801.
Study Design • Randomized, unblinded ( n = 77) Treated, uncontrolled hypertension Renin Test ‐ Guided Therapeutics (RTGT) n = 38 Primary Outcome Uncontrolled: ≥ 140/90 mm Hg or ≥ 130/80 Clinical Hypertension Specialists‘ Difference in BP mm Hg in patients Care (CHSC) with DM and/or n = 39 nephropathy Exclusion Criteria Uncontrolled DM or hyperlipidemia Alcohol or drug abuse in the past 5 years ESRD and CKD with SCr > 2.5 Intolerance to ≥ 2 classes of anti ‐ hypertensive medications DM ‐ diabetes mellitus SCr ‐ serum creatinine Am J Hypertens. 2009;22:792 ‐ 801. ESRD ‐ end stage renal disease
Baseline Characteristics RTGT ( n = 38) CHSC ( n = 39) P value Age, years 63.9 58.2 0.02 Men, % 84 74 0.29 Race, % Caucasian 68 41 0.02 BMI, kg/m 2 30.6 28.9 0.44 Diabetic, % 24 36 0.24 CKD, % 13 5 0.21 PRA, ng/mL/h 5.8 4.6 0.52 SCr, mg/dL 1.09 1.09 0.93 eGFR, mL/min/1.73m 2 77 92 0.02 BMI – body mass index eGFR ‐ estimated glomerular filtration rate Am J Hypertens. 2009;22:792 ‐ 801.
Blood Pressure Effect 180 P = 0.27 160 Blood Pressure, mm Hg P = 0.10 140 120 P = 0.17 100 P = 0.01 80 RTGT 60 CHSC 40 20 0 Baseline Last Visit Last Visit Baseline SBP DBP SBP DBP RTGT 157 87.1 127.9 73.1 CHSC 153.2 91.1 134 79.8 SBP ‐ systolic blood pressure Am J Hypertens. 2009;22:792 ‐ 801. DBP ‐ diastolic blood pressure
Changes in Blood Pressure 0 SBP DBP Change in Blood Pressure, mm Hg ‐ 5 ‐ 10 ‐ 11.3 ‐ 15 ‐ 14.1 RTGT P = 0.32 CHSC ‐ 20 ‐ 19.2 ‐ 25 ‐ 30 ‐ 29.1 P = 0.03 ‐ 35 Am J Hypertens. 2009;22:792 ‐ 801.
Number of Medications 3.5 P = 0.73 P = 0.21 3.1 3.1 3 3 2.7 2.5 2 RTGT 1.5 CHSC 1 P = 0.25 0.5 0.3 0 0 Baseline Last Visit Change Am J Hypertens. 2009;22:792 ‐ 801.
Conclusions & Limitations Conclusions Limitations RTGT group older, more Using PRA levels may provide better BP control without a Caucasians, worse kidney net increase in the number of function medications Unblinded Small sample size Hypertension specialist group may not mimic general practice Am J Hypertens. 2009;22:792 ‐ 801.
Pressor Responses To Antihypertensive Drug Types Alderman MH, Cohen HW, Sealey JE, Laragh JH. Am J Hypertens. 2010;23:1031 ‐ 7.
Study Design • Retrospective analysis ( n = 945) Anti ‐ V Drug: Diuretic or CCB Untreated Primary Endpoint n = 537 hypertension Incidence of pressor responses, and influence Anti ‐ R Drug: ‐ blocker or ACEI SBP ≥ 140 mm Hg of PRA status n = 408 • Pressor Response – SBP rise ≥ 10 mm Hg Am J Hypertens. 2010;23:1031 ‐ 7.
Blood Pressure Response V Drug R Drug P Value ( n = 537) ( n = 408) Categories of SBP Change (%) ≥ 10 mm Hg rise 5.2 11.0 0.001 ≥ 10 mm Hg fall 62.0 54.9 0.03 Categories of DBP Change (%) ≥ 5 mm Hg rise 6.3 7.8 NS ≥ 5 mm Hg fall 63.1 63 NS NS ‐ not significant Am J Hypertens. 2010;23:1031 ‐ 7.
Pressor Response by PRA Status 18 17 P < 0.001 16 Incidence of Pressor Response, % 14 P = 0.02 12 P = 0.08 10 10 9 V Drug 8 R Drug 6 6 6 4 4 2 0 Low PRA Middle PRA High PRA Am J Hypertens. 2010;23:1031 ‐ 7.
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