Plasma Renin Activity- Little Foot or Big Step for Blood...
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Plasma Renin Activity- Little Foot or Big
Step for Blood Pressure Management?
Christine Heath, Pharm.D. PGY2 Ambulatory Care Pharmacy Resident
UT Pharmacotherapy Grand Rounds Presentation
South Texas Veterans Health Care System
The University of Texas at Austin College of Pharmacy
University of Texas Health San Antonio
October 25th, 2019
Lecture Objectives:
1. Provide a basic overview of hypertension
2. Discuss treatment methods for hypertension
3. Evaluate the literature pertaining to the utilization of plasma renin activity to guide treatment of
hypertension
4. Recommend optimal pharmacotherapeutic regimens in an adult with resistant hypertension
given plasma renin activity levels
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1 HYPERTENSION BACKGROUND 1.1 IMPACT OF HYPERTENSION (HTN)1
• Utilizing the American College of Cardiology and American Heart Association (ACC/AHA)
2017 HTN definition, 45.6% of US adults have HTN
• From 2005 to 2015 there has been a significant increase in death rates attributable to elevated
blood pressure (BP) from 10.5% up to 37.5% (78,862 deaths)
• Projections show that by 2035, the total direct cost of high BP could increase to an estimated
$220.9 billion
Figure 1. Rates of Hypertension
1.2 PATHOPHYSIOLOGY OF PRIMARY HYPERTENSION2
• The pathogenesis of primary HTN is multifactorial and highly complex
• Numerous genetic and environmental factors (polygenic disorders, diet, physical activity, alcohol
consumption) result in neurohumoral dyfunction and promote inflammation and insulin
resistance
• These dysfunctions all lead to increased peripheral resistance or increased blood volume, which
are 2 primary causes of sustained HTN
Figure 2. Pathophysiology of Primary Hypertension
45.6%
24.0%
47.1%
66.6%
75.6%82.5%
47.3%54.9%
36.7% 34.4%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
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1.3 CARDIOVASCULAR RISK FACTORS2
• HTN and modifiable cardiovascular risk factors share several mechanisms of action and
pathophysiology
• Treating some of the modifiable risk factors may reduce BP through modification of shared
pathology, and cardiovascular risk may be reduced by treating global risk factor burden.
1.4 SECONDARY CAUSES OF HYPRTENSION2
Table 1. Secondary Causes of Hypertension
Common
Causes Prevalence Clinical Indications
Obstructive
Sleep Apnea
25-50% - Resistant HTN
- Snoring
- Fitful sleep
- Breathing pauses during sleep
- Daytime sleepiness
Primary
Aldosteronism
8-20% HTN with:
- Hypokalemia
- Muscle cramps or weakness
- Obstructive sleep apnea
- Family history of early-onset HTN or stroke
Renovascular
Disease
5-34% - Resistant HTN
- HTN of abrupt onset or worsening
- Flash pulmonary edema
- Early-onset HTN
- Commonly in women
Drug or
Alcohol
Induced
2-4% - Sodium containing antacids
- Caffeine
- Nicotine
- NSAIDs
- Oral contraceptives
- Cyclosporine or tacrolimus
- Sympathomimetics
- Cocaine, amphetamines
- Neuropsychiatric agents
- Erythropoiesis-stimulating
agents
- Clonidine withdrawal
- Herbals
Modifiable Risk Factors
▪ Cigarette smoking
▪ Diabetes mellitus
▪ Dyslipidemia
▪ Overweight/obesity
▪ Physical inactivity/low fitness
• Unhealthy diet
Non-Modifiable Risk Factors
▪ Chronic kidney disease
▪ Family history
▪ Increased age
▪ Low socioeconomic/educational status
▪ Male sex
▪ Obstructive sleep apnea
▪ Psychosocial stress
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1.5 HYPERTENSION GUIDELINES
Table 2. Comparing Hypertension Guidelines
Guideline Categories (mmHg) Goals
JNC 7 (2003)3
Normal <120 and <80
Pre-HTN 120-139 or 80-89
Stage 1 140-159 or 90-99
Stage 2 ≥160 or ≥100
CKD or DM <130/<80
Others <140/<90
JNC 8 (2014)4 Age ≥60 ≥150 or ≥90
Age <60 ≥140 or ≥90
CKD ≥140 or ≥90
DM ≥140 or ≥90
CKD or DM <140/<90
Age <60 <140/<90
Age ≥60 <150/<90
ACC/AHA (2017)2 Normal <120 and <80
Elevated 120-129 and <80
Stage 1 130-139 or 80-89
Stage 2 ≥140 or ≥90
All <130/<80
*Blood pressure categories based on an average of ≥2 careful readings obtained on ≥2 occasions
CKD= chronic kidney disease; DM= diabetes mellitus; JNC= Joint National Committee;
ACC= American College of Cardiology; AHA= American Heart Association
1.6 RECOMMENDATIONS FOR TREATMENT AND FOLLOW-UP2
• Per the ACC/AHA 2017 guidelines, treatment and follow-up are dependent on degree of BP
elevation as well as the presence of atherosclerotic cardiovascular disease (ASCVD) risk
Figure 3. Recommendations for Hypertension Treatment and Follow-Up
Recommendations for Treatment and Follow-up
Normal
Promote optimal lifestyle
habits
Reassess in 1 year
Elevated
Nonpharmacologic therapy
Reasses in 3-6 months
Stage 1 Hypertension
Clinical ASCVD or estimated risk
≥10%?
