p2019b1 Sample PDF

Hypertension
By Toni L. Ripley, Pharm.D., FCCP, BCPS, AHSCP-CHC;

and Anna Barbato, Pharm.D., BCPS, AHSCP-CHC
Reviewed by Adam Bress, Pharm.D., MS; David L. Nickerson, Pharm.D., BCPS; and Kathryn Rice, Pharm.D., BCPS
Learning Objectives
1. Distinguish between the recommendations for hypertension management among recent hypertension- and disease-specific
guidelines.
2. Justify blood pressure goals for individual patients on the basis of the primary literature and hypertension guidelines.
3. Apply understanding of blood pressure results and measurement technique to a patient case.
4. Design an evaluation and treatment plan for a patient presenting with hypertension.
Introduction
Abbreviations in This Chapter
Hypertension Overview
AAFP American Academy of Family
Physicians Blood pressure elevations are associated with an increased risk of
ABPM Ambulatory blood pressure cardiovascular (CV) disease in a linear fashion. Starting at a blood
monitoring pressure of 115/75 mm Hg, every increase of 20 mm Hg in systolic
ACC American College of Cardiology blood pressure (SBP) and/or increase of 10 mm Hg in diastolic blood
ACP American College of Physicians pressure (DBP) is associated with a doubling of the risk of death from
AHA American Heart Association stroke, heart disease, or other vascular disease (Lewington 2002).
AOBP Automated office blood pressure Increases in SBP have the strongest link with CV disease, though
ASCVD Atherosclerotic cardiovascular other blood pressure components have been linked to CV disease as
disease well, including DBP, pulse pressure, blood pressure variability, and
CV Cardiovascular mean arterial blood pressure (Whelton 2018; Muntner 2015).
JNC Joint National Committee This chapter will review the new recommendations for blood pres-
MRA Mineralocorticoid receptor sure management and will focus on the pharmacotherapy of hyper-
antagonist
tension. Because hypertension is largely managed with drug therapy,
RAS Renin-angiotensin system
clinical pharmacists often participate in management, especially
TOD Target organ damage
when hypertension may be difficult to manage because of factors
such as adverse effects or resistant hypertension.
Table of other common abbreviations.
Hypertension Epidemiology
The prevalence of hypertension in U.S. adults has continued to
increase. In 2018, the American Heart Association (AHA) heart dis-
ease and stroke statistics update reported that about 34% of U.S.
adults had hypertension, using a diagnostic SBP/DBP threshold of
140/90 mm Hg (Benjamin 2018). However, the American College of
Cardiology and AHA (ACC/AHA) 2017 blood pressure guidelines low-
ered the threshold for the diagnosis of hypertension to an SBP/DBP
of 130/80 mm Hg, which led to a new hypertension prevalence of 46%
of U.S. adults. Despite the 12 percentage point increase in prevalence
with the lower diagnostic threshold, the 2017 ACC/AHA blood pres-
sure guideline estimates that only an additional 2% of patients will
be recommended antihypertensive medications because the new
guideline does not recommend that all patients with blood pressure
PSAP 2019 BOOK 1 • Cardiology 7 Hypertension
01_1_Ripley.indd 7 20/12/18 10:57 am

readings of 130–139/80–89 mm Hg should receive drug ther- Joint National Committee Guidelines
apy (Muntner 2018). The Joint National Committee (JNC) published the first hyper-
Hypertension prevalence increases as patients age. Using tension management guidelines in the 1970s. These guide-
the lower threshold as defined by the 2017 ACC/AHA guidelines were constructed primarily as an expert consensus
lines, the prevalence of hypertension for patients 20–44 years rather than an evidence-based set of recommendations.
of age is 30% in men and 19% in women. This increases to 77% Nonetheless, the JNC guidelines were the authoritative rec-
for men and 75% for women 65–74 years of age (Whelton 2018). ommendations for hypertension until 2013, when the National
Hypertension prevalence also differs on the basis of eth- Heart, Lung, and Blood Institute (NHLBI) announced the trans-
nicity and sex. Overall, hypertension is more prevalent in fer of responsibility for guideline development to other organiza-
blacks, with an estimated prevalence of 59% and 56% in black tions. At that time, the ACC and AHA accepted responsibility for
men and women, respectively. White, Asian, and Hispanic leading the development of comprehensive and evidence-based
men have a prevalence of 47%, 45%, and 44%, respectively, hypertension guidelines. At the same time, the NHLBI published
and white, Asian, and Hispanic women have an estimated the recommendations of the JNC 8 committee.
prevalence of 41%, 36%, and 42%, respectively (Whelton 2018). Although this was a controversial publication, the intent of
These numbers are based on the 2017 ACC/AHA guidelines the JNC 8 committee was to bridge the gap between JNC 7
and are higher than previous estimates because of the lower and the new ACC/AHA guidelines that were in development,
diagnostic threshold for hypertension in the new guidelines. given that JNC 7 was published in 2003 and many believed
it to be outdated. For example, JNC 7 recommended β-block-
Clinical Guideline Update ers as an acceptable first-line therapy, whereas by 2017, most
hypertension experts considered β-blockers to be inferior to
In 2017, the long-awaited ACC/AHA guidelines for the prevention,
other first-line hypertension medications in the absence of
detection, evaluation, and management of high BP in adults were
compelling indications.
published. These are the first comprehensive, evidence-based
The JNC 7 guidelines were a comprehensive expert consen-
guidelines for hypertension in the United States.
sus of the prevention, detection, evaluation, and treatment of
high blood pressure in adults (Chobanian 2003), whereas the
JNC 8 guidelines were an evidence-based, focused set of rec-
Baseline Knowledge Statements ommendations. The JNC 8 panel chose three critical questions
on which to focus its update (Box 1) and revised the process
Readers of this chapter are presumed to be familiar
with the following: such that recommendations were graded on the basis of the
available evidence, as is the contemporary guideline standard.
• Pathophysiology of hypertension.
One unique aspect of JNC 8 was the evidence included in its
• Knowledge of oral pharmacologic agents used to review to inform its recommendations. Only randomized con-
treat hypertension.
trolled clinical trials were reviewed; meta-analyses, systematic
• Knowledge of parenteral agents used to treat
hypertension. reviews, and epidemiologic analyses were excluded. Although the
intention to restrict review to the gold standard evidence of ran-
• Consequences of poor blood pressure control.
domized trials is understandable, the process was criticized for not
• Standard process of blood pressure measurement.
considering the totality of evidence for managing hypertension.
Table of common laboratory reference values
Additional Readings Box 1. Critical Questions Addressed

in JNC 8
The following resources have additional background In adults with hypertension:
information on this topic: 1. Does initiating antihypertensive pharmacologic therapy
• Seventh Report of the Joint National Committee on at specific BP thresholds improve health outcomes?
Prevention, Detection, Evaluation, and Treatment of 2. Does treatment with antihypertensive pharmacologic
High Blood Pressure: the JNC 7 report. JAMA therapy to a specified BP goal improve health outcomes?
2003;289:2560-672. 3. Do various antihypertensive drugs or drug classes
• 2014 evidence-based guideline for the manage- differ in comparative benefits and harms on specific
health outcomes?
ment of high blood pressure in adults: report from
the panel members appointed to the Eighth Joint
BP = blood pressure.
National Committee (JNC 8). JAMA
2014;311:507-20. Information from: James PA, Oparil S, Carter BL, et al. 2014
evidence-based guidelines for the management of high blood
• ASCVD risk calculator. pressure in adults. Report from the panel members appointed
• 2017 ACC/AHA hypertension guidelines. to the Eighth Joint National Committee (JNC 8). JAMA
2014;311:507-20.
01_1_Ripley.indd 8 20/12/18 10:57 am

The JNC 8 guidelines contained nine recommendations However, some guidelines remain that were not developed
surrounding the three critical questions. The most controver- in collaboration with the ACC or AHA that continue to support
sial recommendation was to relax the target blood pressure clinical practice. The American College of Physicians (ACP)
for adults without diabetes or chronic kidney disease, age 60 and the American Academy of Family Physicians (AAFP) pub-
and older, to less than 150/90 mm Hg. In fact, a group within lished recommendations for managing hypertension in adult
the JNC 8 committee separately published a “minority view” patients 60 and older in early 2017, before release of the 2017
supporting the continued goal of less than 140/90 mm Hg for ACC/AHA guidelines (Qaseem 2017). After publication of
adults 60 and older (Wright 2014). These authors cited con- ACC/AHA guidelines, the ACP and AAFP published a state-
cerns about the adverse effects on public health if blood pres- ment that they would not be endorsing the ACC/AHA hyper-
sure goals were relaxed in older patients because older age tension recommendations (Crawford 2017). Hence, the ACP/
is a risk factor for CV disease. Although no randomized con- AAFP 2017 guidelines should be considered a current and
trolled trials supported treating patients 60 and older to less active set of recommendations.
than 140/90 mm Hg, they contended that there were also no Finally, the role of the JNC 8 panel recommendations remains
data at the time to support the higher blood pressure target. less clear. Some groups such as ACP and AAFP have endorsed
the JNC 8 recommendations. However, JNC 8 is not a com-
Other Hypertension Guidelines prehensive guideline and leaves many questions unanswered.
The delay in comprehensive U.S. guidelines led to a surge in Table 1 presents highlights from the guideline recommendations.
blood pressure recommendations from several groups. Many BP = blood pressure; TIA = transient ischemic attack.
of these guidelines were focused on subgroups, such as those
with heart failure, coronary artery disease, or stroke. Guide- 2017 ACC/AHA Recommendations for Managing
lines such as these were developed by the ACC; therefore, it Hypertension in Adults
is reasonable to consider that the goals recommended by the The 2017 ACC and AHA updated guidelines were endorsed by
2017 ACC/AHA guidelines supersede former blood pressure many other organizations. The guidelines are extensive, and
recommendations by past ACC-endorsed guidelines. several recommendations are new and worthy of discussion.
Table 1. Comparison of BP Target Recommendations
BP Categoriesa
SBP DBP
BP Targets (mm Hg) (mm Hg)
JNC 7, 2003 < 140/90 mm Hg Normal < 120 < 80

< 130/80 mm Hg for those with diabetes
Prehypertension 120–139 80–89
or chronic kidney disease
Stage 1 hypertension 140–159 90–99
Stage 2 hypertension ≥ 160 ≥ 100
JNC 8, 2014 < 150/90 mm Hg for patients ≥ 60 Was not a comprehensive set of recommendations, and did
< 140/90 mm Hg for patients < 60, diabetes, not discuss hypertension diagnostic thresholds
and chronic kidney disease
ACP/AAFP, 2017 < 150/90 mm Hg for patients ≥ 60 Was not a comprehensive set of recommendations and did
< 140/90 mm Hg for patients at higher CV not discuss hypertension diagnostic thresholds
risk, or with a history of stroke or TIA Did not address recommendations in patients < 60
ACC/AHA, 2017 ≤ 130/80 mm Hg Normal < 120 < 80
Elevated 120–129 < 80
Stage 1 hypertension b
130–139 80–89
Stage 2 hypertension ≥ 140 ≥ 90
a
Patients with SBP and DBP in two different categories should be classified in the higher category.
b
Antihypertensive medication should be initiated in stage 1 hypertension only in patients with clinical CV disease, a 10-year risk of
ASCVD of 10% or higher, diabetes mellitus, or chronic kidney disease.
BP = blood pressure; TIA = transient ischemic attack.
01_1_Ripley.indd 9 20/12/18 10:57 am

