Pharmacology Consult

A ‘new’ strategy for improving hypertension management

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.

Kade Birkeland, PharmD
Kade Birkeland
Augustus Hough, PharmD
Augustus Hough

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 patient’s “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 “renin profiling.”

Insights from plasma renin activity measurement

PRA measurements provide insight into a patient’s 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 elevation.

Furthermore, knowledge of a patient’s 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 patient’s 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.

Utility of individualized renin profiling

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 Europe.

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 uncontrolled hypertension.

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 patient’s renin profile classification. It was found that individualization of a patient’s 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 treatment guidelines.

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 stepwise approach.

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 Today’s Pharmacology Consult.

Disclosures: Drs. Birkeland and Hough report no relevant financial dislosures.

For more information:

  • Alderman M. Am J Hypertens. 2010;23:1031-1037.
  • Egan B. Am J Hypertens. 2009;792-801.
  • Hartman D. Clin Chem. 2004;50:2159-2161.
  • Hulley S. JAMA. 2002;288:58-66.
  • Laragh J. Am J Hypertens. 2001;14:491-503.
  • Sealey J. Hypertension. 2010;55:e16-e17.
  • Turner S. Am J Hypertens. 2010;23:1014-1022.

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.

Kade Birkeland, PharmD
Kade Birkeland
Augustus Hough, PharmD
Augustus Hough

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 patient’s “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 “renin profiling.”

Insights from plasma renin activity measurement

PRA measurements provide insight into a patient’s 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 elevation.

Furthermore, knowledge of a patient’s 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 patient’s 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.

Utility of individualized renin profiling

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 Europe.

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 uncontrolled hypertension.

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 patient’s renin profile classification. It was found that individualization of a patient’s 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 treatment guidelines.

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 stepwise approach.

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 Today’s Pharmacology Consult.

Disclosures: Drs. Birkeland and Hough report no relevant financial dislosures.

For more information:

  • Alderman M. Am J Hypertens. 2010;23:1031-1037.
  • Egan B. Am J Hypertens. 2009;792-801.
  • Hartman D. Clin Chem. 2004;50:2159-2161.
  • Hulley S. JAMA. 2002;288:58-66.
  • Laragh J. Am J Hypertens. 2001;14:491-503.
  • Sealey J. Hypertension. 2010;55:e16-e17.
  • Turner S. Am J Hypertens. 2010;23:1014-1022.