Current Hypertension Reports (2018) 20: 56

https://doi.org/10.1007/s11906-018-0854-2

ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (ME ERNST, SECTION EDITOR)

Focused Update on Pharmacologic Management

of Hypertensive Emergencies
Kristin Watson 1,2 & Rachael Broscious 1 & Sandeep Devabhakthuni 1,2 & Zachary R. Noel 1,2

Published online: 8 June 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Hypertensive emergency is defined as a systolic blood pressure > 180 mmHg or a diastolic blood
pressure > 120 mmHg with evidence of new or progressive end-organ damage. The purpose of this paper is to review
advances in the treatment of hypertensive emergencies within the last 5 years.
Recent Findings New literature and recommendations for managing hypertensive emergencies in the setting of pregnancy,
stroke, and heart failure have been published.
Summary Oral nifedipine is now considered an alternative first-line therapy, along with intravenous hydralazine and labetalol for
women presenting with pre-eclampsia. Clevidipine is now endorsed by guidelines as a first-line treatment option for blood
pressure reduction in acute ischemic stroke and may be considered for use in intracranial hemorrhage. Treatment of hypertensive
heart failure remains challenging; clevidipine and enalaprilat can be considered for use in this population although data
supporting their use remains limited.

Keywords Hypertensive emergency . Hypertensive crisis, intravenous antihypertensive medications

Introduction mortality associated with a hypertensive emergency ranges

Hypertension affects an estimated 85.7 million adults in the
USA [1]. Acute and severe elevations in blood pressure (BP),
also known as a hypertensive crisis, can occur and may result
in target organ damage including stroke, myocardial infarction
(MI), and heart failure (HF). A hypertensive crisis is defined
as a systolic blood pressure (SBP) > 180 mmHg or a diastolic
blood pressure (DBP) > 120 mmHg. This is further catego-
rized as a hypertensive urgency or emergency with the latter
having evidence of new or progressive end-organ damage [2].
The number of emergency room visits and hospitalizations
for hypertensive emergencies has been reported as 1670 per
million and 111 per 100,000, respectively [3, 4]. In-hospital
This article is part of the Topical Collection on Antihypertensive Agents:
Mechanisms of Drug Action
* Kristin Watson
Kristin.watson@rx.umaryland.edu
1
University of Maryland School of Pharmacy, 20 N Pine Street,
Baltimore, MD 21201, USA
2
ATRIUM Cardiology Collaborative, Baltimore, MD, USA
from 0.48 to 12.5% [4–6]. Patients presenting with a hyper-
tensive emergency require admission to an intensive care unit
to allow for close monitoring and administration of parenteral
antihypertensive therapy.
The goals of therapy, for a hypertensive emergency, are to
reduce a patient’s BP and to minimize progressive or addition-
al target organ damage while preventing consequences of rap-
id correction. The target BP, swiftness of lowering, and selec-
tion of therapy(ies) is dictated by the type of end-organ dam-
age that is present (Tables 1 and 2 and Fig. 1) [2]. Readers are
referred to reviews by Rhoney and Peacock for further infor-
mation about dosing, limitations, side effects, etc. of intrave-
nous (IV) antihypertensive therapies [7, 8]. There are no data
available which demonstrate that treatment of a hypertensive
crisis reduces mortality and other consequences [2]. However,
if left untreated, the 1-year mortality rate, for patients present-
ing with a hypertensive emergency, exceeds 79% [9].
This article will review the data surrounding the manage-
ment of hypertensive emergencies that have emerged in the
last 5 years. A PubMed and Medline search using the terms
hypertensive crisis, hypertensive emergency, and the types of
end-organ damage and agents used to treat the emergencies as
listed in Table 1. Clinical trials were limited to human studies
56 Page 2 of 8 Curr Hypertens Rep (2018) 20: 56