New Diagnostic Criteria and Staging Treatment Goals
The 2017 guidelines lowered the threshold for the diagnosis Epidemiologic evidence has shown that the risk of vascular
of hypertension to 130/80 mm Hg from the 140/90 mm Hg death increases as blood pressure increases above 115/75
standard of the past several decades. The JNC 7 guidelines mm Hg (Lewington 2002).
categorized patients with a blood pressure of 130–139/80– Blood pressure goals have been intensely debated since
89 mm Hg as “pre” hypertensive on the basis of cohort data 2013, when the JNC 8 recommendations became avail-
showing a gradient of increased CV risk as SBP crossed the able. Whereas the thet JNC 8 recommendation to relax the
threshold of 120 mm Hg. The lower threshold for the diagno- SBP goals from less than 140 mm Hg to less than 150 mm
sis of hypertension increased the prevalence of hypertension, Hg in patients older than 60 without diabetes or kidney dis-
as previously discussed. ease was met with criticism, the 2017 ACC/AHA hyperten-
The 2017 guidelines also updated the blood pressure cate- sion guidelines now call for stricter blood pressure control.
gories (see Table 1) and highlighted the blood pressure mea- A review of clinical trials that have tried to tackle this chal-
surement technique (discussed below). lenging question regarding optimal blood pressure targets
follows. Of importance, several well-conducted meta-analy-
Risk Assessment ses have further explored this issue (Bundy 2017; Reboussin
The 2017 ACC/AHA guidelines recommend incorporating CV 2017). A comprehensive review of this complicated question
risk estimates with blood pressure levels to determine when is beyond the scope of this chapter.
to initiate antihypertensives. The guidelines suggest initiat-
ing medication in those at high CV risk when SBP is 130 mm SPRINT
Hg or greater or DBP is 80 mm Hg or greater. In those at lower The Systolic Blood Pressure Intervention Trial (SPRINT) was a
CV risk, they suggest initiating antihypertensives when SBP sentinel clinical trial that compared CV outcomes in patients
is 140 mm Hg or greater or DBP is 90 mm Hg or greater (Whel- diseasewith increased CV risk who were randomized to an
ton 2018). intensive blood pressure goal of less than 120 mm Hg or a
High CV risk is defined as a history of clinical CV disease standard blood pressure goal of less than 140 mm Hg (Wright
or an estimated 10-year atherosclerotic CV disease (ASCVD) 2015). This trial has affected hypertension management and
risk of 10% or higher according to the pooled cohort equa- clinical guidelines more than any other trial since the land-
tions. Clinical CV disease is defined as coronary artery dis- mark Antihypertensive and Lipid-Lowering Treatment to Pre-
ease, heart failure, or stroke. vent Heart Attack Trial (ALLHAT).
The inclusion of risk estimation in determining when In the SPRINT study, more than 9000 patients were ran-
to initiate antihypertensives comes, in part, from SPRINT, domized. ).)To be included, patients had to be 50 or older and
which included CV risk assessment as part of the inclu- have an increased CV risk, defined as clinical or subclinical
sion criteria. Using the 10-year Framingham risk score, the CV disease, chronic kidney disease, or a 10-year CV risk of
SPRINT investigators set the threshold for high CV risk at 15% or more on the basis of the Framingham risk score, or be
15%, which has been estimated to be similar to a 10-year 75 or older. On average, patients were 68 years of age with a
ASCVD risk of 6–7% according to the pooled cohort equa- baseline blood pressure of 140/78 mm Hg, about 28% were 75
tions (Whelton 2018). or older, 17% had clinical CV disease, and the average 10-year
Use of the pooled cohort equations has been controversial, CV risk score was 25%.
given that their role for estimating the risk of initiating antihy- Diastolic BP was not a criterion for inclusion in SPRINT. Eli-
pertensives has not been formally evaluated in a clinical trial. gibility was based on a combination of SBP and the number
Conversely, the pooled cohort equations have become more of antihypertensive medications being taken at enrollment.
common in clinical practice and are integrated into some Patients with an SBP of 130–180 mm Hg and taking no more
electronic medical records for efficient risk assessment. than four antihypertensives were included.
The pooled cohort equations are also used to determine the Patients with a history of stroke or diabetes, symptomatic
appropriate drug therapy for dyslipidemia and have played a heart failure or heart failure with an ejection fraction less than
role as the contemporary CV risk estimator, in place of Fram- 35%, severely elevated blood pressure (defined as SBP greater
ingham, since 2014. than 180 mm Hg), orthostasis (defined as an SBP decrease to
Although evidence to evaluate the pooled cohort equa- less than 110 mm Hg after 1 minute of standing) and nursing
tions in hypertension is beginning to surface, their use and home patients were excluded from the SPRINT trial.
the thresholds to consider for various risk levels continue to Exclusion of patients with diabetes was based on the ACCORD
be debated. Regardless of the method used to assess CV risk, trial, which was ongoing at the time SPRINT was designed, with
clinicians must be aware that CV risk should be considered in the thought that intensive blood pressure control in patients
hypertension management, given that the benefits of treating with diabetes was already being adequately evaluated.
hypertension are greatest in those with the highest CV risk Of note, 14,692 patients were screened for enrollment, and
(Muntner 2017). 5331 were ineligible to participate. Forty-three percent of the
01_1_Ripley.indd 10 20/12/18 10:57 am

excluded patients were excluded because they took too many or CV risk factors. The primary outcome was the first occur-
medications or had an SBP out of the range noted previously. rence of a CV event, defined as a composite of nonfatal MI,
The primary composite outcome was myocardial infarc- nonfatal stroke, or CV death.
tion (MI), non-MI acute coronary syndromes, stroke, heart On average, patients were 62 years of age and had a base-
failure, or death from CV causes. line blood pressure of 139/76 mm Hg; 33.7% had CV disease.
The trial was terminated early, after 3.26 years of follow-up, Patients were followed for an average of 5 years.
because of the significant benefits in those randomized to the Patients in the intensive arm achieved a blood pressure of
intensive blood pressure arm. Patients in the intensive group 119.3/64.4 mm Hg and patients in the standard arm, 133.5/70.5
achieved an average SBP of 121.5 mm Hg compared with 134.6 mm Hg. Despite the blood pressure difference, the primary com-
mm Hg in patients in the standard care group, taking an aver- posite outcome was similar between the intensive and stan-
age of 2.8 and 1.8 antihypertensive medications, respectively. dard blood pressure treatment groups (1.87%/year vs. 2.09%/
The intensive group had a 25% relative risk reduction for year; HR 0.88; 95% CI, 0.73–1.06; p=0.20). However, intensive
the primary composite end point compared with the standard blood pressure reduction did reduce the rate of stroke, one of
care group (HR 0.75; 95% CI, 0.64–0.89; p<0.001). The results the prespecified secondary outcomes, compared with stan-
were largely driven by a reduction in heart failure in the inten- dard treatment (0.32%/year for intensive vs. 0.53%/year for
sive group (HR 0.62; 95% CI, 0.45–0.84; p=0.002). No differ- standard treatment; HR 0.59; 95% CI, 0.39–0.89; p=0.01).
ences occurred between the groups in MI, acute coronary Patients in the intensive blood pressure treatment arm had
syndrome, or stroke. more hypotension, syncope, bradycardia, increases in serum
Overall serious adverse events were similar between the creatinine, and hypokalemia than did patients in the standard
groups, but the intensive group had more hypotension, syn- treatment group.
cope, electrolyte abnormalities, and acute kidney injury than The conclusion from the ACCORD BP trial is that intensive
the standard care group. The standard care group had more blood pressure management in patients with type 2 diabetes
asymptomatic orthostasis (18.3% vs. 16.6%, p=0.01). does not improve CV end points, despite improved blood pres-
Blood pressure measurement in SPRINT differed from the sure values.
standard of most clinical practices. Blood pressure in SPRINT
was assessed using an automated device that measured HYVET Study
blood pressure after the patient rested for 5 minutes, which The Hypertension in the Very Elderly Trial (HYVET) was one
then provided the average of three blood pressure measure- of the first large-scale clinical trials to establish the benefit
ments. Blood pressure assessed using this method is around of lowering blood pressure in patients 80 and older (Beckett
10 mm Hg lower than the measurements used in most office 2008). The HYVET trial adds to our understanding of blood
settings. Discussion of blood pressure measurement tech- pressure targets by evaluating blood pressure control in older
nique will be provided in another section. patients at high risk of CV events and adverse drug events.
The conclusion from SPRINT is that intensive blood pres- HYVET was a non–U.S.-based study that evaluated the
sure reduction is more effective than standard blood pressure occurrence of fatal or nonfatal stroke in 3845 adults with a
reduction at reducing CV events and all-cause mortality in baseline SBP of 160 mm Hg or greater taking indapamide 1.5
patients without diabetes or stroke who are at risk of CV dis- mg daily or placebo. Perindopril 2 or 4 mg daily or placebo
ease. However, the measurement technique used in SPRINT was added to the intervention or placebo groups, respec-
may limit extrapolation of the findings to settings that do not tively, if needed, to target a goal blood pressure of less than
use similar automated blood pressure measurement devices. 150/80 mm Hg.
Patients were, on average, 84 years of age with a baseline
ACCORD BP Study blood pressure of 173/91 mm Hg. Median follow-up was 1.8
Another important clinical trial that has influenced contem- years. Blood pressure fell in both groups. After 2 years, the
porary hypertension management is the Action to Control mean seated blood pressure reduction in the placebo group
CV Risk in Diabetes BP (ACCORD BP) trial (Cushman 2010). was 14.5 ± 18.5/6.8 ± 10.5 mm Hg and was 29.5 ± 15.4/12.9 ±
In ACCORD BP, 10,521 patients were randomized to intensive 9.5 mm Hg in the intervention group.
or standard glycemic control. Patients were then further ran- There was a nonsignificant reduction in the primary end-
domized in a 2 x 2 factorial design to intensive versus stan- point with active treatment (p=0.06). However, there was a
dard care of either blood pressure or lipids. The results of the 39% reduction in death from stroke (p=0.046), a 21% reduc-
blood pressure arm, in which 4733 patients were randomized, tion in all-cause death (p=0.02), a 74% reduction in heart fail-
will be discussed here. ure (p<0.001), and a 34% reduction in the occurrence of any
Patients in ACCORD BP had uncontrolled type 2 diabetes CV event (p<0.001).
and an SBP of 130–180 mm Hg on three or fewer antihyper- The conclusion from HYVET supports targeting a blood
tensives. Included patients were age 40–54 with CV disease, pressure goal of less than 150/80 mm Hg for patients with
or age 55 and older with subclinical CV disease, albuminuria, hypertension who are older than 80.
01_1_Ripley.indd 11 20/12/18 10:57 am

SPRINT Study – Adults 75 and Older Individual characteristics should be considered when
Subanalysis estimating the risk of lowering DBP. For example, in older
Evaluation of the adults 75 and older enrolled in the SPRINT patients, arterial stiffness leads to elevated SBP and lower
trial was a prespecified analysis. Patients in this subanalysis DBP. However, lowering DBP to less than 65 or 70 mm Hg in
were 80 years of age on average and had a blood pressure of this specific group may increase vascular risk, and prudence
142/71 mm Hg (Williamson 2016). is warranted (de Boer 2017).
Thirty-one percent of patients were classified as frail,
according to a 37-item index. The average 10-year risk of CV Blood Pressure Measurement
disease was similar to that in the whole SPRINT cohort and
The 2017 ACC/AHA guidelines place more emphasis on
was 24% and 25% in the intensive and standard care groups,
proper blood pressure measurement than do previous guide-
respectively.
lines. The impetus for this comes from the recognition that
During follow-up, SBP was 123 mm Hg in the intensive arm
blood pressure measurement is error prone and there is
and 135 mm Hg in the standard care arm.
potential for harm if a provider titrates medications to the
The primary outcome was 34% lower in the intensive arm
lower blood pressure target recommended by the guide-
than in the standard care group (HR 0.66; 95% CI, 0.51–0.85).
lines using a falsely elevated blood pressure measurement
Similar to the main study results, improvement in this cohort
(Whelton 2018).
was primarily driven by a reduction in heart failure.
The most common question in treating older patients to a Proper Measurement Technique
more intensive blood pressure goal appears to be their tolera- Standard techniques for blood pressure measurement are
bility of the lower blood pressure, especially frail patients, and well established and can be done with manual auscultation
this analysis sought to address that question. or with an automated oscillometric device. Interest in using
Patients who were classified as “less fit” had a reduction automated office blood pressure (AOBP) devices has contin-
in the primary composite outcome with intensive blood pres- ued to grow, given the belief that some measurement errors
sure reduction compared with standard reduction (HF 0.63; (e.g., auscultatory errors) can be eliminated. Furthermore,
95% CI, 0.43–0.91; p=0.01). Patients who were “less fit” or AOBP devices can be programmed to minimize the white-
“frail” also had less all-cause mortality with intensive treat- coat effect by delaying blood pressure measurement such
ment, whereas patients who were classified as “fit” had no that the health care professional can leave the room and the
benefit with intensive blood pressure reduction. No differ- patient can be resting for a prescribed period (typically 1–5
ence occurred in adverse outcomes with intensive blood minutes) before measurement. The AOBP devices can also
pressure treatment using markers of frailty. provide an average of three readings.
Overall, this subanalysis helps inform hypertension man- Given that there are different methods of measuring blood
agement in older patients and supports a more intensive pressure, different blood pressure results should be expected,
strategy than was suggested with the recommendations from depending on the procedure. Providers involved with manag-
the panel appointed to the JNC 8 committee. ing hypertension should be familiar with the differences and
should consider these during clinical decision-making. Man-
DBP Considerations ual office blood pressure measurements average about 10
Another area of debate within hypertension management is mm Hg higher than measurements from daytime ambulatory
the threshold to which DBP can safely be lowered while tar- blood pressure monitoring (ABPM) or AOBP, whereas ABPM
geting the lower SBP goals recommended in the 2017 ACC/ and AOBP usually provide similar results (Sica 2016).
AHA guidelines. Of note, AOBP was used in SPRINT. Because the mean
The diastolic J- or U-curve phenomenon suggests that CV SBP achieved with intensive treatment in SPRINT was 121.4
and stroke risk increase as DBP is reduced. The rationale for mm Hg, the 2017 ACC/AHA guidelines factored in that many
increased risk is that most coronary and cerebral blood flow offices are not using AOBP and recommended an SBP goal of
occurs during diastole. Therefore, excessively low DBP could less than 130 mm Hg, rather than 120 mm Hg.
cause ischemia. It is vital to recognize the potential sources of error during
However, evidence is mixed about this phenomenon. A blood pressure measurement and how the error could affect
post hoc analysis of SPRINT found a U-curve association the blood pressure reading. Using AOBP does not remove
for baseline DBP, but the benefit of intensely lowering SBP the potential for all errors. Indeed, attention still needs to be
was not influenced by the baseline DBP. Other nonrandom- given to proper procedure, and patients should be instructed
ized analyses show no increased risk when DBP is lowered to maintain the correct body position and avoid talking during
to achieve SBP goals. Data from observational studies and measurement.
secondary analyses suggest that a combination of low DBP Box 2 provides examples of factors that can cause inac-
and wide pulse pressure is associated with increased vascu- curate blood pressure readings and the direction of effect on
lar events (Ahmed 2018). SBP and DBP.
01_1_Ripley.indd 12 20/12/18 10:57 am