No: Nonpharmacologic
therapy
Reassess in 3-6 months
Yes: Nonpharmacologic
therapy + medication
Reassess in 1 month
Stage 2 Hypertension
Nonpharmacologic therapy + medication
Reassess in 1 months
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2 PHARMACOLOGICAL STRATEGIES FOR HYPERTENSION 2.1 STEPPED-CARE STRATEGY
• Defined as the step-wise addition of medications until BP control is achieved7
• Example: 2017 ACC/AHA Hypertension Guidelines2
1. Identify compelling indications:
Table 3. Compelling Indications for BP Medications Per ACC/AHA
Disease State 1st Line Agents Other Recommendations
Stable ischemic heart
disease
- Beta-blockers
- ACE inhibitors/ARBs
If further control needed:
- Dihydropyridine CCBs
- Thiazide diuretics
- Aldosterone antagonists
Heart failure with
reduced ejection fraction
(HFrEF)
- ACE inhibitors/ARBs
- Aldosterone antagonists
- Diuretics
- Neprilysin inhibitors
- Beta-blockers (carvedilol,
metoprolol succinate, or
bisoprolol)
Nondihydropyridine CCBs are
not recommended
Heart failure with
preserved ejection
fraction (HFpEF)
- Diuretics
- ACE inhibitors/ARBs
- Beta-blockers
Limited data exist to guide the
choice of alpha-blockers, beta-
blockers, and CCBs
Chronic kidney disease - ACE inhibitors/ARBs
Cerebrovascular disease - Thiazide diuretics
- ACE inhibitors/ARBs
Reduction in BP appears to be
more important than the
choice of specific agents
Peripheral artery disease No specific
recommendation
Diabetes mellitus - ACE inhibitors (if
albuminuria present)
Atrial fibrillation - ARBs
Valvular heart disease Avoid beta-blockers
Aortic disease - Beta-blockers ACE inhibitors were not seen
to improve survival ACE= angiotensin-converting enzyme; ARBs= Angiotensin II receptor blockers; CCBs= calcium channel blockers
2. Add any first line agent:
▪ Preferred first line agents (thiazide diuretics, long acting CCBs, and ACE
inhibitors/ARBs) have been shown to reduce clinical events
▪ ACE inhibitors/ARBs are not a preferred first line agent in African Americans
3. Continue adding agents until BP control is achieved
• Efficacy study: “ALLHAT”5
o In the ALLHAT trial, 66% of patients were controlled to goal of <140/90 mmHg
o Patients required an average of 2 medications, though there were 13% of patients that
required ≥4 medications
o A subgroup analysis of race noted that in blacks with HTN and without renal disease or HF,
thiazide diuretics lowered rates of stroke compared to ACE inhibitors6
• Potential Limitations
1. Agents that are ineffective or minimally effective are rarely discontinued7
2. Variable control rates
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2.2 THIAZIDE FIRST STRATEGY
• Example: JNC 7 Guidelines recommended thiazide diuretics as the preferred initial agent due to
studies showing favorable results in preventing the cardiovascular complications of HTN3
• “First-line drugs for hypertension (Review)”8
Table 4. Mortality and Morbidity Reduction with Different First-Line Agents
Low-dose
thiazide
diuretic vs.
placebo
High-dose
thiazide
diuretic vs.
placebo
Beta-
blocker vs.
placebo
ACE
inhibitor
vs. placebo
CCB vs.
Placebo
Total Mortality ARR= 1.2%
NNT= 83
Not
significant
Not
significant
ARR= 2.3%
NNT= 43
Not
significant
Total Stroke ARR= 2.0%
NNT= 50
ARR= 1.0%
NNT= 100
ARR= 0.6%
NNT= 167
ARR= 2.1%
NNT= 48
ARR= 1.5%
NNT= 67
Total Coronary
Heart Disease
ARR= 1.1%
NNT= 91
Not
significant
Not
significant
ARR= 2.5%
NNT= 40
Not
significant
Total
Cardiovascular
Events
ARR= 3.9%
NNT= 26
ARR= 1.4%
NNT= 71
ARR= 0.8%
NNT= 125
ARR= 4.8%
NNT= 21
ARR= 2.4%
NNT= 42
Withdrawal due
to adverse effects
ARR= -6.8%
NNH= 15
ARR= -7.6%
NNH= 13
ARR= -11.3%
NNH= 9 *ARR= absolute risk reduction; NNT= number needed to treat; NNH= number needed to harm
o Objective: to quantify the mortality and morbidity effects from different first-line agents
o Author’s Conclusions:
▪ First-line low-dose thiazide diuretics reduced all morbidity and mortality outcomes in
adult patients with moderate to severe primary HTN
▪ First-line ACE inhibitors and CCBs may be similarly effective, but the evidence was of
lower quality
▪ First-line high-dose thiazides diuretics and first-line beta-blockers were inferior to first-
line low-dose thiazide diuretics
• Efficacy study:” Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for
primary hypertension (review)”9
o In a meta analysis, chlorthalidone resulted in 12-point reduction in systolic blood pressure
(SBP) and 3.9-point reduction in diastolic blood pressure (DBP)
o Hydrochlorathiazide resulted in 6.9-point reduction in SBP and 3.3-point reduction in DBP
• Potential Limitations:
o Responses to BP agents is characterized by marked interindividual response10
o Many people will require treatment with more than one agent to achieve BP control2
o Patients may be unable to tolerate thiazide diuretics
2.3 AGE-RACE STRATEGY • Tailoring therapy decisions to patient demographics such as age or race/ethnicity11,12
• Example: British Hypertension Society guidelines for hypertension management 200413
Table 5. Recommended Agents for Different Age-Race Populations
Younger Patients
(<50 years)
Black Patients and Older Adults
(≥50 years)
• ACE Inhibitors/ARBs
• Beta-blockers
• Thiazide diuretics
• Long-acting CCBs
Data Quality: High Moderate Low
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• This strategy is based on the assumption that younger Caucasians have renin-dependent HTN
and other racial ethnic groups and older individuals have predominately low renin14
• Efficacy study: “Age-race subgroups compared with renin profile as predictors of blood pressure
response to antihypertensive therapy”15
o Age-race strategy resulted in 64.5% of patients achieving goal DBP (<90 mmHg)
o There was a 13.3-point reduction in SBP and 11.9-point reduction in DBP
• Potential Limitations:8
o Relies on population statistics that may not be accurate for all persons in a given group
o Limited use for patients that are already treated, but remain uncontrolled
2.4 TREATMENT RESISTANT HYPERTENSION (TRH)16 • Uncontrolled HTN on ≥3 agents preferably including a diuretic
• Management:
1. Maximize thiazide diuretics
2. Add aldosterone antagonist