Table 1 Preferred treatment

options for hypertensive End-organ damage Treatment options Comments
emergency [1]a
Acute renal failure Clevidipine Avoid nitroprusside due to
Nicardipine risk of cyanide toxicity
Fenoldopam
Encephalopathy, ischemic stroke, Nicardipine Avoid aggressively lowering
or hemorrhagic stroke Fenoldopam BP
Clevidipine
Labetalol
Acute coronary syndromes Esmolol
Nitroglycerin
Labetalol
Acute aortic dissection Esmolol +/− nicardipine Avoid reflex tachycardia;
or clevidipine control heart rate before
Labetalol adding vasodilator
Acute heart failure and pulmonary Clevidipine
edema Nitroglycerin
Nitroprusside
Pre-eclampsia/eclampsia Labetalol
Nifedipine (oral)
Hydralazine
Sympathetic crisis Clevidipine
(e.g., pheochromocytoma, Nicardipine
post-carotid endarterectomy)
Phentolamine
a
Intravenous unless otherwise indicated

published in the last 5 years. Based on the review of the recent of select end-organ damages including pre-eclampsia/eclamp-
literature, this article will focus on updates in the management sia, stroke, and HF.

Table 2 Blood pressure goals for end-organ damage [2]

End-organ damage Acute BP goal (within 1 h of presentation) Subacute BP goal (1–72 h)

Acute renal failure SBP reduced by 25% < 160/100 mmHg within 6 h and
to normal within 24–48 h
Acute intracerebral hemorrhagea SBP < 220 mmHgb 150–220 mmHg
Acute ischemic stroke < 180/105 mmHg if receiving thrombolysis < 180/105 mmHg for 24 h
or endovascular repair
< 220/120 mmHg if not receiving thrombolysis < 220/120 mmHg
or endovascular repairc
Encephalopathy SBP reduced by 25% < 160/100 mmHg within 6 h and
to normal within 24–48 h
Acute coronary syndromes SBP reduced by 25% < 160/100 mmHg within 6 h and
to normal within 24–48 h
Acute aortic dissection SBP < 120 mmHg SBP < 120 mmHg
Acute heart failure and pulmonary edema SBP reduced by 25% < 160/100 mmHg within 6 h and
to normal within 24–48 h
Pre-eclampsia/eclampsia SBP < 140 mmHg SBP < 140 mmHg
Sympathetic crisis (e.g., pheochromocytoma, SBP < 140 mmHg SBP < 140 mmHg
post-carotid endarterectomy)