Box 2. Selected Causes of BP Box 3. Instructions for Home BP
Measurement Errors Measurement
Factors that can falsely increase SBP and DBP: Step 1: Obtain an appropriate home BP measurement device.
• Bladder distension • Choose a fully automated device (avoid auscultatory
• Cuff too small home devices).
• Insufficient rest period • Choose an arm device (brachial BP). Use wrist monitors
• Talking during measurement only for patients whose arm circumference prevents
Factors that can falsely decrease SBP and DBP: proper fitting of a brachial measurement device.
• Cuff too large • Choose validated devices, if possible.
Factors that have mixed errors on SBP and DBP • Ensure correct cuff size.
measurements: Step 2: Prepare for BP measurement.
• Deflating the cuff too quickly • Empty bladder; refrain from drinking caffeine or
• Standing or supine position rather than sitting position smoking 30 min before measurement.
• White-coat effect • Rest at least 5 min before BP measurement.
• Sit with back supported and feet flat on the floor
Information from: Kallioinen N, Hill A, Horswill MS, et al. (legs uncrossed).
Sources of inaccuracy in the measurement of adult patients’
resting blood pressure in clinical settings: a systematic review.
• Place cuff directly above the antecubital fossa.
Step 3: Measure BP.
J Hypertens 2017;35:421-41.
• Take two readings 1 min apart.
• Avoid unnecessary movement or talking during
measurement.
Out-of-Office Measurement • Minimize excessive measurements.
Step 4: Record BP values with date and time, noting anything
Emphasis on proper blood pressure measurement includes
unusual (e.g., pain, stress, illness, missed medication).
both office and out-of-office measurement. In fact, out-of-of-
fice measurements are strongly recommended to confirm the
hypertension diagnosis as well as to titrate medications.
Patients measuring home blood pressure must be properly
Controversy exists about which method of blood pressure
trained on selecting a device and blood pressure measure-
assessment is best correlated with clinical outcomes. Three
ment procedure. Box 3 summarizes key training points.
types of blood pressure assessment can be used: (1) office
blood pressure measurement with a manual sphygmomanom-
Masked and White-Coat Hypertension
eter or automated oscillometric device; (2) ABPM; (3) and home
blood pressure monitoring. Of these, ABPM is considered the Including out-of-office blood pressure measurement as part
gold standard, given that elevations in 24-hour blood pressure of the hypertension diagnosis allows diagnosticians to iden-
on ABPM are clearly associated with stroke and CV events. tify patients with masked or white-coat hypertension.
Ambulatory blood pressure monitoring is a form of con- Patients with masked hypertension are not hypertensive
centrated blood pressure monitoring over 24–48 hours. A in a health care setting but are hypertensive in the home
blood pressure device is worn constantly, and blood pressure or ambulatory setting. This may occur in up to 15–20% of
is usually measured every 20–30 minutes, including during patients without a hypertension diagnosis. Of importance,
sleep. Information gained from ABPM is unique because masked hypertension is associated with an increased risk
blood pressure is assessed during activities of daily living. of CV disease, and patients with confirmed out-of-office
Data from ABPM include average awake and asleep blood hypertension should be treated with lifestyle changes and
pressure values, range of blood pressure, and nocturnal blood antihypertensives.
pressure. These data can inform underlying causes of hyper- The association between white-coat hypertension and CV
tension. For example, a “non-dipping” pattern, in which blood risk is less well established. However, patients with white-
pressure does not decrease by at least 10% during sleep, coat hypertension have a risk of progressing to sustained
suggests sleep-disordered breathing (e.g., obstructive sleep hypertension. As such, patients with white-coat hypertension
apnea). In addition, ABPM can assess response to medication should be counseled on lifestyle modifications and screened
and degree of blood pressure control. When available, ABPM annually with either ABPM or home blood pressure monitor-
should be used to confirm the initial diagnosis but is also a ing for sustained hypertension.
valuable tool during treatment, especially in difficult-to-treat
or resistant hypertension. Drug Therapy
However, ABPM is not easily accessible in some prac- Fundamentals of initial pharmacologic therapy of hyperten-
tices, and cost can be a barrier to use. As such, home blood sion have not changed significantly with the 2017 ACC/AHA
pressure measurement is a viable alternative. Elevated home guidelines. Recommended options for initial therapy still
blood pressure readings are also associated with CV events, include angiotensin-converting enzyme inhibitors (ACEIs)
though there is less evidence than with ABPM. or angiotensin II receptor blockers (ARBs), calcium channel
01_1_Ripley.indd 13 20/12/18 10:57 am

blockers (CCBs), or thiazide-type diuretics, given that these common in African American patients than in whites (3.9
classes reduce the risk of adverse CV and/or renal outcomes. cases per 1000 person-years among African American vs.
Patient- and drug-specific characteristics may guide selec- 0.8 cases per 1000 person-years among whites) (Taler 2018).
tion for initial monotherapy (Whelton 2018). For patients Historically, ACEIs offered a significant cost advantage over
whose hypertension is uncontrolled with an appropriate com- ARBs, as well as more robust outcomes data. Now, almost
bination of first-line agents, several other medication classes all ARBs are available in generic form in the United States,
are potentially appropriate as add-on therapy. and a large body of literature supports their benefit in CV and
renal outcomes. Consequently, many practitioners now pre-
First-line Treatment fer ARBs to ACEIs as initial therapy, particularly in patients at
Initial treatment of all patients should include lifestyle mod- a higher risk of cough or angioedema (Messerli 2018).
ifications designed to lower blood pressure. Evidence-based Patients who experience cough with ACEIs may safely
lifestyle modifications include moderation in alcohol intake, be changed to ARBs. Those who experience ACEI-induced
regular exercise, weight loss in overweight patients or angioedema should discontinue the ACEI for at least 6 weeks.
patients with obesity, decreased sodium intake, and increased If RAS blockade is still indicated, these patients may then
intake of potassium-rich foods. The Dietary Approaches to begin ARB therapy in most cases, though there is a small risk
Stop Hypertension (DASH) diet limits sodium, incorporates of cross-reactivity (Whelton 2018).
high-potassium foods, and can facilitate weight loss. Adher- Both ACEIs and ARBs decrease the activity of angioten-
ence to a DASH-style dietary pattern has been associated sin II. The clinically important ramifications of this include
with an SBP decrease of about 11 mm Hg; this effect is mag- arterial and venous dilation, increased potassium concen-
nified when combined with stricter sodium reduction and/or trations, and reduced glomerular filtration pressure. Some
weight loss (Whelton 2018). of these effects are particularly beneficial when ACEIs and
For patients with stage 1 hypertension whose 10-year ARBs are used in combination with other first-line drugs.
ASCVD risk score is less than 10%, lifestyle modification Venous dilation occurs with both classes but appears to be
alone is reasonable. A combination of lifestyle modification more pronounced with ACEIs. This pharmacodynamic effect
and antihypertensives should be used in patients with stage can help offset CCB-induced edema. Increased potassium
1 hypertension with established CV disease or a 10-year may help offset potassium losses when these agents are
ASCVD risk score greater than 10%, and in those with stage used in combination with thiazides. Reduced glomerular fil-
2 hypertension. tration pressure is responsible for the small, expected, and
often transient physiologic increase in serum creatinine that
ACEIs and ARBs follows initiation of either of these classes, as well as their
The two primary pharmacologic classes targeting the renoprotective effects in patients with proteinuria.
renin-angiotensin system (RAS) are ACEIs and ARBs. Both ACEIs and ARBs are fetotoxic and should be avoided
Treatment with one of these agents is a necessary part in pregnant women; women of childbearing age should be
of guideline-directed medical therapy for patients with counseled regarding effective contraception before begin-
heart failure or overt proteinuria (greater than 300 mg ning ACEI or ARB therapy.
albumin/24 hours or the equivalent).
Patients with greater RAS activation should theoretically Calcium Channel Blockers
have a more robust response to RAS blockade, and initial ther- The two major subgroups of CCBs are the dihydropyridine
apy with an ACEI or ARB is logical in these patients. Increased (DHP) type and the non-dihydropyridine (non-DHP) type. Both
RAS activation is more common in patients restricting salt subgroups are safe and well tolerated in most patients, includ-
intake, as well as younger, white patients, and/or those with ing those with chronic kidney disease and, unlike many other
higher measured renin concentrations. Consistent with this classes of antihypertensive medications, have a low risk of
theory, evidence shows that African American patients have electrolyte abnormalities. These subgroups help treat vaso-
a diminished blood pressure response to RAS blockade as spastic conditions such as Raynaud disease and Prinzmetal
monotherapy (Helmer 2018). However, data on the benefits angina. By reducing myocardial oxygen demand, CCBs can
of choosing the initial therapy on the basis of these consid- also improve symptoms in chronic stable angina. Peripheral
erations are not conclusive, and other patient factors may edema can occur with either subgroup, though this is signifi-
outweigh race or age in some individuals. Measurement of cantly more common with the DHPs. Management of CCB-in-
plasma renin activity is not routinely recommended before duced edema is discussed later.
beginning therapy. The DHP CCBs have no direct effect on heart rate, though
Although ACEIs are usually well tolerated, a dry cough may indirect reflex tachycardia sometimes occurs. The non-DHP
occur in up to 20% of patients treated with these drugs; cough CCBs are less potent vasodilators than the DHPs. The hypo-
is more common among Asian Americans. Angioedema is tensive effects of the non-DHP CCBs occur by combining
an infrequent but more serious risk that is 2–4 times more vasodilation with reduced cardiac output through negative
01_1_Ripley.indd 14 20/12/18 10:57 am