3. Add beta-blocker (unless heart rate <70 beats/minutes)
4. Add hydralazine
5. Substitute minoxidil for hydralazine
6. Refer to HTN specialist
• Efficacy studies:
o Adding spironolactone: “PATHWAY-2”17
▪ 58% control rate in SBP (<135 mmHg)
▪ Serum potassium increased by 0.43 mEq/L
▪ Hyperkalemia resulted in 2% of the population
▪ Mean eGFR was reduced by 10.02 mL/min/1.73 m2
o Referal to HTN specialist: “Blood pressure control in the hypertensive clinic” 18
▪ Referals to HTN specialist for TRH increased control rates from 18% to 52%
• Limitations: “14
o Tolerability issues of aldosterone antagonists, including the development of CKD with an
eGFR <45 mL/min/1.73 m2 or baseline serum potassium >4.5 mEq/L
o Prolonged spironolactone use at higher doses may be limited by gynecomastia and erectile
dysfunction in men and menstrual irregularities in women
o Increased pill burden, especially with the twice daily dosing of eplerenone
2.5 PLASMA RENIN ACTIVITY (PRA) STRATEGY 2.5.1 Renin Background18
• Renin: an enzyme secreted by and stored in the kidneys involved in the regulation of fluid
volume and arterial vasoconstriction
• BP is sustained by:
1. Body sodium-volume content (V)
▪ Body salt increases or decreases the extracellular fluid volume
▪ This increase or decrease in the volume of fluid delivered to the arterial tree affects BP
via a hydraulic effect
2. Plasma renin-angiotensin vasoconstrictor activity (R)
▪ Compensatory adjustments in arteriolar caliber are mediated by changes in circulating
angiotensin II
▪ The renal juxtaglomerular apparatus of each nephron detects changes in body-sodium
volume and adjusts angiotensin II levels through PRA
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Figure 4. Relationship Between Arterial Volume and Vasocontriction
o A normal BP can have low, medium, or high PRA levels when it is simultaneously present
with reciprocally high, medium or low levels of body sodium volume content
o HTN occurs when the kidneys fail to sufficiently reduce PRA in response to an increase in
body salt (i.e. normal PRA levels x elevated sodium volume= elevated BP)
▪ PRA is low in ~30% of hypertensive patients, indicating an appropriate renal
baroreceptor response to high pressure20
▪ PRA is moderate in ~55% of hypertensives20
▪ PRA is high in ~15% of hypertensives20
• PRA Levels
o Assessed using a blood test that measures the activity of the plasma renin enzyme
o PRA levels can be affected by age, race, diet, medications, and disease states
o The PRA level test is available commercially, costs less than a urinary albumin and is
reimbursed in the United States by Medicare and most insurance carriers
o No special patient preparation is needed and there is no need to stop antihypertensive
drugs
Table 6. Assessing Plasma Renin Activity Levels
Category PRA Level
Low <0.65
Moderate 0.65-6.5
High ≥6.5
2.5.2 Selecting Antihypertensive Drug Types19
• All effective antihypertensive drugs lower BP by either reducing sodium-volume content (anti-V
drugs) or reducing or blocking the vasoconstrictor activity of the circulating renin-angiotensin
system (anti-R drugs)
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Table 7. Drug Class Blood Pressure Lowering Mechanisms
Anti-V Drug Types Anti-R Drug Types
• Thiazide diuretics
• Aldosterone antagonists
• Alpha-blockers
• CCBs
• Beta-blockers
• Alpha-2 agonists
• ACE inhibitors/ARBs
• Direct renin inhibitors (DRIs)
• PRA levels can be used to guide selection of antihypertensive medication:
Table 8. Studies Assessing Blood Pressure Response with Various PRA Levels
Study Agent(s) Population Findings
Anti-V Drugs
Vaughan et
al. (1973)21
Spironolactone
Chlorthalidone
- 71 patients
- PRA levels: 37
low; 36 normal
Reductions in BP were significantly
greater in patients with low renin
compared with normal renin.
Bolli et al.
(1980)22
Prazosin - 27 patients
- PRA levels: 12
low; 15 normal
Prazosin monotherapy lowers BP in
about 1/3 of hypertensive patients and
most effectively in those with low renin-
HTN.
Buhler et
al. (1982)23
Verapamil - 43 patients
- PRA levels: 11
low; 24 normal; 8
high
The antihypertensive response to
verapamil was greatest in older and low
renin patients.
Anti- R Drugs
Buhler et
al. (1973)24
Propranolol - 74 patients
- PRA levels: 17
low; 38 normal; 19
high
Reductions in BP were greater in
patients with high renin levels compared
to low and moderate.
Minami et
al. (2008)25
Telmisartan - 11 patients
- PRA levels: 6 low;
5 high
Reductions in BP were significantly
greater in patients with high renin levels
than those with low renin levels
2.5.3 Historical Perspectives26
• The concept of PRA measurements for the prediction of antihypertensive effects is not new
• During the formative years (1960s-1970s), three major issues dissuaded clinicians from using
PRA measurements:
1. Unaware of need to proper pH control of PRA assay
2. Belief that patients must discontinue antihypertensives prior to PRA tests
3. Belief that patients had to have sodium-controlled diets prior to PRA tests
• The truth: PRA testing can be done regardless of a patient's drug regimen or salt intake
o Patients should continue their usual sodium intake and drug therapy before testing to
provide the truest picture of what is supporting a patient's elevated BP
• Studies comparing the utility of PRA compared with current antihypertensive management
strategies are limited, possibly due to:
1. Misunderstanding of the potential utility of the modern PRA assay
2. Lingering methodologic concerns
3. Assay expense
4. Extended laboratory turnaround time
5. The lack of recommendations for PRA testing in practice guidelines
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3 CLINICAL QUESTION: SHOULD PLASMA RENIN ACTIVITY
LEVELS BE USED TO MANAGE BLOOD PRESSURE? 3.1 INITIAL TREATMENT DECISIONS
Table 9. THE ROLE OF PLASMA RENIN ACTIVITY, AGE, AND RACE IN SELECTING
EFFECTIVE INITIAL DRUG THERAPY FOR HYPERTENSION27
BACKGROUND AND OVERVIEW
Citation Schwartz GL, Bailey K, Chapman AB, Boerwinkle E, Turner ST. The role of plasma
renin activity, age, and race in selecting effective initial therapy for hypertension.