BP blood pressure, SBP systolic blood pressure

a
BP goal within 6 h of presentation
b
The 2015 American Heart Association/American Stroke Association Spontaneous Intracranial Hemorrhage guidelines recommend acute, aggressive
SBP lowering to < 140 mmHg
c
If no other comorbidities present that acutely require lower BP goal
Curr Hypertens Rep (2018) 20: 56
Fig. 1 Blood pressure
management of acute ischemic
stroke [2]. BP blood pressure
Pre-eclampsia-eclampsia
Pre-eclampsia and eclampsia can develop 20 weeks after ges-
tation and is associated with an increased risk of complications
and death for the mother and the fetus. Pre-eclampsia is de-
fined, by the American College of Obstetricians and
Gynecologists (ACOG), as (1) a SBP ≥ 160 mmHg or a
DBP ≥ 110 mmHg, confirmed within minutes, or (2) a SBP
≥ 140 mmHg or a DBP ≥ 90 mmHg on two occasions, at least
4 h apart, in a woman with a previously normal BP.
Additionally, one of the following must also be present: pro-
teinuria, thrombocytopenia, impaired liver function, new or
worsening renal insufficiency, pulmonary edema, or new ce-
rebral or visual disturbances. Pre-eclampsia is considered a
hypertensive emergency, according to ACOG, when the
SBP ≥ 160 mmHg or a DBP ≥ 110 mmHg lasts for more than
15 min [10]. Eclampsia is when a woman with pre-eclampsia
develops new-onset grand mal seizures [11, 12•].
Until recently, the ACOG recommended the use of IV
labetalol or hydralazine as first-line therapy. Concerns about
the safety of hydralazine in this population had been raised,
leading to investigations for alternative therapies [13–15].
Two trials suggested oral nifedipine as a safe alternative.
Shekhar et al. conducted a randomized, double-blind,
placebo-controlled trial to further evaluate the use of oral ni-
fedipine. Women aged 18–45 who were 24 or more weeks
gestation with a SBP ≥ 160 or a DBP ≥ 110 mmHg on two
separate readings, more than 30 min apart, were enrolled.
Notable exclusion criteria were moderate-severe bronchial
asthma, HF, or heart block. Sixty women were randomized
to nifedipine 10 mg (up to five doses) or IV labetalol in esca-
lating doses of 20, 40, 80, 80, and 80 mg. Patients received a
Page 3 of 8 56
subsequent dose every 20 min if the SBP was > 150 mmHg or
the DBP was > 100 mmHg. Patients could receive the alter-
nate therapy if the initial treatment did not control the BP after
five doses. The primary outcome of BP control, defined as a
SBP ≤ 150 mmHg and a DBP ≤ 100 mmHg, was attained
more quickly with nifedipine (median 40 min [interquartile
range (IQR) 20–60] vs. 60 min [IQR 40–85], p = 0.008).
Less doses of nifedipine were required (median 2 doses
[IQR 1–3] vs. 3 doses [IQR 2–4.25], p = 0.008). Five women
in the labetalol group and one in the nifedipine group did not
achieve BP control and were subsequently changed to the
alternate therapy. The five who were not controlled with
labetalol and switched to nifedipine achieved BP control after
two doses. There was no difference in Apgar scores, a mea-
sure of the status of a newborn, at 1 and 5 min, birth weight, or
maternal hypotension between groups [16•].
Shi et al. compared IV labetalol to oral nifedipine in preg-
nant women, more than 30 weeks of gestational age, with pre-
eclampsia in a double-blind randomized study. Participants
were required to have a BP ≥ 160/110 mmHg. Exclusion
criteria were use of antihypertensive therapy or HF. Those
enrolled were randomized to oral nifedipine (n = 74) or IV
labetalol (n = 73). Those randomized to nifedipine could re-
ceive up to five 10-mg tablets. Those in the labetalol group
received a dose regimen of 20, 40, and 80 mg. Doses were
administered every 15 min until the BP was controlled.
Control was defined as a BP ≤ 150/100 mmHg. Cross-over
treatment was utilized if the initial therapy was unsuccessful.
There was no difference in the primary outcome, which was
time to achieve goal BP between groups (35 min with nifed-
ipine vs. 42 min with labetalol, p = 0.37). The median number
of doses needed to achieve the target BP was 2.4 ± 0.43 with
56 Page 4 of 8
nifedipine and 2.6 ± 0.33 with labetalol (p = 0.46). Adverse
effects were reported by 14.9% of patients in the nifedipine
group and 19.3% of those in the labetalol group (relative risk
1.04, 95% confidence interval 0.51–2.46). The most common
side effects for nifedipine were headache (5.4%), maternal
tachycardia (4.1%), and dizziness (2.7%). The most common
adverse effects in the labetalol group were maternal tachycar-
dia (5.5%) and nausea and dizziness (4.1% for each). There
was no difference in Apgar scores or birthweight [17].
Sharma et al. compared IV hydralazine versus oral nifedi-
pine in pregnant woman, 24 weeks or more gestation, with the
same BP criteria utilized in the previously discussed trials.