inotropic and chronotropic effects. Non-DHPs can maintain does not reduce blood pressure sufficiently, the dose can be
rate control in atrial fibrillation; however, their negative ino- increased, or a regimen containing a combination of two or
tropic effects are harmful in patients with heart failure with more of the recommended initial drug classes can be pre-
reduced ejection fraction. Non-DHPs should also be avoided scribed. Most patients with hypertension will require two or
in patients with bradycardia. more medications to reach their blood pressure goal. Guide-
lines recommend initiating treatment with two or more drug
Thiazide and Thiazide-like Diuretics classes in patients with stage 2 hypertension. However,
The term thiazide is usually considered to include both thia- in patients with a history of drug intolerance or at high risk
zide-type and thiazide-like diuretics, which have identical sites of adverse effects, establishing tolerability with one agent
of action despite differing molecular structure (Olde Engberink before adding a second may help avoid removing both
2015). Since the publication of ALLHAT, thiazides have been classes as therapeutic options. In patients who are already
well recognized as a major first-line class of antihypertensives. tolerating two medications, or in those in whom adherence is
The three thiazides most commonly used for hypertension in a concern, fixed-dose combination regimens are convenient
clinical practice are hydrochlorothiazide, chlorthalidone, and to reduce pill burden, though optimal dosing or drug selection
indapamide. Of these three, hydrochlorothiazide is the most may not be available.
widely prescribed. Hydrochlorothiazide is also the least effec- Relatively few head-to-head trials of different drug combi-
tive at lowering blood pressure and has the shortest duration nations are available. Thiazide diuretics often cause compen-
of action, with the antihypertensive benefit generally last- satory up-regulation of the RAS, and combining them with
ing less than 24 hours (Roush 2015). A meta-analysis com- RAS blockers may have synergistic benefit. However, the clin-
paring head-to-head trials of hydrochlorothiazide with other ical significance of this synergy was challenged by the Avoid-
antihypertensive drugs showed that hydrochlorothiazide is ing Cardiovascular Events through Combination Therapy in
consistently inferior to other antihypertensive drugs at low- Patients Living with Systolic Hypertension (ACCOMPLISH)
ering ambulatory blood pressure (Messerli 2011). Both chlor- trial. This study compared benazepril plus amlodipine with
thalidone and indapamide have robust data supporting their benazepril plus hydrochlorothiazide. Benazepril plus amlodip-
benefit in improving CV outcomes. Conversely, evidence ine was more beneficial in both blood pressure lowering and
showing an outcomes benefit with hydrochlorothiazide is CV outcomes (Jamerson 2008). Whether this improvement
limited, despite its widespread use. For most patients, there- would have been maintained if a more efficacious thiazide
fore, chlorthalidone and indapamide are preferred. Although had been used is unknown.
thiazides are usually well tolerated, electrolyte abnormalities, Some combinations should be avoided. In general, two
including hyponatremia, can occur. In patients at a higher risk drugs within the same class should not be combined. A com-
of problems, indapamide may be more convenient because it bination of an ACEI and an ARB, or either of these agents
offers greater flexibility in available dosage strengths. combined with a direct renin inhibitor, increases the risk of
Virtually all thiazide-containing fixed-dose combination reg- hyperkalemia and renal impairment without improving CV or
imens, including both of the FDA-approved triple-therapy (ARB renal outcomes (Whelton 2018). However, combinations of
plus CCB plus thiazide) tablets, use hydrochlorothiazide. In different classes of diuretics, or DHP plus non-DHP CCBs, can
some patients, the benefits of these combinations with respect sometimes be appropriate (Whelton 2018).
to improved adherence and reduced pill burden may outweigh
the reduced intrinsic efficacy of the thiazide component. Fourth-line Drugs
Most patients should be initiated on a RAS inhibitor, a CCB,
β-Blockers and/or a diuretic (usually a thiazide), with second and third
β-Blockers have been shown to be inferior to other first-line agents from the remaining classes. For most patients, good
agents in patients with uncomplicated hypertension. How- adherence to well-chosen drugs in these classes, at appropri-
ever, these data are largely based on trials that used atenolol. ate doses, will ensure adequate blood pressure control.
Outcomes evidence is insufficient with more contemporary However, around 12–13% of patients have true resistant
β-blockers (e.g., carvedilol or nebivolol) to determine whether hypertension despite this combination (Benjamin 2018); the
the inferiority is a class effect or is limited to atenolol. Nonethe- percentage will be higher with lower blood pressure goals.
less, no β-blocker is appropriate for initial hypertension ther- Some patients may also have intolerances or contraindica-
apy except when another indication requires β-blocker use, tions that limit dosing or preclude the use of one or more
such as heart failure, rate control, MI, or migraine prophylaxis. classes altogether. Consequently, for some, a fourth medi-
cation is necessary to achieve blood pressure control. Two
Combination and Add-on Therapy recent trials have been published to guide clinicians in select-
Patients who do not tolerate a medication from one first-line ing fourth-line agents. Both suggest spironolactone is an
class should discontinue it and begin an agent from a differ- effective and well-tolerated add-on therapy for appropriately
ent first-line class. If the initial dose of the first medication selected patients.
01_1_Ripley.indd 15 20/12/18 10:57 am

Mineralocorticoid Antagonists ARB, though long-term outcomes benefit data are lacking
The PATHWAY-2 study was a randomized, double-blind, cross- (Mavrakanas 2014). For patients with primary aldosteronism,
over trial comparing spironolactone with placebo, bisoprolol, one of the most common and often under-recognized causes
or doxazosin as add-on therapies for patients with drug-resis- of secondary hypertension, MRAs are the medical treatment
tant hypertension, defined as a home SBP over 130 mm Hg on of choice.
maximally tolerated doses of an ACEI or an ARB plus a CCB Two MRAs are currently marketed. Spironolactone is well
and a diuretic. Care was taken to rule out nonadherence as a studied, inexpensive, and commonly well tolerated and should
cause for resistance. Spironolactone reduced SBP by an addi- be the MRA of choice in most cases. However, because of its
tional 10.2 mm Hg relative to placebo; SBP was 5–6 mm Hg structural similarity to progesterone, dose-dependent antian-
lower in the spironolactone group than in the doxazosin and drogenic effects can occur. These can be exploited for clini-
bisoprolol groups (p<0.0001) (Williams 2015). cal benefit; spironolactone is widely used to decrease acne
More recently, the Resistant Hypertension Optimal Treat- and hirsutism in women. However, they can also be respon-
ment (ReHOT) trial compared spironolactone with cloni- sible for gynecomastia and erectile dysfunction in men, can
dine as fourth-line therapy for resistant hypertension in an cause breast pain or tenderness in both sexes, and can lead
open-label, randomized study (Krieger 2018). Of note, about to menstrual irregularities in premenopausal women. Spi-
85% of screened patients were excluded because their blood ronolactone is contraindicated in pregnancy because of the
pressure became controlled during the 12-week lead-in when risk of feminizing male fetuses.
they were placed on standard therapy, leaving the trial under- For patients with resistant hypertension who do not toler-
powered. Patients were randomized to treatment with cloni- ate spironolactone, eplerenone is a good alternative. Epler-
dine or spironolactone. The percentage of patients achieving enone is more selective for the aldosterone receptor and
their goal blood pressure was similar between the two arms, typically avoids the hormonal adverse effects. Eplerenone is
though overall blood pressure control using office readings less potent than spironolactone and has a shorter half-life;
was low (around 21% of patients). Both drugs were surpris- for resistant hypertension, twice-daily dosing is often neces-
ingly well tolerated in this trial; no gynecomastia was reported sary. Although eplerenone has been available as a generic for
with spironolactone, and discontinuations because of som- at least 10 years, it still costs more than spironolactone, and
nolence with clonidine were rare. However, the authors sug- insurance coverage is less universal.
gested that although efficacy was comparable between the
drugs, spironolactone has simpler dosing, making it the more Miscellaneous Approaches for Difficult-to-Treat
attractive fourth-line agent for most patients. Hypertension
Although both of these trials concluded that spironolac- Individual patient characteristics will play a large role in deter-
tone was beneficial as a fourth-line agent, mineralocorticoid mining which fourth-line therapy is most appropriate, particu-
receptor antagonists (MRAs) are clearly not appropriate in all larly for patients in whom MRAs are contraindicated. Table 2
patients, particularly those with impaired renal function. The compares characteristics that may influence the choice to
mean estimated glomerular filtration rate (eGFR) of patients select or avoid particular agents in a given patient.
in the PATHWAY-2 trial was 91.1 mL/minute/1.73 m2; patients
with an eGFR of less than 45 mL/minute/1.73 m2 were Controversies and Special Populations
excluded. Patients randomized in ReHOT had similarly good The 2017 ACC/AHA guidelines provide recommendations for
renal function, with a mean eGFR of 88.9 mL/minute/1.73 m2. treating patients with comorbidities or in certain high-risk
Close monitoring of potassium and renal function, particu- groups. However, not all groups endorse the recommenda-
larly in patients with chronic kidney disease or those receiv- tions provided in the 2017 ACC/AHA update.
ing concomitant ACEI/ARB therapy, is critically important,
particularly with initiation of therapy or dose adjustment. Hypertension and Diabetes
Similar to ACEI or ARB initiation, a small increase in serum The 2017 ACC/AHA guidelines suggest treating patients
creatinine is expected when initiating an MRA, and serum cre- with diabetes to a goal blood pressure of less than 130/80
atinine should be monitored to ensure that it remains stable mm Hg, whereas the American Diabetes Association (ADA)
or moves back toward baseline. Some very common medica- 2018 guidelines for CV disease and risk management recom-
tions can have serious drug interactions when used together mend a blood pressure target of less than 140/90 mm Hg.
with MRAs. For example, additive hyperkalemia can result The ADA suggests reserving a blood pressure target of less
from use of MRAs with sulfamethoxazole/trimethoprim or than 130/80 mm Hg for patients at high risk of CV disease (de
drospirenone-containing contraceptives. Acute kidney injury Boer 2018).
can result from MRA use in combination with high-dose The ADA recommendation for the blood pressure targets
NSAIDs. of less than 140/90 mm Hg is largely based on the ACCORD
Mineralocorticoid receptor antagonists have additive ben- BP and Hypertension Optimal Treatment (HOT) trials (Cush-
efits in reducing proteinuria when combined with an ACEI or man 2010; Hansson 1998). As previously discussed, the
01_1_Ripley.indd 16 20/12/18 10:57 am

Table 2. Fourth-line and Beyond Antihypertension Options
Therapy Potential Population Precautions Notes
MRA Hypokalemia, HFrEF, Advanced kidney disease, hyperkalemia, hormonal Spironolactone is better studied in
proteinuria, edema effects with spironolactone resistant hypertension; consider
eplerenone for spironolactone
intolerance because of
antitestosterone effects
β-Blocker HFrEF, MI, atrial Bradycardia, asthma
fibrillation,
tachycardia, migraine
prophylaxis, tremor
α-Blocker BPH, ED, PTSD/ Orthostatic hypotension
nightmares
Hydralazine HFrEF (in combination Adherence problems with TID dosing, drug-induced
with nitrates) lupus, increased BP variability, reflex tachycardia
Minoxidil Very resistant Often profound salt and water retention. Reflex Give in conjunction with loop
hypertension tachycardia, hirsutism, pericardial effusion diuretic and rate control agent
Central Anxiety disorders, Anticholinergic effects, sedation, and cognitive
α-agonist ADHD effects may be especially pronounced in older
adult patients. Rebound hypertension and/
or bradycardia may be exacerbated in patients
receiving β-blockers. Skin irritation and/or
adhesion problems with clonidine patch
ADHD = attention-deficit/hyperactivity disorder; BPH = benign prostatic hyperplasia; ED = erectile dysfunction; HFrEF = heart failure with
reduced ejection fraction; MRA = mineralocorticoid receptor antagonist; PTSD = posttraumatic stress disorder; TID = three times daily.
Patient Care Scenario