American Journal of Hypertension. Aug 2013; 26(8):957-964.
Objective To compare control rates among 3 drug selection strategies for initial drug therapy:
1. Thiazide diuretic for all
2. Thiazide diuretic for white subjects ≥50 years and all black subjects and a
renin-angiotensin system (RAS) blocker for white subjects <50 years
3. Thiazide diuretic for PRA <0.6 and RAS blocker for PRA ≥0.6
METHODS
Study Design o Retrospective analysis of data previously collected in the Genetic Epidemiology
Responses to Antihypertensives (GERA) study
Inclusion
Criteria
o Patients 30-59 years of age
o Essential HTN (BP >140/90 mmHg or diagnosis with current treatment)
Exclusion
Criteria
o Known secondary causes of HTN
o Women using oral contraceptives
o BP >180/110 mmHg after washout period
Interventions o Antihypertensives were stopped and subjects were evaluated every other week
during a 4-6 week washout phase
o Antihypertensive therapy was administered for 4-6 weeks with either:
▪ Hydrochlorothiazide 25mg daily x 4 weeks
▪ Candesartan 16mg daily x 2 weeks then increase to 32mg x 4 weeks
Outcomes o BP control rates (<140/90 mmHg) for each 3 drug selection categories
Monitoring o BP was checked at study visits (completed in triplicate)
o Subjects were to maintain a standard sodium intake of 2 mmol/kg/day
▪ Monitored weekly by 24-hr urine collection alternating with diaries
o Compliance with drug therapy was assessed by pill counts at each study visit
Statistical
Analysis
o Utilized p-values for quantitative variables (analysis for variance for normally
distributed; Mann-Whitney rank sum test for non-normally distributed)
o The overall difference in control rates between strategies is a weighted average
of the 8-stratum-specific (age/race/PRA) differences in control rates
RESULTS
Participant
Demographics
o Overall patients included in the study were obese and had type 1 HTN
o There were no significant differences between treatment groups
Outcomes BP control rates (%) by treatment strategy:
Strategy Overall Black
Subjects
White
Subjects
Thiazide only 53.8 55.2 52.4
Age-race 61.3 55.2 67.1
PRA 69.4* 62.1* 76.3*
* indicates statistical significance vs. other strategies
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AUTHORS’ CONCLUSIONS
The results of this study suggests that in patients aged <60 years with uncomplicated essential HTN,
choice of initial antihypertensive drug therapy using a PRA strategy is associated with higher control
rates than a strategy based on age-race criteria or thiazide only.
CRITIQUE/DISCUSSION
Strengths o Compared commonly used strategies to determine initial agent
o Utilized commonly used “maximum” dose of both agents
Limitations o Retrospective study design
o Lower upper age limit
o PRA assays were run for 3 hours (less accuracy for low PRA levels)
o Different durations between groups
o Not “real-life” use of PRA levels (sodium restrictions)
o Only utilized one drug from each category
Discussion This study provides the beginning basis to consider using PRA levels to guide initial
therapy decisions. However, future studies are needed to verify results and
demonstrate the applicability into a “real-world” world setting.
Table 10. COMPARISON OF BLOOD PRESSURE CONTROL RATES AMONG
RECOMMENDED DRUG SELECTION STRATEGIES FOR INITIAL THERAPY OF
HYPERTENSION28
BACKGROUND AND OVERVIEW
Citation Gharaibeh KA, Turner ST, Hamadah AM, et al. Comparison of blood pressure
controle rates among recommended drug selection strategies for initial therapy of
hypertension. American Journal of Hypertension. October 2016; 29(10):1186-1194.
Objective To compare control rates among 3 drug selection strategies:
1. Thiazide diuretic for all
2. Thiazide diuretic for all black subjects and white subjects ≥50 years and a
RAS blocker for white subjects <50 years
3. Thiazide diuretic for PRA <0.6 and RAS blocker for PRA ≥0.6
METHODS
Study Design o Retrospective analysis of data previously collected in the PEAR-1 study
(prospective, multicenter, randomized, open-label, parallel group study)
Inclusion
Criteria
o Patients 17-65 years of age
o Essential HTN (BP ≥140/90 mmHg or diagnosis with current treatment)
Exclusion
Criteria
o Known secondary causes of HTN
o Isolated systolic HTN
o Known cardiovascular disease
o HR <55 beats/minute in the absence of beta-blocker
o DM or screening fasting blood glucose >126 mg/dL
o Primary renal disease
o Concomitant diseases treated with BP-lowering medications
o BP >180/110 mmHg after washout period
o Chronic treatment with BP-elevating drug
Interventions o Antihypertensives were stopped and subjects were evaluated every other week
during a 4-week washout phase
o Antihypertensive therapy was administered for 9 weeks of treatment
▪ Hydrochlorothiazide 12.5mg daily (increase to 25mg if BP >120/70)
▪ Atenolol 50mg daily (increase to 100mg if BP >120/70)
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Outcomes o BP control rates (<140/90 mmHg) for each 3 drug selection categories
Monitoring o Home BP was measured throughout the 9-week treatment period
o 24-hour ambulatory BP was measured at the beginning and end
Statistical
Analysis
o Utilized p-values for quantitative variables (Analysis for variance for normally
distributed; Mann-Whitney rank sum test for non-normally distributed)
o The overall difference in control rates between strategies is a weighted average
of the 8-stratum-specific (age/race/PRA) differences in control rates
RESULTS
Participant
Demographics
o Patients were obese with a BMI of ~30 kg/m2
o Average baseline BP: 151/98 mmHg
o No significant differences between treatment groups
Outcomes BP control rates (%) by treatment strategy:
Strategy Clinic BP Home BP 24-hr Ambulatory BP
Thiazide-only 31.7* 26.4* 43.9*
Age-race 40.8* 36.1* 51.6*
PRA 48.9* 42.6* 61.3*
* indicates statistical significance vs. other strategies
Secondary Analysis:
o Preferred agent for each PRA/racial/age subgroup
Blacks Whites
PRA levels <50 years ≥ 50 years <50 years ≥ 50 years
Suppressed HCTZ HCTZ Atenolol HCTZ
Non-Suppressed Atenolol HCTZ Atenolol Atenolol
AUTHORS’ CONCLUSIONS
The results of this study confirms their previous findings that drug selection based on PRA levels is
associated with higher BP control rate than either alternative strategy. Based on the observations of
this study, a combination of PRA + age-race criteria may be effective (PRA utilized in whites ≥50 years
of age and blacks <50 years of age).