Exclusion criteria were similar to those in the trial by
Shekhar and colleagues. Women were randomized to hydral-
azine (n = 30) or oral nifedipine (n = 30) in this double-blind,
placebo-controlled trial. Treatment was administered until a
SBP ≤ 150 mmHg or a DBP ≤ 100 mmHg was achieved.
Participants received hydralazine a 5-, 10-, 10-, and 10-mg
dose or nifedipine. The authors adopted the nifedipine dosing
strategy utilized by Shekhar et al. [16•] The alternate treatment
was administered if the BP was not controlled after four doses.
The primary outcome, the time to achieve both the SBP and
DBP goal, was similar between treatment groups (median
40 min). The median number of doses required to achieve
the goal BP was also similar between groups (hydralazine 2
doses [interquartile interval 1]; nifedipine 2 [2], p = 0.809).
Side effects were similar except vomiting was more common
with hydralazine (9 vs. 2 women, p = 0.042). There were no
differences in neonatal outcomes. There was one case of a
precipitous decrease in BP in the nifedipine group. The BP
responded and there were no serious maternal or fetal side
effects [18•]. These combined data suggest that oral nifedipine
is an attractive alternative to traditional first-line therapies.
The need for second-line therapies exists. Intravenous
nicardipine has been demonstrated to reduce BP effectively
in this population, but there is conflicting data regarding safe-
ty. Cardiac failure and acute pulmonary edema have occurred
in pregnant women receiving IV nicardipine; fetal death and
other complications have occurred in animal studies [19•,
20–22]. Intravenous nicardipine, in a study of ten women with
pre-eclampsia, was shown to significantly reduce mean arte-
rial pressure and total vascular resistance but induced a reflex
tachycardia and subsequent elevation in cardiac output. No
changes in fetal hemodynamics were observed. Fetal and ma-
ternal cardiac monitoring should be used if this agent is ad-
ministered [19•].
In 2017, the ACOG updated their recommendations for the
treatment of acute-onset, severe hypertension given the recent
literature surrounding the use of oral nifedipine. First-line
therapies now include intravenous labetalol and hydralazine
and immediate-release oral nifedipine, when IV access is not
available. Although concerns regarding safety have been
raised in this population, especially maternal hypotension
Curr Hypertens Rep (2018) 20: 56
and tachycardia, hydralazine is still commonly used due to
its efficacy. Yet, clinicians should consider hydralazine cau-
tiously since its pharmacological properties make it less ideal
due to its delayed onset of action, unpredictable hypotensive
effect, and prolonged duration of action up to 12 h. Treatment
should be initiated as soon as possible, ideally in the first 30–
60 min of confirmed severe hypertension. Nifedipine capsules
should not be punctured or administered sublingually.
Intravenous nicardipine and esmolol are considered second-
line therapies due to less data supporting their use in this
population. The decision on selecting a second-line agent
should be made in consultation with a specialist.
Nitroprusside should be reserved for extenuating circum-
stances given the risk of cyanide and thiocyanate toxicity
and potential increase in intracranial pressure, which can
worsen cerebral edema in pre-eclamptic patients [11]. The
use of ketanserin, a 5-HT-2 antagonist with a high affinity
for alpha-1 adrenergic receptors, should not be used due to
lack of efficacy [23].
Stroke
Acute Ischemic Stroke
Acute BP elevation is common during stroke presentation
even in patients without a history of hypertension. Patients
presenting with an elevated BP at the time of acute ischemic
stroke (AIS) are at risk for cerebral edema, hemorrhagic con-
version, and increased risk of hemorrhage if thrombolytics are
administered [24]. The American Heart Association/
American Stroke Association (AHA/ASA) provides recom-
mendations in reducing BP carefully for patients who are re-
ceiving thrombolytic therapy as well as those who are not
candidates (Fig. 1) [25].
Current guidelines recommend the use of IVagents such as
labetalol, nicardipine, and clevidipine to lower arterial BP;
however, few comparative studies exist among these agents
[25]. Two studies were recently published comparing these
agents. DeRyke et al. conducted a prospective, pseudo-ran-
domized, active-controlled study to compare efficacy and
safety of IV labetalol and IV nicardipine in patients presenting
with confirmed hemorrhagic or ischemic stroke. Patients had
to be 18 years or older with elevated BP defined by the stroke
guidelines at the time of enrollment. Notable exclusion criteria
included patients with previous administration of an IV anti-
hypertensive agent, traumatic brain injury (TBI), intracranial