A 68-year-old woman was in the ED 1 week ago with a regular antihypertensives include lisinopril 20 mg/hydro-
blood pressure of 192/98 mm Hg and no symptoms of chlorothiazide 12.5 mg daily (fixed-dose combination) and
TOD. She was given two doses of clonidine 0.1 mg, and amlodipine 5 mg daily. Her laboratory values today are Na
1 hour later, her blood pressure was 152/80 mm Hg. She 130 mEq/L, K 4.2 mEq/L, and SCr 1.1 mg/dL. Her blood
was released with a prescription for clonidine to take pressure in the clinic today is 164/88 mm Hg. How should
as needed for blood pressure over 180/100 mm Hg. Her this patient’s antihypertensive regimen be modified?
Answer
The first step in determining the best modification to the The patient is hyponatremic, likely from hydrochlo-
patient’s regimen is to confirm the accuracy of the blood rothiazide. Therefore, hydrochlorothiazide cannot be
pressure results. For example, ensure that the patient was titrated to treat the uncontrolled hypertension and should
resting for at least 5 minutes before blood pressure mea- be discontinued. If this patient were not hyponatremic,
surement, that she was properly positioned, and that she changing from hydrochlorothiazide to chlorthalidone as
was not talking during measurement. Furthermore, if the the more effective thiazide diuretic could be considered.
blood pressure reading is a single measurement, repeat it The most rational adjustments to her regimen would
and use the average of two readings. be to discontinue the fixed-dose lisinopril/hydrochloro-
Next, assess adherence, especially before the ED thiazide and to change to lisinopril at the higher dose of
visit. If antihypertensives have been discontinued, rein- 40 mg daily. Given that this alone is unlikely to lower blood
stating medication rather than adding or increasing pressure sufficiently to her goal of less than 130/80 mm
doses may be best. It is also important to determine Hg, titration of amlodipine to 10 mg daily is also needed.
how much “as-needed” clonidine she has taken since However, that adjustment could be done at a follow-up
the ED visit. visit within 1–2 weeks if there are concerns about making
additional medication changes in one visit.
1. W helton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the pre-
vention, detection, evaluation, and management of high blood pressure in adults. J Am Coll Cardiol 2018;71:e127-e248.
2. Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med 2011;124:1064-72.
01_1_Ripley.indd 17 20/12/18 10:57 am

ACCORD BP trial was the largest prospective comparison of Hypertensive Emergency
intensive with standard hypertension treatment in patients The goal of treating patients with hypertensive emergency
with type 2 diabetes. No difference occurred in the primary is to prevent or limit further TOD. Treatment of hyperten-
endpoint between the treatment groups, though a subanal- sive emergency should include ICU admission for immediate
ysis showed a reduction in stroke. Conversely, a subanaly- reduction of blood pressure using a parenteral antihyperten-
sis of the HOT trial found that targeting a DBP of 80 mm Hg sive, plus treatment of the acute TOD.
or less, rather than 90 mm Hg or less, was associated with a Of importance, blood pressure should not be lowered too
51% reduction of CV events in patients with diabetes (de Boer quickly. Most patients should have their blood pressure low-
2017). Of importance, patients with diabetes were excluded ered by 25% within the first hour, though some circumstances
from SPRINT. (e.g., acute aortic dissection) may require more rapid blood
The rationale for recommending the more intensive goal pressure lowering. Guidelines differ on which blood pressure
of less than 130/80 mm Hg in the 2017 ACC/AHA guidelines marker to use for monitoring during acute hypertensive emer-
is largely based on ASCVD risk assessment. The position of gencies. The 2017 ACC/AHA guidelines use SBP to guide ther-
the guideline authors is that most adults with diabetes have a apy, but mean arterial pressure may also be used to monitor
10-year ASCVD risk that is at least 10%, thereby making them acute blood pressure–related emergencies (Adebayo 2015).
part of the higher-risk category (Whelton 2018). Although a complete review of managing hypertensive
emergencies is beyond the scope of this chapter, it helps to
Other Comorbidities be aware of the parenteral agents used in managing hyperten-
The 2017 ACC/AHA guidelines advocate a goal of less than sive emergency (Table 3).
130/80 mm Hg across other comorbidities and high-risk
groups with one exception. The guidelines suggest that in Hypertensive Urgency
those who have had a stroke or transient ischemic attack Treatment of hypertensive urgency is discretely different
(TIA), a blood pressure goal of less than 130/80 mm Hg is from that of hypertensive emergency. No evidence shows
reasonable, but evidence is limited to support initiating treat- that immediate reduction of blood pressure in those with a
ment when blood pressure is less than 140/90 mm Hg. As severe asymptomatic blood pressure elevation improves clin-
such, the recommendations for blood pressure targets in ical outcomes. Current consensus recommendations state
those with stroke or TIA are not as strongly endorsed. that patients with an asymptomatic blood pressure elevation
should be treated by adjusting or reinstating chronic medica-
Hypertensive Crisis tions, ideally within 24–48 hours (Wolf 2013).
Hypertensive crisis includes two types of patients with It is especially important to ensure proper measurement
severely elevated blood pressure (greater than 180 mm Hg of blood pressure and medication adherence and to mini-
SBP or greater than 120 mm Hg DBP). Patients with hyper- mize excessive blood pressure lowering. In addition, patients
tensive emergency have severely elevated blood pressure prone to anxiety may need to avoid excessive blood pressure
plus new or worsening target organ damage (TOD) (Box 4). measurement.
Patients with hypertensive urgency have severely elevated
blood pressure with no evidence of TOD. differentiatedIt is Secondary Hypertension
important to distinguish these conditions because their man- Around 10% of patients with hypertension have a specific,
agement differs. identifiable cause for their elevated blood pressure. Patients
Both types of hypertensive crisis lack robust clinical trials with resistant hypertension or other suggestive clinical fac-
to guide management, and most clinical recommendations tors should be screened for secondary causes. A chart
are based on consensus expert opinion. describing the known causes of secondary hypertension as
well as when and how to test for them is available in the 2017
AHA hypertension guidelines.
Pharmacists are in a unique position to identify and address
Box 4. Types of Target Organ Damage medications that may be inducing or exacerbating hyperten-
Related to Acute Hypertension sion. Several commonly encountered classes of medica-
tions raise blood pressure, including NSAIDs, decongestants,
• Acute coronary syndrome
• Acute (“flash”) pulmonary edema attention-deficit/hyperactivity disorder medications (ato-
• Acute renal failure moxetine as well as amphetamine derivatives), estrogens,
• Aortic dissection and serotonin-norepinephrine reuptake inhibitors. Patients
• Cerebrovascular event (ischemic or hemorrhagic) should also be questioned about supplement use because
• Eclampsia
some supplements (e.g., licorice, yohimbine, bitter orange)
• Encephalopathy
can also exacerbate hypertension. Mirabegron, a relatively
• Papilledema
new treatment for overactive bladder, is a β3-agonist that may
01_1_Ripley.indd 18 20/12/18 10:57 am

Table 3. Intravenous Antihypertensives for Hypertensive Emergencies
Class Drug Comments
DHP CCBs Nicardipine Avoid in aortic stenosis

Can be titrated every 5–15 min to achieve BP control
Fluid may be excessive in those with acute pulmonary edema or acute
heart failure
Can cause phlebitis
Clevidipine Avoid in those with allergy to soy or eggs, those with severe aortic stenosis
or with defective lipid metabolism
Effects occur within 2–4 min
Cost may affect availability
Vasodilators Sodium nitroprusside Fast onset of action

Caution for cyanide toxicity with prolonged use and/or high doses
Avoid in cerebrovascular events
Nitroglycerin Avoid in right ventricular infarction

Good choice in pulmonary edema
Hydralazine Option for eclampsia or preeclampsia
β-Blockers Esmolol Good option for aortic dissection
Labetalol Ideal choice in eclampsia or preeclampsia
α-Blocker Phentolamine Preferred in sympathetic overload (e.g., pheochromocytoma)
Dopamine agonist Fenoldopam Ideal for nephropathic emergencies. Cost may affect availability
ACEI Enalaprilat Does not require hepatic activation; enalaprilat is the active form of enalapril
and is 10–20 times as potent as captopril
Avoid in acute coronary syndrome
DHP = dihydropyridine.
Information from: 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. J Am Coll Cardiol
2018;71:e127-e248.
also raise blood pressure. Corticosteroids raise blood pres- treating hypertension related to VEGF inhibitors; in refractory
sure through their mineralocorticoid effects; MRAs may be cases, nitrates or nebivolol may be appropriate because they
especially beneficial in patients with resistant HTN related to specifically address the nitric oxide deficiency (Touyz 2018).
chronic corticosteroid use. Atypical antipsychotics, particu-
larly olanzapine and clozapine, cause a variety of metabolic
Difficult-to-Treat
derangements, including hypertension. If alternative drugs
Hypertension
cannot be substituted, aggressive lifestyle interventions and
intensification of pharmacotherapy are usually necessary. Resistant Hypertension
Vascular endothelial growth factor (VEGF) inhibitors such Resistant hypertension is defined as blood pressure that
as bevacizumab induce nitric oxide deficiency. Endothelial remains above goal despite the concurrent use of three anti-
nitric oxide deficiency inhibits arterial vasodilation; inhibiting hypertensive agents of different classes. Ideally, one of these
renal nitric oxide signaling adds salt and fluid retention as an agents should be a diuretic, and the other agents should be
additional mechanism for exacerbating hypertension. Hyper- prescribed at maximally tolerated doses. A companion defini-
tension is well recognized as a problem among patients using tion of resistant hypertension is blood pressure that requires
these drugs for cancer treatment. However, smaller-dose, intra- four or more medications to maintain control (Calhoun 2008).
vitreal injections of VEGF inhibitors used for retinal disorders The exact prevalence of resistant hypertension is unknown,
are also commonly associated with hypertension (Fiebai 2017). in part because of pseudoresistance, in which blood pressure
Calcium channel blockers and diuretics are often effective for is uncontrolled because of factors such as nonadherence,
01_1_Ripley.indd 19 20/12/18 10:57 am

poor blood pressure measurement technique, or a white-coat as NSAIDs or selective serotonin reuptake inhibitors, as well as
effect. Temporary or persistent volume overload related to a history of hyponatremia or a low-normal baseline sodium con-
inadequate diuresis can also cause pseudo-resistant hyper- centration (Rodenburg 2013). If a thiazide is needed in patients
tension. However, current estimates are that truly treat- with hyponatremia risk factors, the clinician should begin with
ment-resistant hypertension occurs in 12–13% of patients a low dose (e.g., indapamide 0.625–1.25 mg daily). In addition,
with hypertension (Benjamin 2018). serum sodium concentrations should be checked 1–2 weeks
A clinical pharmacist involved in hypertension manage- after initiating treatment and intermittently thereafter, espe-
ment will undoubtedly have to consider alternative diagno- cially if there is any acute change in water intake or fluid han-
ses in patients referred for treatment-resistant hypertension. dling (e.g., UTI, acute GI illness, heart failure exacerbation).
To effectively treat these patients, the pharmacist must con- High-risk patients should be counseled against excessive water
sider underlying causes or other factors contributing to the consumption. Those who develop hyponatremia should be
resistance, such as secondary hypertension. changed to another class of drugs. If a diuretic is still required,
An early step in treating patients with apparently resistant a low dose of a long-acting loop diuretic (e.g., torsemide 2.5–5
hypertension is to assess and address medication adher- mg daily) is as effective as usual thiazide doses at treating
ence. When adherence is a concern, addressing causes such hypertension and has minimal effects on electrolyte concentra-
as adverse effects, cost, or misperceptions about medications, though outcomes data are more limited (Baumgart 1993).
tions is necessary. Once barriers to adherence have been
addressed, ensure the regimen includes antihypertensives Edema
that are maximally effective. For example, change from hydro- Edema is common in patients undergoing treatment for
chlorothiazide to chlorthalidone for more potency (Roush hypertension, with several possible etiologies that may com-
2015). In addition, consider changing to an agent with a lon- monly coexist. Many patients with hypertension present with
ger duration of action, simplifying regimens, or changing to salt sensitivity that predisposes them to mild hypervolemia
fixed-dose combinations, when feasible. and edema. Hypertension is a risk factor for many comorbidi-
Once patients have been evaluated for underlying causes ties that can induce edema, including chronic kidney disease,
of resistance, if blood pressure remains uncontrolled, adding heart failure, and venous insufficiency; these should be con-
fourth-line agents, especially spironolactone, is reasonable. sidered before assuming that edema is medication induced.
Nevertheless, edema is the most common adverse effect in
Managing Adverse Effects patients taking DHP CCBs. Because CCBs have intrinsic mild
Many common adverse effects from blood pressure medica- natriuretic properties, this effect is not related to overall salt
tions, such as β-blocker–induced bradycardia and ACEI cough, and water retention. Rather, the primary mechanism seems
are clinically troublesome but straightforward to detect and treat. to be arteriolar dilation without concomitant venodilation;
Other complications of therapy may be more difficult to manage. the increased venous pressure can lead to capillary leak and
increased interstitial fluid. Unless the edema is multifactorial,
Hypokalemia adding a diuretic usually does not provide significant relief.
Several antihypertensives cause electrolyte abnormalities. Women may be particularly susceptible to CCB-induced
Diuretic-induced hypokalemia is well recognized and can gener- edema. Peripheral edema can be minimized by decreasing
ally be avoided or treated by rational medication combinations. the dose, foot elevation, compression stockings, changing to
Combining low-dose thiazides with an ACEI or ARB is often suffi- a non-DHP CCB, or using CCBs in combination with venodilat-
cient to balance potassium concentrations. If hypokalemia per- ing agents such as ACEIs (Gradman 1997).
sists, an MRA may provide blood pressure lowering as well as In contrast, edema from direct vasodilators such as hydral-
potent potassium-sparing effects. Triamterene and amiloride azine and minoxidil is related to salt and water retention.
are alternatives to potassium supplements in patients with Minoxidil is particularly notorious and usually requires coad-
hypokalemia whose blood pressure is already at or near goal. ministration of a loop diuretic to prevent hypervolemia.
Hyponatremia Erectile Dysfunction