CRITIQUE/DISCUSSION
Strengths o Allowed for medicine titrations
o Slightly higher age limit than previous study
o Assessed home BP readings
o Utilized 24-hour BP readings at beginning and end
o “Real-life” PRA levels (no sodium restrictions)
Limitations o PRA assays were run for 3 hours (less accuracy for low PRA levels)
o Retrospective study design
Discussion This study helps to verify that PRA levels can be utilized to determine initial agents
specifically in older white patients and younger black patients.
3.2 TREATED, UNCONTROLLED HYPERTENSION
Table 11. PLASMA RENIN TEST-GUIDED DRUG TREATMENT ALGORITHM FOR
CORRECTING PATIENTS WITH TREATED BUT UNCONTROLLED
HYPERTENSION: A RANDOMIZED CONTROLLED TRIAL29
BACKGROUND AND OVERVIEW
Citation Egan BM, Basile JN, Rehman SU, et al. Plasma renin test-guided drug treatment
algorithm for correcting patients with treated but uncontrolled hypertension: a
randomized controlled trial. American Journal of Hypertension.2009; 22(7): 782-801.
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Objective To compare change in BP in treated, uncontrolled hypertensives managed using
renin test-guided therapeutics (RTGT) vs. clinical hypertension specialists’ care
(CHSC)
METHODS
Study Design o Randomized, open-label controlled trial
▪ Randomized in a 1:1 ratio to be managed using RTGT vs. CHSC
▪ Not stratified for any demographic or clinical variables
Inclusion
Criteria
o Adults ≥21 years of age
o Uncontrolled HTN (Defined as 3 quietly sitting clinic readings at the single
baseline visit ≥140/90 mmHg (≥130/80 mmHg if DM and/or CKD present)
o Taking one or more anti-hypertensive agent
Exclusion
Criteria
o Uncontrolled DM or hyperlipidemia requiring medication changes
o Any active disease process requiring new diagnostic and therapeutic plans
o Any life-threatening illness
o History of alcohol or drug abuse in the last 5 years
o Mental illness or personality disorder that might interfere with adherence to
study protocol
o End-stage renal disease/progressive CKD (SCr >2.5 mg/dL)
o Intolerance to 2 or more antihypertensive medications
o Home BP readings <135/85 mmHg at baseline (or <125/75 mmHg in patients
with CKD/DM)
Interventions Renin test-guided therapeutics algorithm (RTGT):
≥1 V drug; no R drug ≥1 R drug; no V drug ≥1 R drug + ≥V drug PRA <0.65: add V drug
PRA 0.65- 6.5: add R drug
PRA >6.5: stop V drug, add R
drug
PRA <0.65: stop R drug,
add V drug
PRA 0.65- 6.5: add V drug
PRA >6.5: add R drug
PRA <0.65: stop R drug,
add V drug
PRA 0.65- 6.5: add V drug
PRA >6.5: add R drug
*If BP uncontrolled at visit 4 → repeat PRA and proceed to the appropriate protocol
o “R drugs”-ACE inhibitors, ARBs, Beta-blockers
o “V drugs”-Thiazide diuretics, Alpha-1 antagonists, CCBs
Clinical hypertension specialists’ care (CHSC):
o PRA was not available to guide medication changes Outcomes Primary Outcome
o Change in SBP and DBP from baseline to follow-up
Secondary Outcomes
o Renin values defining low-, medium-, and high-renin patients
o Medication changes from baseline to follow-up
Monitoring o Patients were managed by 1 of 3 clinical HTN specialists
o Patients were scheduled every 2-4 weeks until BP was controlled
o Clinic BP was an average of 3 readings
o Home BPs were checked twice daily
Statistical
Analysis
o Estimated sample size: 60 patients to detect a 4-point difference in both SBP
and DBP with 90% power
o Intention to treat analysis: Included patients with baseline and ≥1 follow-up visit
o Primary outcome compared using student unpaired t-test
RESULTS
Participant
Demographics
o 77 patients were included in the intention-to-treat analysis (41 RTGT vs. 43
CHSC)
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o Patients in the RTGT group were older (63 vs. 58 years), mostly Caucasian, and
had lower eGFR
o Baseline PRA levels were not different between groups
o No significant difference in baseline BP between groups (RTGT: 157/87 mmHg
vs. CHSC: 153/91 mmHg)
Outcomes Primary Outcome
o Change in SBP: RTGT -29.1 mmHg vs. CHSC -19.2 mmHg (p= 0.03)
o Change in DBP: RTGT -14.1 mmHg vs. CHSC -11.3 mmHg (p= 0.32)
Secondary Outcomes
o RTGT group had no change in the number of BP medications, while CHSC saw
a slight increase in average number of BP meds 2.7 → 3.0 (p= 0.25)
o Number of clinic visits were similar between groups (3.6 vs 3.4)
o CHSC added mostly V drugs while making few changes in R drugs
o Higher rates of BP control in RTGT group, though this was not statistically
significant
o Low-renin: Decreased number of medications in RTGT group while numbers
increased in CHSC group (p= 0.01)
o Medium-renin: Significantly greater BP reduction in the RTGT group (p= 0.01)
o High-renin: No significant differences between groups
AUTHORS’ CONCLUSIONS
The overall success of the RTGT algorithm demonstrates that using ambulatory PRA testing in treated
but uncontrolled HTN provides key information about their current sodium-volume status and/or
renin status that can be used to improve BP control.