neoplasm, brain herniation or imminent brain death, acute MI,
or bradycardia. Using admission date, patients were allocated
to receive either labetalol or nicardipine; selection of medica-
tion alternated in a bi-weekly block. Twenty-eight patients
received labetalol as a 20 mg-IV bolus with repeat dosing
allowed every 15 min up to a total of 300 mg, and 26 patients
Curr Hypertens Rep (2018) 20: 56
received nicardipine at a starting rate of 5 mg/h titrated every
15 min by 2.5 mg/h with a maximum rate of 15 mg/h.
Treatment could be discontinued at the discretion of the
treating physician and rescue antihypertensive therapy could
be added if BP remained uncontrolled. Blood pressure goals
were set by consensus recommendations at the time of the trial
based on presenting stroke subtype. The most common stroke
subtype was intracranial hemorrhage (ICH) representing 46%
of patients receiving labetalol and 62% receiving nicardipine.
Approximately one third of the patients in each group present-
ed with an AIS. Primary outcome measures were achievement
of goal BP and time spent within goal range. All patients in the
nicardipine group achieved their BP goal at 24 h with 89% of
patients achieving goal SBP within the first 60 min; none
required rescue therapy. In comparison, 61% of patients in
the labetalol group achieved their target BP goal at 24 h with
25% attaining their goal within the first 60 min. Goal BP
achievement and time within goal BP range both significantly
favored nicardipine (p < 0.001 and p < 0.001). In the labetalol
arm, 77% of patients required one or more additional agents to
attain their SBP goal. Bradycardia was noted more often in the
labetalol group (14 vs. 0%, p = 0.065), and hypotension, de-
fined as SBP < 90 mmHg, was similar between the groups (4
vs. 4%, p = 1) [24].
Allison et al. completed a retrospective, observational, co-
hort study to compare clevidipine and nicardipine in faster
achievement of goal BP as determined by the treating provid-
er. Clinical outcomes included time to administration of
alteplase, overall length of stay, and mortality. Patients were
identified through retrospective chart review and included if
they were at least 18 years old and received clevidipine or
nicardipine for BP management in AIS or spontaneous ICH.
Notable exclusion criteria included patients presenting with
TBI. Seventy patients received clevidipine starting at a rate
of 2 mg/h. If goal BP was not met, the dose was doubled every
90 s until a rate of 12 mg/h and if patients’ BP remained
elevated, doses were increased by 4 mg/h to a maximum rate
of 32 mg/h. One hundred forty patients received nicardipine,
initiated at a rate of 5 mg/h, and titrated every 15 min to a
maximum rate of 15 mg/h. At baseline, more patients in the
nicardipine group presented with ICH (71.4 vs. 47.1%, p =
0.001), but more patients in the clevidipine group had a his-
tory of hypertension (88.6 vs. 73.6%, p = 0.013) and presented
with higher SBP on admission (199 vs. 184 mmHg, p =
0.002). There was no difference in mean percentage of BP
reduction in the first 2 h (20% with clevidipine vs. 16% with
nicardipine, p = 0.058). The 24-h mean SBP was lower with
nicardipine compared to that with clevidipine (146 vs.
150 mmHg, p = 0.041). More patients in the nicardipine group
presented with ICH, which may have influenced their target
BP goal. The incidence of hypotension was similar between
the groups (clevidipine 4% vs. nicardipine 6%, p = 0.755).
There were no differences found between clevidipine and
Page 5 of 8 56
nicardipine with regard to time to alteplase administration
(56 vs. 59 min, p = 0.684), length of stay (6 vs. 7 days, p =
0.226), or mortality (15.7 vs. 20%, p = 0.452) [26•].
Given risks associated with elevated BP in the setting of
AIS, use of antihypertensive agents that provide rapid but safe
reduction of BP is preferred. Clevidipine and nicardipine, both
rapid-acting titratable agents, appear to confer similar benefit
as single-agent therapy in rapid BP reduction and achieved
clinically similar SBP at 24 h. Labetalol when used as a single
agent for BP reduction in AIS did not reliably achieve goal
SBP, requiring a second BP agent in approximately 77% of
patients. In the absence of contraindications, the use of calci-
um channel blockers may be an ideal first-line option prior to
using other agents to achieve rapid BP reduction.
Intracranial Hemorrhage
Uncontrolled hypertension is a leading cause of ICH, and
approximately 90% of ICH present with an elevated BP.
Outcomes are generally influenced by the severity of hemato-
ma expansion. Some evidence suggests acute reduction in BP
may reduce hematoma expansion and theoretically improve
outcomes [27••, 28••]. The 2015 AHA/ASA Spontaneous
ICH guidelines modified the SBP goal to 140 mmHg in pa-