One of the most common, troublesome, and underrecognized Erectile dysfunction is estimated to affect at least 30% of men
problems with thiazide diuretics is hyponatremia. In one retro- with hypertension (DeLay 2016). Because both hypertension
spective study, 30% of patients taking a thiazide over 5 years and erectile dysfunction are essentially disorders of endothe-
developed a serum sodium concentration of 130 mmol/L or lial dysfunction, many of the risk factors and common comor-
lower (Leung 2011). Risk of hyponatremia is related to treatment bidities, such as diabetes mellitus, CV disease, and metabolic
intensity, with higher doses and more efficacious agents such syndrome, overlap. Although hypertension itself can lead to
as chlorthalidone posing a higher risk. Several other risk factors erectile dysfunction, erectile dysfunction is also commonly
for hyponatremia exist, including older age, lower BMI, female a treatment-emergent adverse event. Thiazide diuretics are
sex, and use of other hyponatremia-inducing medications such the most commonly implicated class in clinical trials, though
01_1_Ripley.indd 20 20/12/18 10:57 am

β-blockers are also associated with increased risk. Nebivolol, day, season, body position (e.g., sitting vs. standing), and stress-
with its increase in endothelial nitric oxide, is an exception, ors. However, in some individuals, this variation is magnified.
and in several small studies has been found to have neutral Blood pressure variation, which is often a marker for
to positive effect on erectile function, particularly in men with increased arterial stiffness, has been found in observational
previous erectile dysfunction related to other β-blockers. trials to be associated with an increased CV risk (Eguchi
Limited data suggest that ARBs actually benefit sexual func- 2012). Blood pressure variability can be measured as visit-
tion. Calcium channel blockers and ACEIs appear to be neu- to-visit variation or using 24-hour ambulatory measurement.
tral in this respect (Nunes 2012). However, although the problem is relatively easy to recognize,
Although α-blockers are inappropriate as monother- it is comparatively more difficult to treat.
apy, they may also be helpful add-on antihypertensives for Several approaches to reducing blood pressure variation
patients with erectile dysfunction or benign prostatic hyper- can be tried, depending on the individual’s blood pressure
plasiaplasia. In the Treatment of Mild Hypertension Study, pattern. One of the most straightforward explanations for vis-
doxazosin was associated with improved erectile function it-to-visit blood pressure variability is sporadic adherence to
in men both with and without reported problems at baseline blood pressure medications and lifestyle recommendations;
(Grimm 1997). Although α-blockers were initially contraindi- identifying and addressing these problems should clearly be
cated with phosphodiesterase type 5 (PDE5) inhibitors, that the initial step. Similarly, pharmacokinetic differences among
prohibition has now been relaxed to a caution to monitor for agents can play a role. Drugs with relatively constant plasma
additive antihypertensive effect. Preliminary evidence sug- concentrations over 24 hours or longer may cause less vari-
gests that the combination of α-blockers and PDE5 inhibitors ability than drugs with shorter half-lives or with large peak-to-
improves both erectile dysfunction and lower urinary tract trough plasma ratios. Choosing long-acting medications may
symptoms compared with either class alone (Yan 2014). reduce blood pressure variability even in patients with good
medication adherence (Parati 2010). Drug class may also
Multiple Medication Intolerances affect blood pressure variability independent of the specific
Although many patients have treatment-emergent adverse agent chosen within the class. One meta-analysis found that
effects, one subset of patients has difficulty tolerating multiple CCBs (both DHPs and non-DHPs) and, to a lesser extent, thi-
agents. Many of these reported adverse effects may be com- azide diuretics, were associated with reduced blood pressure
mon, nonspecific symptoms that are only questionably the variability. Therapies with ACEIs, ARBs, and β-blockers were
result of drug therapy (Colloca 2011). Several approaches to associated with increased variability (Webb 2010). Clonidine
this difficult clinical situation may be considered. All patients deserves special mention in this respect. Because of its rapid
benefit from positive lifestyle modifications, but these should onset of action, clonidine is often prescribed for as-needed
be particularly encouraged in patients who have difficulty use in patients with a history of hypertensive urgency. How-
taking medications. Many patients tolerate moderate doses ever, with frequent use, clonidine can exacerbate the problem
of two drugs better than high-dose monotherapy, and this and become an underrecognized iatrogenic cause of severe
approach has been extended in one center to try fractional blood pressure variability.
doses of two or more medications, often including alternative Ensuring regular adherence to antihypertensive therapy
dosage forms such as liquids or transdermal formulations to and choosing medications with “smooth” pharmacokinet-
improve tolerability (Antoniou 2016). Finally, the importance ics will improve blood pressure variability in many patients.
of the nocebo effect cannot be overlooked. Nocebo effect, the Other patients may pose a greater challenge. No universally
inverse of placebo, is strongly associated with patient expec- accepted definition of “highly labile” or “variable” hyperten-
tations of the benefits and harms of therapy. Positive fram- sion exists. However, from a practical management stand-
ing of the expected risks, focusing on the large percentage point, blood pressure variability is a problem when an
of patients who do tolerate the medication, may help modify individual patient’s day-to-day blood pressure range includes
patient expectations and improve tolerability (Wells 2012). readings that are too high to safely leave untreated in con-
Non–drug-specific intolerance to several unrelated anti- junction with readings that are too low to safely allow for
hypertensive drugs is significantly more common in patients increased antihypertensive therapy. Measurement error
with psychiatric conditions such as anxiety disorders and should be ruled out to avoid unnecessarily treating spurious
depression (Davies 2003). In patients who present with a long readings. Ambulatory blood pressure monitoring, in combina-
list of unrelated drug intolerances, recognition and treatment tion with a detailed diary of activity, medications, and symp-
of any psychiatric comorbidities may be necessary before toms, can help identify patterns. Patients with a consistent
antihypertensive therapy is successful. pattern of predictable highs and lows (e.g., “non-dippers” or
others with abnormal circadian variability) can sometimes be
Labile Hypertension treated with judicious use of short-acting medications.
Physiologic blood pressure variation occurs in healthy individu- Patients who describe episodic, severely elevated blood
als from beat to beat and is affected by factors such as time of pressure, especially if associated with tachycardia, headache,
01_1_Ripley.indd 21 20/12/18 10:57 am

Autonomic dysfunction can present as severe, frequent
Table 4. Short- and Long-Acting Antihypertensives blood pressure fluctuations within minutes or hours. Pat-
terns of orthostatic hypotension and supine hypertension, as
Drug Class Drug
well as postprandial hypotension, are common, though many
Drugs with ACEI Captopril
of the dramatic blood pressure fluctuations in these patients
expected β-Blocker Metoprolol are unpredictable. Dysfunctional autonomic blood pressure
duration ≤ 12 hra tartrate regulation is most common in neurologic disorders such as
DHP CCBs Nicardipine Parkinson disease, or as a consequence of trauma or radia-
Isradipine tion to the carotid baroreceptors, but can sometimes occur in
Non-DHP CCBs Diltiazem IR patients without obvious predisposing factors. Referral to a
neurologist and/or tertiary care center is necessary for these
Verapamil IR
patients.
Diuretics Hydrochloro
Pharmacokinetic differences among agents can become
thiazide
particularly important when managing labile hypertension.
Furosemideb Drugs with longer durations of action help ensure 24-hour
Miscellaneous Prazosin blood pressure coverage and may be particularly beneficial
agents Clonidine in patients with nonadherence. Conversely, some patients
Hydralazine have blood pressure fluctuations that may benefit from short-
er-acting, more targeted treatments, either at consistent
Nitrates
times of day (e.g., evening dosing for patients with nocturnal
Drugs with ACEIs Trandolapril
hypertension) or as needed (Table 4).
expected Perindopril
antihypertensive
ARBs Eprosartan
duration ≥ 24 hr
Telmisartan
Practice Points
β-Blockers Nadolol
Clinical pharmacists involved in treating hypertension
Betaxolol
are often presented with complex hypertension cases.
Nebivolol Newly available guidelines can be a resource while caring
CCB Amlodipine for patients with challenging hypertension situations.
Consider applying these practice points:
Diuretics Chlorthalidone
• Incorporate lifestyle changes in all patients with
Indapamide hypertension.
α-Blocker Doxazosin • Initiate antihypertensives in patients with stage 1 hyper-
tension if they have clinical CV disease, an ASCVD risk
α-Agonist Clonidine patch score of 10% or higher, diabetes mellitus, or chronic kidney
disease.
Immediate-release nifedipine is not appropriate for hyper- • Initiate antihypertensives in patients with stage 2 hyper-
a
tension treatment in most patients. tension, regardless of their risk factors.

b
Antihypertensive effect usually lasts longer than diuretic • Target a goal of less than 130/80 mm Hg for most patients,
effect, but is still usually < 24 hr. but consider individual factors (e.g., older adult patients
with wide pulse pressures, fall risk) that could affect safety
with titrating medication to meet this goal.
• Optimize first-line treatments by choosing the most
palpitations, diaphoresis, and/or pallor, should be tested to
evidence-based antihypertensives and titrating the dose on
rule out pheochromocytoma. However, most patients, even the basis of safety and efficacy.
those with classic pheochromocytoma symptoms, do not • Choose combination treatments that have synergistic or
have this disorder. A much more common disorder, termed par- complementary mechanisms of action, such as an ACEI
oxysmal hypertension or pseudopheochromocytoma, is charac- plus a CCB.
terized by sudden and often dramatic rises in blood pressure, • Consider fourth-line agents such as MRAs, direct-acting
vasodilators, or α-blockers in patients whose hypertension
often accompanied by pheochromocytoma-type symptoms
is still uncontrolled despite optimized first-line antihyper-
or flushing, in the absence of any recognizable trigger. Unlike tensives. Spironolactone has the most evidence in this
patients with panic disorder or with large blood pressure population.
swings triggered by emotional distress, these patients usu- • Consider long-acting agents and/or CCBs to manage spo-
ally state that their anxiety is a consequence of the hyperten- radic adherence or labile blood pressure readings.
• Be prepared to manage hyponatremia in patients taking
sive episode, rather than a cause. Nevertheless, the treatment
thiazide diuretics by changing to other first-line agents or a
approach is similar; limited data suggest benefit from anxio- low-dose loop diuretic.
lytics and/or combined α/β-blockade (Mann 2015).
01_1_Ripley.indd 22 20/12/18 10:57 am