CRITIQUE/DISCUSSION
Strengths o Randomized control trial
o Ruled out white coat HTN
o Utilized clinic and home BP readings
o Real-life plasma renin activity values (did not require stopping HTN agents)
o Utilized intention-to-treat analysis
Limitations o Unbalanced treatment groups (race, age, eGFR)
o Potential patient population underrepresented due to changes in BP goals in
new guidelines
o No standardization of CHSC group (guidelines, protocols, etc.)
o RTGT guidelines provide no guidance on starting doses of medication or dose
titrations
Discussion o RTGT was able to decline BP without any net change in medication number
▪ Lower costs, fewer adverse effects, better compliance
▪ May counterbalance or exceed benefits of current recommendations to just
add an aldosterone antagonist
o Showed the applicability of PRA levels in the ambulatory care setting
COST EFFECTIVENESS ANALYSIS- AUTHORS’ CONCLUSIONS5
o A PRA guided strategy that lowered mean SBP by ≥10mmHg than standard of care is likely cost
effective
o At least for younger adults or those with higher cardiovascular risk, PRA guided strategy may be a
reasonable and cost-effective strategy to aid clinicians in improving BP control
o This study did not take into account medication costs, which can be potentially decreased though
PRA guidance
o PRA guided strategy appears to dominate standards of care when PRA tests costs <$70 per test
o This suggests that future reductions in the cost of PRA should warrant increased consideration of
PRA guided treatment
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Table 12. ALDOSTERONE ANTAGONISTS OR RENIN-GUIDED THERAPY FOR
TREATMENT-RESISTANT HYPERTENSION: A COMPARATIVE EFFECTIVENESS
PILOT STUDY IN PRIMARY CARE30
BACKGROUND AND OVERVIEW
Citation Egan BM, Laken MA, Sutherland SE, et al. Aldosterone antagonists or renin-guided
therapy for treatment-resistant hypertension: a comparative effectiveness pilot
study in primary. American Journal of Hypertension. August 2016; 29(8): 976-983.
Objective To test the feasibility and preliminary effectiveness of either adding an aldosterone
antagonist (AA) or using renin-guided therapy (RGT) in adults with uncontrolled
TRH in usual primary care settings.
METHODS
Study Design o Comparative effectiveness TRH pilot study
▪ Patients were recruited from 4 community practice site
▪ Each site was randomly assigned to one of 2 treatment protocols (RGT vs.
AA)
Inclusion
Criteria
o Patients 18-80 years old
o Elevated BP on 2 separate screening visits, while taking ≥3 different classes of
BP meds at ≥50% of maximum recommended dose per JNC7 (or the FDA
maximum approved dose if not included in JNC7)
Exclusion
Criteria
o Required legal guardian
o Non-English speaking
o Known or suspected secondary HTN
o Symptomatic or significant orthostatic hypotension (standing BP falling ≥15/10
mmHg)
o Life threatening or severe illness likely to worsen during the next 6 months
o Nonadherence with BP medications (per refill history)
o eGFR <50 mL/min/1.73 m2
Interventions AA arm:
o Received usual care with the addition of spironolactone at a starting dose of
12.5-25mg daily
RGT arm:
o R drugs-ACE inhibitors, ARBs, Beta-blockers
o V drugs-Thiazide diuretics, Alpha-1 antagonists, CCBs
o Physicians were encouraged to manage patients according to the baseline PRA:
Low PRA <0.65
o Discontinue R drugs in the absence of compelling indications
o Add or increase V drugs
Moderate PRA 0.65-4.5
o If regimen predominantly V drugs, add an R drug
o If regimen predominantly R drugs, add a V drug
High PRA >4.5
o Discontinue V drugs in the absence of compelling indications
o Add or increase R drugs
Outcomes Primary Outcome:
o Change in clinic BP
Secondary Outcomes:
o Final BP reading
o Proportion of patients achieving goal
o Changes in BP medications
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Monitoring o BP was tested in the clinic 7 times following appropriate resting period
▪ 1st: staff present
▪ 2-6th: without staff present (automatic re-inflation at 1 minute intervals)
▪ 7th: after standing for 3 minutes to rule out orthostasis
o Readings ≥135/85 mmHg (or ≥125/75 mmHg in patients with DM or CKD)
required second BP screening visit following similar protocol + home BP
readings taken twice daily for 1 week
o PRA was collected in upright patients on their usual diet and antihypertensive
medications
o Patients were followed for a max of 6 visits over a 6-month period (including 2
baseline visits)
o Patients could be discharged early if BP controlled at earlier visit
Statistical
Analysis
o Intention-to-treat analysis
o Categorical data: assessed using Chi square tests (or Fisher’s exact test when
count <5)
o Continuous data: assessed using pooled t-test
o Logistic regression models were used to estimate relative risk of BP control
adjusted for age, BMI, and baseline BP
RESULTS
Participant
Demographics
o 44 patients included in intention-to-treat analysis (20 AA vs. 24 RGT)
o Demographic and baseline measures were similar between treatment arms
o Average age was 57 and 58 years
o High rates of DM (>45%), African Americans (>70%)
Outcomes
Outcomes AA Arm
(n= 20)
RGT Arm
(n= 24)
p-value
Primary Outcome
Change in SBP (mmHg) -17.6 -20.4 0.655
Change in DBP (mmHg) -4.0 -9.7 0.103
Secondary Outcomes
Final SBP (mmHg) 144 132 0.068
Final DBP (mmHg) 86 75 0.014
“Controlled” (5/5 mmHg
less than goal)
5 (25%) 15 (63%) 0.017
BP <140/90 mmHg 7 (35%) 16 (66%) 0.036
BP <130/80 mmHg 3 (15%) 12 (50%) 0.025
BP medications 4.8 4.0 0.003
Change in BP medications 0.9 0.4 0.009
o Adjusting for age, BMI, and baseline BP, there was a non-significant increase in
the odds ratio for BP control at the last follow up with RGT
o The low PRA group had the most significant drop in BP, followed by moderate,
then high
Adverse
Events
o 2 serious ADRs were reported (one in each group)
