Despite the prescription of antihypertensive therapy and the widespread
availability and promotion of practice guidelines, an estimated 17 million
people in the United States suffer from uncontrolled BP.
Current management strategies for hypertension are based on practice
guidelines that recommend clinicians utilize a stepwise approach when
initiating antihypertensive therapy. This practice strategy was in part
influenced by the landmark BP treatment study, Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). However,
ALLHAT, although internationally acclaimed, resulted in only 66% of patients
treated with antihypertensive therapy achieving BP control (<140 mm Hg
systolic and <90 mm Hg diastolic), with 62.5% requiring combination of two
or three antihypertensives.
Global underachievement in reaching BP targets, when considered in the
context of the ALLHAT results, have ignited an interrogation of
guideline-recommended hypertension treatment strategies, specifically the
one-size-fits-all stepwise approach. In fact, it has been reported
that up to 73% of hypertensive patients treated with antihypertensives can be
controlled with monotherapy if a patients best
antihypertensive is selected using independent trials of diuretics, calcium
channel blockers, beta-blockers and ACE inhibitors.
Based on these findings, clinicians and scientists continue to pursue
methods to individualize, or tailor, antihypertensive therapies. One promising
strategy includes the measurement of plasma renin activity (PRA) and subsequent
identification and classification of renin activity, also referred to as
PRA measurements provide insight into a patients specific
pathophysiology, allowing identification of the system that is maintaining
hypertension. A low PRA level (<0.65 ng/mL/hour) indicates a salt-volume
excess-mediated BP elevation, whereas a high PRA level (≥0.65 ng/mL/hour)
indicates a renin-angiotensin system vasoconstriction-mediated BP
Furthermore, knowledge of a patients PRA can help guide selection
of antihypertensive therapy most likely to effectively reduce BP. Hypertensive
patients with low PRA, or volume-mediated hypertension, will likely respond
favorably to anti-volume drugs, such as diuretics, aldosterone receptor
blockers, or calcium channel blockers. Conversely, hypertensive patients with
high PRA, or renin-mediated hypertension, are likely to respond favorably to
anti-renin drugs, such as ACE inhibitors, angiotensin receptor blockers, direct
renin inhibitors, beta-blockers or central alpha agonists.
When contemplating the use of renin profiling in patients currently
treated with antihypertensive agents, it is important to understand how various
agents can influence a patients PRA result. For example, initiation of a
thiazide or loop diuretic may result in a rise in PRA secondary to a reactive
increase in renin secretion in response to natriuresis. Similarly, a rise in
PRA may occur after initiation of an ACE inhibitor or angiotensin receptor
blocker caused by a loss of negative feedback on renin release.
In patients treated with ACE inhibitors and angiotensin receptor
blockers, it is suggested that an effective PRA be calculated (as
opposed to PRA) to account for downstream inhibition of angiotensin II
activities and incomplete renin blockade. Because ACE inhibitors and
angiotensin receptor blockers inhibit approximately 90% of angiotensin II
activities (and thus approximately 90% of renin activities), it is proposed
that effective PRA is 10% of measured PRA (effective PRA=PRA × 0.10).
Although theoretically sound, further study is needed to confirm whether this
calculation improves the utility of PRA in guiding antihypertensive therapy.
Despite the concept of utilizing PRA in the management of hypertension
having been proposed for more than a decade, testing impracticalities that
include availability, cost, offsite processing, difficult assay,
interlaboratory variability and prolonged incubation in low-renin subjects have
prevented routine use clinically. However, the mounting evidence demonstrating
assessment of PRA as a way to successfully individualize hypertensive therapy
has prompted clinicians to revisit the once neglected strategy to address
inadequacies in modern hypertension management.
Direct renin measurement (DRM), an immunoassay that measures circulating
renin concentration, has generated interest among investigators as an
alternative to PRA because of its ability to generate high throughput with
preserved efficacy in low-renin hypertensives. DRM has yet to be approved by
the FDA for clinical use in the United States, but it is currently available in
The predictive ability of PRA testing was recently evaluated and
confirmed that renin profiling strongly predicts a patient response, or lack
thereof, to either renin- (beta-blocker) or volume- (thiazide diuretic)
mediated therapies. Importantly, this predicted power was present throughout
all phases of hypertension management, including initiation of therapy in
treatment-naïve patients or initiation of add-on therapy in patients with
In a proof of concept study, PRA testing was integrated into clinical
practice using a treatment algorithm intended to guide addition or subtraction
of anti-volume or anti-renin drugs based on a patients renin profile
classification. It was found that individualization of a patients
antihypertensive regimen using renin profiling resulted in significant gains in
BP control without a net addition of medications, thus circumventing potential
blind initiation of additional antihypertensives as recommended by current
At the core of renin profiling is the possibility to predict
antihypertensive BP response. Renin profiling was recently shown to be
predictive of BP reduction to anti-volume or anti-renin drugs. Additionally,
when a therapeutic mismatch was created (eg, initiation of an anti-renin drug
in a patient with low-renin activity), the possibility of a pressor response
has been demonstrated, thus extending the utility of renin profiling in
matching the right drug to the right patient.
Hypertension continues to be a significant burden to the health care
system. Despite development of new therapies and broad acceptance of practice
guidelines, overall control rates remain suboptimal. Renin profiling provides
clinicians with a strategy to manage hypertension by individualizing therapy,
particularly in patients who have failed to achieve control by the current
Kade Birkeland, PharmD, is a clinical pharmacy specialist in the
cardiology masters of pharmaceutical care program and guest faculty at the San
Marcos University School of Pharmacy and Biochemistry in Lima, Peru.
Augustus Hough, PharmD, is a community-based outpatient
clinic/ambulatory care clinical pharmacy specialist at the West Palm Beach VA
Medical Center in Florida.
Rhonda M. Cooper-DeHoff, PharmD, MS, is an associate professor at the
University of Florida College of Pharmacy in Gainesville, Fla. and is the
column editor for Cardiology Todays Pharmacology Consult.
Disclosures: Drs. Birkeland and Hough report no relevant
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- Sealey J. Hypertension. 2010;55:e16-e17.
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