Conclusion prevention, detection, evaluation, and treatment of high
Pharmacists have many opportunities to manage the care of blood pressure. Hypertension 2003;42:1206-52.
patients with hypertension. Emerging research continues to Colloca L, Miller FG. The nocebo effect and its relevance for
support a role for clinical pharmacists as a vital member of a clinical practice. Psychosomat Med 2011;73:598-603.
health care team managing hypertension.
Crawford C. AAFP Decides to Not Endorse AHA/ACC Hyper-
Because almost one-half of the U.S. adult population now tension Guideline. Academy Continues to Endorse JNC8
has hypertension, the importance of having a strong work- Guideline. December 12, 2017.
ing knowledge of hypertensive pharmacotherapy transcends
Cushman WC, Evans GW, Byington RP, et al.; for the ACCORD
specialty areas and health care settings.
Study Group. Effects of intensive blood-pressure control in
Pharmacists should continue to advocate the optimization
type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
of first-line hypertension medications and to address adher-
ence issues and adverse events. Davies SJ, Jackson PR, Ramsay LE, et al. Drug intolerance
due to nonspecific adverse effects related to psychiat-
ric morbidity in hypertensive patients. Arch Intern Med
References 2003;163:592-600.
Adebayo O, Rogers RL. Hypertensive emergencies in the
emergency department. Emerg Med Clin North Am de Boer IH, Bakris G, Cannon CP. Individualizing blood pres-
2015;33:539-51. sure targets for people with diabetes and hypertension:
comparing the ADA and the ACC/AHA recommendations.
Ahmed A, Oparil S. Reply to: Diastolic J curve, cuff artefact JAMA 2018;319:1319-20.
and low targets for SBP: a need for caution. J Hypertens
2018;36:1423-4. de Boer IH, Bangalore S, Benetos A, et al. Diabetes and
hypertension: a position statement by the American Dia-
ALLHAT Collaborative Research Group. Major out- betes Association. Diabetes Care 2017;40:1273-84.
comes in high-risk hypertensive patients randomized
to angiotensin-converting enzyme inhibitor or calcium DeLay KJ, Haney N, Hellstrom WJ. Modifying risk factors in
channel blocker vs diuretic: the Antihypertensive and the management of erectile dysfunction: a review. World J
Lipid-Lowering Treatment to Prevent Heart Attack Trial Mens Health 2016;34:89-100.
(ALLHAT). JAMA 2002;288:2981-97.
Eguchi K, Hoshide S, Schwartz JE, et al. Visit-to-visit and
Antoniou S, Saxena M, Hamedi N, et al. Management of ambulatory blood pressure variability as predictors of inci-
hypertensive patients with multiple drug intolerances: dent CV events in patients with hypertension. Am J Hyper-
a single-center experience of a novel treatment algorithm. tens 2012;25:962-8.
J Clin Hypertens (Greenwich) 2016;18:129-38.
Fiebai B, Odogu V. Intravitreal anti vascular endothelial
Baumgart P. Torasemide in comparison with thiazides in growth factor agents in the management of retinal dis-
the treatment of hypertension. Cardiovasc Drugs Ther eases: an audit. Open Ophthalmol J 2017;11:315-21.
1993;7(suppl 1):63-8.
Gradman AH, Cutler NR, Davis PJ, et al. Combined enalapril
Beckett NS, Peters R, Fletcher AE, et al. HYVET Study Group. and felodipine extended release for systemic hyperten-
Treatment of hypertension in patients 80 years of age or sion. Enalapril-Felodipine ER Factorial Study Group. Am J
older. N Engl J Med 2008;358:1887-98. Cardiol 1997;79:431-5.
Benjamin EJ, Virani SS, Callaway CW, et al. Heart dis- Grimm RH Jr, Grandis GA, Prineas RJ, et al.; for the TOMHS
ease and stroke statistics – 2018 update. A report Research Group. Long-term effects on sexual function of
from the American Heart Association. Circulation five antihypertensive drugs and nutritional hygienic treat-
2018;137:e67-e492. ment in hypertensive men and women. Treatment of Mild
Hypertension Study (TOMHS). Hypertension 1997;29:8-14.
Bundy JD, Li C, Stuchlik P, et al. Systolic blood pres-
sure reduction and risk of cardiovascular disease and Hansson L, Zanchetti A, Carruthers SG, et al. Effects of inten-
mortality: a systematic review and network meta-analysis. sive blood-pressure lowering and low-dose aspirin in
JAMA Cardiol 2017;2:775-81. patients with hypertension: principal results of the Hyper-
tension Optimal Treatment (HOT) randomized trial. Lancet
Calhoun DA, Jones D, Textor S, et al. Resistant hyperten- 1998;351:1755-62.
sion: diagnosis, evaluation, and treatment. A scientific
statement from the American Heart Association Profes- Helmer A, Slater N, Smithgall S. A review of ACE inhibitors
sional Education Committee of the Council for High Blood and ARBs in black patients with hypertension. Ann Phar-
Pressure Research. Circulation 2008;117:e510-e526. macother 2018;52:1143-51.
Chobanian AV, Bakris GL, Black HR, et al. The National High Jamerson K, Weber MA, Bakris GL, et al.; for the ACCOM-
blood Pressure Education Program Coordinating Commit- PLISH Investigators. Benazepril plus amlodipine or hydro-
tee. Seventh report of the Joint National Committee on chlorothiazide for hypertension in high-risk patients.
N Engl J Med 2008;359:2417-28.
01_1_Ripley.indd 23 20/12/18 10:57 am

Krieger EM, Drager LF, Giorgi DMA, et al. Spironolactone ver- American Academy of Family Physicians. Ann Intern Med
sus clonidine as a fourth-drug therapy for resistant hyper- 2017;166:430-7.
tension: the ReHOT randomized study. Hypertension
2018;71:681-90. Reboussin DM, Allen NB, Griswold ME, et al. Systematic
review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/
Leung AA, Wright A, Pazo V, et al. Risk of thiazide-induced APhA/ASH/ASPC/NMA/PCNA guideline for the preven-
hyponatremia in patients with hypertension. Am J Med tion, detection, evaluation, and management of high blood
2011;124:1064-72. pressure in adults. J Am Coll Cardiol 2017;71:2176-98.
Lewington S, Clarke R, Qizilbash N, et al. Age-specific rel- Rodenburg EM, Hoorn EJ, Ruiter R, et al. Thiazide-associated
evance of usual blood pressure to vascular mortality: a hyponatremia: a population-based study. Am J Kidney Dis
meta-analysis of individual data for one million adults in 2013;62:67-72.
61 prospective studies. Lancet 2002;360:1903-13.
Roush GC, Ernst ME, Kostis JB, et al. Head-to-head com-
Mann SJ. Labile and paroxysmal hypertension: common parisons of hydrochlorothiazide with indapamide and
clinical dilemmas in need of treatment studies. Curr Car- chlorthalidone: antihypertensive and metabolic effects.
diol Rep 2015;17:99. Hypertension 2015;65:1041-6.
Mavrakanas TA, Gariani K, Martin PY. Mineralocorticoid Sica DA, Phillips RA, White WB, et al. “Translational” medi-
receptor blockade in addition to angiotensin-converting cine: transforming SPRINT findings into clinical practice.
enzyme inhibitor or angiotensin II receptor blocker treat- J Am Soc Hypertens 2016;10:382-6.
ment: an emerging paradigm in diabetic nephropathy: a
systematic review. Eur J Intern Med 2014;25:173-6. Taler SJ. Initial treatment of hypertension. N Engl J Med
2018;378:636-44.
Messerli FH, Bangalor S, Bavishi C, et al. Angiotensin-con-
verting enzyme inhibitors in hypertension: to use or not to Touyz RM, Herrmann SMS, Herrmann J. Vascular toxici-
use? J Am Coll Cardiol 2018;71:1474-82. ties with VEGF inhibitor therapies-focus on hyperten-
sion and arterial thrombotic events. J Am Soc Hypertens
Messerli FH, Makani H, Benjo A, et al. Antihypertensive effi- 2018;12:409-25.
cacy of hydrochlorothiazide as evaluated by ambulatory
blood pressure monitoring: a meta-analysis of randomized Webb AJ, Fischer U, Mehta Z, et al. Effects of antihyper-
trials. J Am Coll Cardiol 2011;57:590-600. tensive-drug class on interindividual variation in blood
pressure and risk of stroke: a systematic review and
Muntner P, Carey RM, Gidding S, et al. Potential US popu- meta-analysis. Lancet 2010;375:906-15.
lation impact of the 2017 ACC/AHA high blood pressure
guideline. Circulation 2018;137:109-18. Wells RE, Kaptchuk TJ. To tell the truth, the whole truth, may
do patients harm: the problem of the nocebo effect for
Muntner P, Whelton PK. Using predicted cardiovascular dis- informed consent. Am J Bioeth 2012;12:22-9.
ease risk in conjunction with blood pressure to guide anti-
hypertensive medication treatment. J Am Coll Cardiol Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/
2017;69:2446-56. AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA
guideline for the prevention, detection, evaluation, and
Muntner P, Whittle J, Lynch AL, et al. Visit-to-visit variabil- management of high blood pressure in adults. J Am Coll
ity of blood pressure and coronary heart disease, stroke, Cardiol 2018;71:e127-e248.
heart failure, and mortality: a cohort study. Ann Intern
Med 2015;163:329-38. Williams B, MacDonald TM, Morant S, et al. Spironolactone
versus placebo, bisoprolol, and doxazosin to determine
Nunes KP, Labazi H, Webb RC. New insights into hyperten- the optimal treatment for drug-resistant hypertension
sion-associated erectile dysfunction. Curr Opin Nephrol (PATHWAY-2): a randomized, double-blind, crossover trial.
Hypertens 2012;21:163-70. Lancet 2015;386:2059-68.
Olde Engberink RH, Frenkel WJ, van den Bogaard B, et al. Williamson JD, Supiano MA, Applegate WB, et al. Intensive
Effects of thiazide-type and thiazide-like diuretics on car- vs standard blood pressure control and CV disease out-
diovascular events and mortality: systematic review and comes in adults aged ≥ 75 years: a randomized clinical
meta-analysis. Hypertension 2015;65:1033-40. trial. JAMA 2016;315:2673-82.
Parati G, Schumacher H, Bilo G, et al. Evaluating 24-h Wolf SJ, Lo B, Shih RD, et al. Clinical policy: critical issues in
antihypertensive efficacy by the smoothness index: a the evaluation and management of adult patients in the
meta-analysis of an ambulatory blood pressure monitor- emergency department with asymptomatic elevated blood
ing database. J Hypertens 2010;28:2177-83. pressure. Ann Emerg Med 2013;62:59-68.
Qaseem A, Wilt TJ, Rich R, et al. Pharmacologic treatment Wright JT Jr, Fine LJ, Lackland DT, et al. Evidence support-
of hypertension in adults aged 60 years or older to higher ing a systolic blood pressure goal of less than 150 mm Hg
versus lower blood pressure targets: a clinical practice in patients aged 60 years or older: the minority view. Ann
guideline from the American College of Physicians and the Intern Med 2014;160:499-503.
01_1_Ripley.indd 24 20/12/18 10:57 am

Wright JT Jr, Williamson JD, Whelton PK, et al.; for the
SPRINT Research Group. A randomized trial of intensive
versus standard blood-pressure control. N Engl J Med
2015;37:2103-16.
Yan H, Zong H, Cui Y, et al. The efficacy of PDE5 inhibitors

alone or in combination with alpha-blockers for the treat-
ment of erectile dysfunction and lower urinary tract symp-
toms due to benign prostatic hyperplasia: a systematic
review and meta-analysis. J Sex Med 2014;11:1539-45.
01_1_Ripley.indd 25 20/12/18 10:57 am

Self-Assessment Questions
1. A 50-year-old African American man has had an aver- A. Increase amlodipine to 10 mg daily.
age blood pressure of 136/78 mm Hg and heart rate of B. Go to the ED for evaluation of hypertensive
72 beats/minute over the past two visits. He is a smoker emergency.
but has no other relevant medical history. His TC is 240 C. Initiate clonidine 0.1 mg every hour until blood
mg/dL and HDL is 32 mg/dL. Which one of the follow- pressure is normalized.
ing is best to recommend to manage this patient’s blood D. Take one extra dose of chlorthalidone 25 mg today
pressure? only.
A. Lifestyle modifications only 5. A 55-year-old woman has a new diagnosis of hyper-
B. Lifestyle modifications plus chlorthalidone 25 mg tension. Her average blood pressure on her ABPM was
daily 158/92 mm Hg. She has implemented dietary changes,
C. Lifestyle modifications plus hydrochlorothiazide but her blood pressure remains elevated. You are con-
12.5 mg and lisinopril 20 mg daily sulted to initiate hypertension treatment. Her other
D. Lifestyle modifications plus atenolol 50 mg daily medical history is significant for allergic rhinitis and
hypothyroidism. Her laboratory values are all within nor-
2. A patient with hypertension and lower-extremity edema
mal limits. Which one of the following is best to recom-
is being treated with amlodipine 10 mg once daily. Her
mend initiating in this patient?
blood pressure in the clinic today is 152/90 mm Hg and
heart rate is 68 beats/minute. Which one of the following A. Metoprolol succinate 50 mg daily
is best to recommend for this patient’s amlodipine-in- B. Chlorthalidone 25 mg plus lisinopril 10 mg daily
duced lower-extremity edema? C. Hydrochlorothiazide 25 mg daily
D. Metoprolol succinate 50 mg plus chlorthalidone 25
A. Decrease amlodipine to 5 mg daily.
mg daily
B. Discontinue amlodipine.
C. Add furosemide 20 mg daily.
D. Add lisinopril 10 mg daily. Questions 6 and 7 pertain to the following case.
H.G. is a 61-year-old man with heart failure with reduced