▪ AA arm: significant HTN with hypertensive symptoms due to nonadherence
▪ RGT arm: heart failure exacerbation likely due to following PRA too closely
(chose atenolol over carvedilol)
o All 20 patients in the AA arm had spironolactone added and serum potassium
levels rose 0.3 mEq/L and eGFR decreased 2.7 mL/min/1.73 m2
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AUTHORS’ CONCLUSIONS
o The need for fewer medications to lower BP with RGT than AA may have potential benefits on
medication costs, adverse effects, and cardiovascular outcomes
o Adherence to both protocols was strong, suggesting either could be successfully implemented in
practice
o This pilot study provides support for a larger comparative effectiveness trial
CRITIQUE/DISCUSSION
Strengths o Inclusion required elevated readings at 2 separate visits
o BP measurement protocol helps eliminate “white coat effect”
o Considered compelling indications
o Real-life plasma renin activity values (did not require stopping HTN agents)
o Used PRA levels in combination with clinical judgement
o Intention-to-treat analysis
Limitations o Potential patient population underrepresented due to changes in BP goals in
new guidelines
o Inclusion BP were 5/5 mmHg lower than BP goals (based on theory that their
BP measurement protocol results in lower readings)
o Different definition of high PRA
o Possible type 2 error (small sample size, limited power, etc.)
o Results may not reflect patients who are older, white, or have eGFR <50
mL/min/1.73 m2
o Did not compare timeline to achieve control (Did RTG or AA result in control
faster?)
Discussion The results show promise for PRA levels to be utilized in primary care in patients
with TRH due to its ability to be effectively implemented in clinic and its ability to
lower medication requirements.
4 SUMMARY AND RECOMMENDATIONS 4.1 INITIAL THERAPY TREATMENT DECISIONS
• Summary:
o In black patients ≥50 years and white patients <50 years, the age-race strategy effectively
selected the most effective medication
o However, in black patients <50 years or white patients ≥50 years, the age-race strategy was
ineffective at selecting the most effective medication
o The ALLHAT trial showed greater reduction in BP and stroke rates with first line thiazide
diuretics compared to ACE inhibitors
• Recommendation:
o Consider a combination of the age-race strategy, thiazide-first (in black patients), and PRA
strategy for initial therapy treatment decisions (See Figure 3.)
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FIGURE 5. Proposed Algorithm for Initial therapy Treatment Decisions
4.2 TREATED, UNCONTROLLED HYPERTENSION • Summary:
o A PRA driven protocol was able to be successfully implemented into a clinic setting for
patients with treated, uncontrolled HTN
o PRA guided therapy lowered BP with either no net change or a decrease in the number of
medications patients were taking
o PRA guided therapy was shown to likely be cost-effective in treated, uncontrolled HTN.
Cost-effectiveness was increased when cardiovascular risk factors were present.
• Recommendations:
o PRA guided therapy should be considered in treated, uncontrolled HTN to help minimize
pill burden (See table 13 for algorithm of therapy initiation and de-escalation)
o In TRH, PRA guided therapy would be preferred in patients already on an aldosterone
antagonist or if there are concerns for tolerability to an aldosterone antagonist
Table 13. Proposed algorithm for treated, uncontrolled hypertension
PRA <0.6 PRA 0.6-6.0 PRA ≥6.0
• Add or maximize Anti-V
drug
• Stop Anti-R drug in the
absence of compelling
indication
• If not on an Anti-R drug,
add an Anti-R drug
• If on ≥1 Anti-R drug,
add an Anti-V drug
• Add or maximize Anti-R
drug
• Stop Anti-V drugs in the
absence of compelling
indications
If BP uncontrolled after 4 weeks, repeat PRA labs and follow appropriate protocol
Initial Therapy
Consider Compelling Indications
Black
Thiazide diuretic
If BP remain uncontrolled:
≥50 years: Anti-V drug
<50 years
Check PRA level
<0.6: Thiazide diuretic or other Anti-V drug
≥0.6: RAS Inhibitor
White
≥50 years<50 years: RAS
inhibitor
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4.3 FUTURE DIRECTIONS
• The most benefit from PRA levels will likely be in patients with TRH or those with a desire to
minimize pill burden
• Before widespread implementation of PRA levels, we will likely need additional trials and specific
recommendations in the treatment guidelines
• Future trials would preferable be large scale randomized controlled trials comparing usual care
to PRA level guided therapy
• Unanswered questions:
o Would PRA levels achieve BP control in fewer visits than the standard of care in TRH?
o If a patient’s BP is controlled, can we utilize PRA levels to remove unnecessary medications
while retaining BP control?
o Would black patients with elevated PRA levels achieve similar reduction in stroke with RAS
inhibitors as seen with thiazide diuretics?
5 REFERENCES 1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics 2018 update: a report from the American Heart
Association. Circulation. 2018. 2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for
the prevention, detection, evaluation, and management of high blood pressure in adults: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. J Am Coll Cardiol 2017;71:127-248.
3. Chonamian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and
treatment of high blood pressure. Hypertension. 2003;42:1206-1252. 4. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Gudieline for the management of high blood pressure in adults report
from the panel members appointed to the eight joint national committee (JNC 8). JAMA. 2014;311(5);507-520.
5. Cushman WC, Ford CE, Cutler JA, et al. ALLHAT collaborative research group. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens. 2002;4:393-404.