tients presenting with a SBP between 150 and 220 mmHg
based on the Rapid Blood Pressure Lowering in Patients with
Acute Intracerebral Hemorrhage (INTERACT2) trial [29].
The authors found that intensive BP lowering did not signif-
icantly reduce the rate of death or severe disability (55.6 vs.
52%, p = 0.06) but did significantly improve functional out-
comes based on the Modified Rankin Scale (odds ratio 0.87,
p = 0.04) and the overall health-related quality of life (p =
0.002) [27]. Since that time, Qureshi et al. conducted the
Intensive Blood-Pressure Lowering in Patients with Acute
Cerebral Hemorrhage (ATACH-2) trial, a randomized, multi-
center, two-group, open-label trial, to determine the relative
efficacy of intensive (goal SBP of 110–139 mmHg) versus
standard antihypertensive treatment (goal SBP of 140–
179 mmHg). There was no significant difference in the prima-
ry outcome of death or disability at 3 months (38.7% in the
intensive treatment vs. 37.7% in the standard treatment group,
p = 0.84) [28]. Based on the results of subsequent data, the
2017 Hypertension Clinical Practice Guidelines state that “im-
mediate lowering of SBP < 140 mmHg is not of benefit to
reduce death or severe disability in adults with spontaneous
ICH presenting within 6 hours” [2].
Guidelines do not make specific recommendations regard-
ing antihypertensive agents for use in ICH; yet, the trials pre-
viously described have all used nicardipine as their first-line
treatment agent. Clevidipine is a rapid-acting antihypertensive
with a short half-life, making it an appealing agent for careful
BP reduction. Graffagnino et al. conducted a multicenter,
open-label, single-arm trial to evaluate efficacy and safety of
56 Page 6 of 8
clevidipine use for acute BP reduction in patients presenting
within 6 to 12 h of ICH symptoms and a SBP > 160 mmHg.
Thirty-three patients received clevidipine to assess the median
time to achieve the target SBP of 140–160 mmHg and the
percent of patients achieving target range within 30 min of
clevidipine initiation. Clevidipine dosing strategies were the
same as those described in previous trials. The primary end-
point, mean time to target SBP, was 5.5 min with all patients
achieving the target SBP within 30 min of clevidipine initia-
tion. Only one patient received an additional agent for BP
control. Within the first 30 min, SBP decreased by an average
of 38.8 mmHg (20%) and remained within the target range.
No patients reported a SBP < 90 mmHg within the first
30 min; however, three patients did experience mild to mod-
erate hypotension, which resolved with a dose reduction [30].
Management of BP in patients with ICH remains difficult
as an optimal BP range remains undefined due to conflicting
evidence, and both hypertension and hypotension can result in
negative consequences [2, 29]. Due to the importance of BP
control, ideal medications for use would be rapid acting, pre-
dictable, precise, and titratable [30]. Historically, these agents
have included labetalol, nicardipine, and fenoldopam; given
its rapid and reliable BP reduction, clevidipine appears to be a
safe and effective option for BP reduction in patients present-
ing with ICH. Medications that can increase intracranial pres-
sure and worsen cerebral edema (e.g., hydralazine, nitroglyc-
erin, and nitroprusside) should be avoided in this population.
Acute Hypertensive Heart Failure
Heart failure is estimated to account for over one million
hospitalizations per year [31]. Patients with hypertensive
acute HF often present with rapid onset dyspnea and a
SBP > 140–160 mmHg. The primary hemodynamic
changes that occur in hypertensive HF patients include
increased systemic vascular resistance (afterload) and de-
creased venous capacitance, which can often lead to fluid
redistribution. A stiff left ventricle in these patients re-
duces the ventricle’s ability to accommodate for even
small changes in volume status (preload), and as a result,
even small increases in volume can lead to elevated BP. In
contrast to chronic hypertension treatment in heart failure
patients, acute hypertension treatment options generally
include fast-acting agents such as nitrates, loop diuretics,
enalaprilat, hydralazine, and nitroprusside [32••].
Ayaz et al. completed a retrospective cohort study to eval-
uate the hemodynamic effects and safety of bolus enalaprilat
in the treatment of patients presenting to the emergency de-
partment with hypertensive acute HF. This was a single-center
retrospective cohort study of 103 patients. All patients re-
ceived at least one dose of IV enalaprilat with or without
additional diuretic or vasodilator therapy. At presentation,
the average SBP was 195.2 mmHg, with mean left ventricular
Curr Hypertens Rep (2018) 20: 56
ejection fraction (LVEF) of 38% and an average N-terminal-