3. A 78-year-old woman with an average clinic blood pres-
ejection fraction, dyslipidemia, diabetes, and hypertension.
sure of 142/82 mm Hg is referred to your clinic. Her
His home blood pressure readings have recently increased
antihypertensive regimen includes telmisartan 40 mg
to 152–168/72–84 mm Hg over the past 7–10 days. Six
daily. The patient is somewhat resistant to adding med-
months ago, his home and clinic average blood pressure
ications because of concern that more medications will
reading was 128/70 mm Hg. H.G. takes carvedilol 25 mg
worsen her daytime fatigue. She undergoes ambulatory
twice daily, lisinopril 40 mg daily, and torsemide 50 mg daily.
blood pressure monitoring (ABPM) for further evaluation
He denies missing doses of his medication, which is con-
before medication is added, with average daytime blood
firmed by assessing his refill history. He admits recently eat-
pressure 144/80 mm Hg and average nighttime blood
ing out for several days and not watching his dietary sodium
pressure 140/78 mm Hg. Which one of the following best
intake. H.G. also admits feeling short of breath and having
assesses this patient’s blood pressure?
more lower-extremity edema. His weight in the clinic today
A. White-coat hypertension is 70 kg, a 10-kg increase from his last visit. His blood pres-
B. Masked hypertension sure in the clinic is 156/86 mm Hg; his laboratory values are
C. Non-dipping blood pressure pattern, consistent with all within normal limits.
sleep-disordered breathing
6. Which one of the following best assesses H.G.’s blood
D. Sporadic hypertension, consistent with
pressure?
pheochromocytoma
A. Treatment-resistant hypertension
4. A patient calls your clinic, worried because his blood
B. Pseudo-resistant hypertension
pressure was 192/98 mm Hg on his home blood pres-
C. White-coat hypertension
sure monitor. He repeated it to confirm and had a simi-
D. Masked hypertension
lar result. He denies feeling any symptoms and denies
missing any of his regular antihypertensives. The patient 7. Which one of the following is best to recommend for
takes chlorthalidone 25 mg daily and amlodipine 5 mg H.G.’s recent uncontrolled blood pressure?
daily. In addition to arranging for prompt outpatient fol- A. Increase carvedilol to 50 mg twice daily.
low up, which one of the following is best to recommend B. Add clonidine 0.1-mg/hour patch; change once weekly.
for this patient?
01_1_Ripley.indd 26 20/12/18 10:57 am

C. Add hydrochlorothiazide 25 mg daily. C. Evidence shows that reducing SBP to lower than
D. Increase torsemide to 100 mg daily for 3–5 days. 130 mm Hg in patients 75 and older improves CV
outcomes.
8. A 78-year-old woman is seen for a hypertension fol-
D. Evidence shows that reducing SBP to lower than 130
low-up. She takes hydrochlorothiazide 25 mg daily, lis-
mm Hg in patients 75 and older increases the risk of
inopril 20 mg daily, and nifedipine XL 30 mg daily. Her
falls.
home and clinic blood pressure readings have been
142–154/64–72 mm Hg. Pertinent laboratory values 11. A 53-year-old man with a history of hypertension, dyslip-
from today are Na 128 mEq/L and K 4.9 mEq/L. Physical idemia, and type 2 diabetes is discharged from the hos-
examination reveals 1+ bilateral lower-extremity edema. pital 2 weeks after an acute MI. His home drugs include
Which one of the following is best to recommend regard- aspirin 81 mg daily, prasugrel 10 mg daily, and atorvasta-
ing this patient’s hypertension regimen? tin 40 mg daily. During his hospitalization, the patient’s
blood pressure was low; his blood pressure medications
A. Discontinue hydrochlorothiazide and replace with
were discontinued and were not resumed on discharge.
chlorthalidone 25 mg daily.
Today, his blood pressure is 146/80 mm Hg and heart
B. Discontinue hydrochlorothiazide and replace with
rate is 52 beats/minute. Which one of the following is
torsemide 5 mg daily.
best to initiate in this patient today?
C. Discontinue nifedipine and replace with diltiazem CD
120 mg daily. A. Lisinopril 10 mg daily
D. Increase lisinopril to 40 mg daily. B. Chlorthalidone 25 mg daily
C. Amlodipine 5 mg daily
9. A 59-year-old man with labile hypertension is seen in
D. Metoprolol succinate 50 mg daily
your clinic. He takes amlodipine 10 mg daily and chlor-
thalidone 25 mg every morning. He reports having blood 12. A 73-year-old woman has difficult-to-treat hypertension.
pressure elevations starting at 4 p.m. that last until Her current regimen includes lisinopril 40 mg daily, chlor-
10 p.m. The patient keeps excellent home blood pressure thalidone 25 mg daily, and amlodipine 10 mg daily. She
records; his average blood pressure during this time is also takes mirabegron 50 daily, rosuvastatin 10 mg daily,
160/90 mm Hg, and his blood pressure during the morn- and loratadine 10 mg daily. Her blood pressure has been
ing and early afternoon is 118–126/62–70 mm Hg. Which 150–155/75–78 mm Hg and heart rate 58–60 beats/min-
one of the following is best to recommend to manage ute during the past three visits, which did not improve
this patient’s blood pressure elevation during this limited with the last medication adjustment. Pertinent labora-
time? tory values today are Na 136 mEq/L, K 4.7 mEq/L, and
SCr 1.4 mg/dL. Which one of the following is best to rec-
A. Start lisinopril 10 mg at 3 p.m.
ommend for this patient’s hypertension?
B. Start lisinopril 10 mg in the morning.
C. Start captopril 12.5 mg at 3 p.m. A. Discontinue mirabegron.
D. Start captopril 12.5 mg in the morning. B. Add doxazosin 4 mg daily.
C. Increase chlorthalidone to 50 mg daily.
10. A physician is caring for a frail 75-year-old woman with
D. Add carvedilol 12.5 mg twice daily.
hypertension. The patient’s blood pressure is 145–
150/70–78 mm Hg on amlodipine 10 mg daily and hydro- 13. A 50-year-old woman was recently given a diagnosis of
chlorothiazide 25 mg daily. The physician asks your hypertension caused by her prednisone therapy for rheu-
opinion on whether he should target the blood pres- matoid arthritis. She takes prednisone 40 mg daily; she
sure goal suggested by the 2017 ACC/AHA hypertension has not yet been initiated on an antihypertensive. Her
guidelines or the goal suggested by the AAFP guidelines. blood pressure is 148–156/80–85 mm Hg and heart
Which one of the following is best to recommend for this rates are 62–70 beats/minute. On physical examination,
patient? she has 2+ pitting edema bilaterally. Pertinent laboratory
values today are Na 140 mEq/L, K 3.4 mEq/L, and SCr 1.0
A. Evidence shows that reducing SBP to lower than 150
mg/dL. Which one of the following is best to recommend
mm Hg in patients 75 and older increases the risk of
for this patient’s hypertension?
falls.
B. Evidence shows that reducing SBP to lower than A. Chlorthalidone 25 mg daily
150 mm Hg in patients 75 and older decreases the B. Metoprolol succinate 100 mg daily
quality of life. C. Amlodipine 10 mg daily
D. Spironolactone 25 mg daily
01_1_Ripley.indd 27 20/12/18 10:57 am

14. A 44-year-old man with hypertension takes chlorthali- 15. A 55-year-old woman takes hydrochlorothiazide 25 mg
done 25 mg daily. His blood pressure in the clinic today is daily and amlodipine 10 mg daily. She presents for a fol-
128/70 mm Hg and heart rate is 76 beats/minute. His lab- low-up of her hypertension. Her blood pressure readings
oratory values are within normal limits. However, he has have been 146–152/70–75 mm Hg. Pertinent laboratory
concerns of new-onset erectile dysfunction. Which one values include Na 140 mEq/L, K 4.8 mEq/L, and SCr 0.9
of the following is best to recommend for this adverse mg/dL. Which one of the following is best to recommend
effect in this patient? for this patient’s hypertension?
A. Change to telmisartan 40 mg daily. A. Add lisinopril 40 mg daily.
B. Change to doxazosin 2 mg daily. B. Add spironolactone 25 mg daily.
C. Change to metoprolol succinate 100 mg daily. C. Change from hydrochlorothiazide to furosemide
D. Change to isosorbide mononitrate ER 30 mg daily. 40 mg daily.
D. Change from hydrochlorothiazide to chlorthalidone
25 mg daily.
01_1_Ripley.indd 28 20/12/18 10:57 am

p2019b1 Sample PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

p2019b1 Sample PDF

Uploaded by

Copyright:

Available Formats

Hypertension

By Toni L. Ripley, Pharm.D., FCCP, BCPS, AHSCP-CHC;

PSAP 2019 BOOK 1 • Cardiology 7 Hypertension

01_1_Ripley.indd 7 20/12/18 10:57 am

Additional Readings Box 1. Critical Questions Addressed

PSAP 2019 BOOK 1 • Cardiology 8 Hypertension

01_1_Ripley.indd 8 20/12/18 10:57 am

Table 1. Comparison of BP Target Recommendations

JNC 7, 2003 < 140/90 mm Hg Normal < 120 < 80

Stage 2 hypertension ≥ 160 ≥ 100

ACC/AHA, 2017 ≤ 130/80 mm Hg Normal < 120 < 80

Elevated 120–129 < 80

Stage 2 hypertension ≥ 140 ≥ 90

PSAP 2019 BOOK 1 • Cardiology 9 Hypertension

01_1_Ripley.indd 9 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 10 Hypertension

01_1_Ripley.indd 10 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 11 Hypertension

01_1_Ripley.indd 11 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 12 Hypertension

01_1_Ripley.indd 12 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 13 Hypertension

01_1_Ripley.indd 13 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 14 Hypertension

01_1_Ripley.indd 14 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 15 Hypertension

01_1_Ripley.indd 15 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 16 Hypertension

01_1_Ripley.indd 16 20/12/18 10:57 am

Therapy Potential Population Precautions Notes

Patient Care Scenario

PSAP 2019 BOOK 1 • Cardiology 17 Hypertension

01_1_Ripley.indd 17 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 18 Hypertension

01_1_Ripley.indd 18 20/12/18 10:57 am

Class Drug Comments

DHP CCBs Nicardipine Avoid in aortic stenosis

Vasodilators Sodium nitroprusside Fast onset of action

Nitroglycerin Avoid in right ventricular infarction

Hydralazine Option for eclampsia or preeclampsia

β-Blockers Esmolol Good option for aortic dissection

Labetalol Ideal choice in eclampsia or preeclampsia

α-Blocker Phentolamine Preferred in sympathetic overload (e.g., pheochromocytoma)

PSAP 2019 BOOK 1 • Cardiology 19 Hypertension

01_1_Ripley.indd 19 20/12/18 10:57 am

Hyponatremia Erectile Dysfunction

PSAP 2019 BOOK 1 • Cardiology 20 Hypertension

01_1_Ripley.indd 20 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 21 Hypertension

01_1_Ripley.indd 21 20/12/18 10:57 am

tension treatment in most patients. tension, regardless of their risk factors.

PSAP 2019 BOOK 1 • Cardiology 22 Hypertension

01_1_Ripley.indd 22 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 23 Hypertension

01_1_Ripley.indd 23 20/12/18 10:57 am

PSAP 2019 BOOK 1 • Cardiology 24 Hypertension

01_1_Ripley.indd 24 20/12/18 10:57 am

Yan H, Zong H, Cui Y, et al. The efficacy of PDE5 inhibitors

PSAP 2019 BOOK 1 • Cardiology 25 Hypertension

01_1_Ripley.indd 25 20/12/18 10:57 am

H.G. is a 61-year-old man with heart failure with reduced

PSAP 2019 BOOK 1 • Cardiology 26 Hypertension

01_1_Ripley.indd 26 20/12/18 10:57 am