6. Wright JT, Dunn JK, Cutler JA. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005; 293(13):1595-1608.
7. Smith SM, Campbell JD. Cost-effectiveness of renin-guided treatment of hypertension. A J of Hypertens. 2013; 26(11):1303-1310. 8. Wright JM, Musini VM, Gill R. First-line drugs for hypertension (Review). Cochrane Database of Systematic Reviews. 2018;4:1-152.
9. Musini VM, Nazer M, Bassett K, Wright JM. Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension (review). Cochrane Database of Systemic Reviews. 2014;5.
10. Schwartz GL, Bailey K, Chapman AB, Boerwinkle E, Turner ST. The role of plasma renin activity, age, and race in selecting effective
initial drug therapy for hypertension. A J of Hypertens. 2013; 26(8):957-964. 11. Dickerson JE, Hingorani AD, Ashby MJ, et al. Optimisation of antihypertensive treatment by crossover rotation of four major
classes. The Lancet. 1999;353(9169);2008-2013.
12. Williams B, Poulter NR, Brown MJ, et al. British hypertension society guidelines for hypertension management 2004 (BHS-IV);summary. BMJ. 2004;328(7445):926.
13. Williams B, Poulter NR, Brown MJ et al. British hypertension society guidelines for hypertension management 2004 (BHS-
IV):summary. BMJ. 2004; 328 (7440):634-640. 14. Brown MJ, Cruickshank JK, Dominiczak AF, et al. Executive committee british hypertension society. Better blood pressure control:
how to combine drugs. J Hum Hypertens. 2003;17:81-86.
15. Preston RA, Materson BJ, Reda DJ, et al. Age-race subgroups compared with renin profile as predictors of blood pressure response to antihypertensive therapy. JAMA.1998;280(13):1168-1172.
16. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management a scientific statement from the American Heart Association. Hypertension. 2018; 72:1-38.
17. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bioprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomized, double-blind, crossover trial. The Lancet. 2015; 386:2059-2068.
18. Bansal N, Tendler BE, White WB, Mansor GA. Blood pressure control in the hypertensive clinic. A J of Hypertens. 2003;16(10):878-
880. 19. Laragh JH, Sealey JE. The plasma renin test reveals the contribution of body-volume content (V) and renin-angiotensin (R)
vasoconstriction to long-term blood pressure. A J of Hypertens. 2011;24(11):1164-1180.
20. Blumenfeld JD, Laragh JH. Renin System Analysis: A rational method for the diagnosis and treatment of the individual patient with hypertension. A J of Hypertens. 1998;11(7);894-896.
21. Vaughan ED, Laragh JH, Gavras I, et al. Volume factor in low and normal renin essential hypertension. Treatment with either
spironolactone or chlorthalidone. Am J Cardiol. 1973;32(4):523-532. 22. Bolli P, Amann FW, Buhler FR. Antihypertensive response to postsynaptic α-blockade with prazosin in low-and normal-renin
hypertension. J Cardiovasc Pharmacol. 1980; 2(3):399-405.
23. Buhler FR, Hulthen UL, Kiowski W, Bolli P. Greater antihypertensive efficacy of the calcium channel inhibitor verapamil in older and low renin patients. Clin Sci. 1982;63(8):439-442.
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24. Buhler FR, Laragh JH, Vaughan D, et al. Antihypertensive action of propranolol: Specific antirenin responses in high and normal renin
forms of essential, renal, renovascular and malignant hypertension. Am J Cardiol.1973;32(4):511-522.
25. Minami J, Ishimitsu T, Matsuoka H. Pretreatment plasma renin activity levels correlates with the blood pressure response to telmisartan in essential hypertension. A J of Hypertens. 2008;21(1):10-13.
26. Olson N, Dejongh BD, Hough A, Parra D. Plasma renin activity-guided strategy for the management of hypertension.
Pharmacotherapy. 2012;32(5):446-455. 27. Schwartz GL, Bailey K, Chapman AB, Boerwinkle E, Turner ST. The role of plasma renin activity, age, and race in selecting effective
initial therapy for hypertension. A J of Hypertens. 2013;26(8):957-964. 28. Gharaibeh KA, Turner ST, Hamadah AM, et al. Comparison of blood pressure control rates among recommended drug selection
strategies for initial therapy of hypertension. A J of Hypertens. 2016; 29(10):1186-1194. 29. Egan BM, Basile JN, Rehman SU, et al. Plasma renin test-guided drug treatment algorithm for correcting patients with treated but
uncontrolled hypertension: a randomized controlled trial. American Journal of Hyperten A J of Hypertens .2009;22(7):782-801.
30. Egan BM, Laken MA, Sutherland SE, et al. Aldosterone antagonists or renin-guided therapy for treatment-resistant hypertension: a comparative effectiveness pilot study in primary. A J of Hypertens. 2016;29(8):976-983.
6 APPENDIX
Table 14. Abbreviations
AA Aldosterone antagonist
ACC/AHA American College of Cardiology and American Heart Association
ACE Angiotensin-converting enzyme
ARB Angiotensin II receptor blockers
ARR Absolute risk reduction
ASCVD Atherosclerotic cardiovascular disease
BP Blood pressure
CCB Calcium channel blocker
CKD Chronic kidney disease
CHSC Clinical hypertension specialists’ care
DM Diabetes Mellitus
DRI Direct renin inhibitor
GERA Genetic Epidemiology Responses to Antihypertensives
HFrEF Heart failure with reduced ejection fraction
HFpEF Heart failure with preserved ejection fraction
HR Heart rate
HTN Hypertension
JNC Joint National Committee
NNH Number needed to harm
NNT Number needed to treat
NSAIDs Nonsteroidal anti-inflammatory
PRA Plasma renin activity
R Plasma renin-angiotensin vasoconstrictor activity
RAS Renin-angiotensin system
RGT Renin guided treatment
RTGT Renin test-guided therapeutics
SCr Serum creatinine
TRH Treatment resistant hypertension
US United States
V Body sodium-volume content