pro brain natriuretic peptide of 3797.8 pg/mL. The mean
enalaprilat dose was 1.3 mg with the majority (76.7%) receiv-
ing a single 1.25-mg dose. In addition to enalaprilat, 88.3% of
patients received IV furosemide, 13.5% received an IV bolus
of nitroglycerin, and 21.3% received nitroglycerin via contin-
uous infusion. Three hours after enalaprilat administration,
the mean reduction in SBP was 30.5 mmHg with only two
patients (1.9%) developing hypotension, defined as a SBP
< 90 mmHg [33•].
Peacock et al. completed a randomized, open-label, active-
controlled trial to determine efficacy and safety of early treat-
ment with clevidipine versus standard of care intravenous an-
tihypertensive therapy in patients presenting with hyperten-
sive heart failure. Patients enrolled were men and non-
pregnant women at least 18 years old presenting to the emer-
gency department with a SBP ≥ 160 mmHg. Patients had to
have a dyspnea score of ≥ 50 on a visual analog scale (0–100)
and a diagnosis of acute HF with pulmonary congestion.
Notable exclusion criteria included patients requiring intuba-
tion, chest pain, or ischemic changes, MI within 14 days, liver
or renal failure, pancreatitis, or a contraindication to
clevidipine. Patients were randomized 1:1 to clevidipine or
standard of care to reach the patients’ goal BP range, deter-
mined by the treating physician but had to be a minimum of a
15% BP reduction. The co-primary outcomes included medi-
an time to target BP and percent of patients achieving target
BP within 30 min. Forty-four patients received clevidipine
initiated at 2 mg/h and titrated every 3 min based on BP.
Forty-one patients received standard of care treatment, which
included IV nitroglycerin (57%) and nicardipine (30%).
Patients receiving clevidipine achieved target BP range more
often (71 vs. 37%, p = 0.002). In addition, patients in the
clevidipine group were less likely to require additional therapy
for BP management (16 vs. 51%, p = 0.0005). The mean
change in SBP was higher for patients receiving clevidipine
when compared to that of the standard of care group; however,
when patients receiving nitroglycerin were removed from the
analysis, nicardipine and clevidipine had similar BP-lowering
effects. Drug-related adverse events were low in this study,
9.8% in the clevidipine group vs. 13.2% in the standard of
care group. The most common side effects in the clevidipine
group were headache, abdominal pain, flushing, myalgia, and
nausea [34•].
At this time, current guidelines do not endorse specific
medication classes or strategies for acute reduction of BP in
patients with hypertensive HF. Vasodilators and diuretics re-
main commonly utilized agents in hypertensive HF, while
calcium channel blockers are discouraged due to a lack of
evidence. Patients with HF with preserved LVEF are preload
dependent due to the decreased compliance that results from
the stiffening of the left ventricle; thus, clinicians should take a
more gentle approach when administering diuretics or
Curr Hypertens Rep (2018) 20: 56
venodilators (e.g., nitroglycerin). Clevidipine appears to be
safe and efficacious in acute BP lowering for hypertensive
HF. Enalaprilat has also shown efficacy reducing BP in the
emergency room setting, although it was often used in com-
bination with other therapies, and this data should not be ex-
trapolated for use as a single agent. Also, hypertensive HF
patients often present with acute kidney injury, which may
limit frequent administration of enalaprilat due to its long
half-life (~ 35 h).
Conclusion
For patients who develop a hypertensive emergency, initiation
of appropriate therapy is critical as delays are associated with
significant morbidity and mortality. Recently published trials
have provided new information for the management of select
end-organ damage including pre-eclampsia/eclampsia, stroke,
and heart failure. For managing patients with pre-eclampsia,
trials have demonstrated that oral nifedipine is safe and effec-
tive, which is now considered an alternative first-line therapy
to IV hydralazine and labetalol. Based on new evidence, the
guidelines now recommend clevidipine as a first-line option
for AIS and is considered an effective option for ICH.
Management of hypertensive HF remains challenging due to
limited data, and vasodilators and diuretics remain as the most
commonly used medications. However, two studies suggest
that clevidipine and enalaprilat are safe and effective options,
which warrant further investigation in larger controlled trials.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant
to this manuscript.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
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• Of importance
•• Of major importance
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