Considerations in Acute Blood
Pressure Control Following Acute
Stroke
Denise H. Rhoney, Pharm.D., FCCP, FCCM, FNCS
Ron and Nancy McFarlane Distinguished Professor and Chair
Division of Practice Advancement and Clinical Education
UNC Eshelman School of Pharmacy
Chapel Hill, NC
Acute Hypertensive Crises
Rapid BP Control
Acute Hypertensive Crises
Hypertensive
Urgency1
Severe BP elevation
WITHOUT
end-organ damage
Hypertensive
Emergency1
Severe BP elevation WITH
end-organ damage
Perioperative
Hypertension2
Severe BP elevation
occurring before, during,
or after surgical
procedures
About 500,000 patients experience a hypertensive emergency annually
BP=blood pressure.
1. Chobanian AV, et al. Hypertension. 2003;42:1206-1252;
2. Varon J, Marik PE. Vasc Health Risk Manag. 2008;4:615-627.
End-Organ Damage in Hypertensive
1,2
Emergencies
Brain
Hypertensive Encephalopathy
Ischemic Stroke
Hemorrhagic Stroke
Subarachnoid Hemorrhage
Cardiovascular System
Unstable Angina
Acute Heart Failure
Acute Myocardial Infarction
Aortic Dissection
References: 1. Varon J, Marik PE. Chest. 2000;118(1):214-227. 2. Rynn KO et al. J Pharm Prac. 2005;18(5):363-376.
Retina
Hemorrhages
Exudates
Papilledema
Kidney
Hematuria
Proteinuria
Decreasing Renal Function
Acute Hypertension
Pathophysiology and Treatment Options
Circulating and local factors acting on
endothelium and vascular smooth muscle
Circulating Vasoconstrictors
BP
=
Abrupt  BP
Circulating Catecholamines
SVR
Abrupt  SVR
X
CO
(SV x HR)
SVR=systemic vascular resistance; CO=cardiac output; SV=stroke volume; HR=heart rate.
Oates JA, Brown NJ. In: Hardman JG, Limbird LE, eds. Goodman and Gilman’s Pharmacological Basis of
Therapeutics. 10th ed. New York, NY: McGraw-Hill; 1997:871-900.
Challenges in Acute BP Control in Critical
Care

The JNC 7 guidelines recommend to “reduce MAP by no more
than 25% within minutes to 1 hour” for hypertensive
emergencies1


Therefore, challenges exist in individualizing treatment for
each particular situation and patient1,2



The variety of patient types and clinical situations preclude more
specific guidelines with regard to treatment timing or targets
The agent of choice depends on the clinical presentation and specific
needs of each patient2
Complications may result from aggressive BP reductions
Titratable IV therapy is essential
BP=blood pressure; JNC 7=Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure.
1. Chobanian AV, et al. Hypertension. 2003;42:1206-1252.
2. Varon J, Marik PE. Vasc Health Risk Manag. 2008;4:615-627;
Optimal Properties of a Parenteral
Antihypertensive Agent

Rapid onset of action1

Predictable dose response1

Titratable to desired BP1

Minimal dose adjustments1

Minimal adverse effects1

No association with coronary steal or increased ICP2,3

Ease of use and convenience1
Abbreviation: BP, blood pressure.
References: 1. Oparil S et al. Am J Hypertens. 1999:12(7):653-664. 2. Seiler C et al. Circulation. 1997;96(12):4261-4267.
http://circ.ahajournals.org/cgi/content/full/96/12/4261. 3. CARDENE I.V. [package insert]. Bedminster, NJ: EKR Therapeutics. Inc.;
2008.
Available Parenteral Agents to Treat
Hypertensive Emergencies

Calcium Chanel
Blockers
 Nicardipine
 Clevidipine


 Hydralazine

 Labetalol
Nitrovasdilators
 Nitroglycerin
Adrenergic Receptor
Blockers
 Esmolol
Vasodilators
 Nitroprusside

ACE Inhibitor
 Enalaprilat
Primary Effects of Available Agents
Considerations of Ready-to-Use Medications

Safety




Cost & Time Savings






Support TJC standards and ASHP guidelines
Eliminate admixture errors and minimizes labeling concerns
Support dosage standardization
Improve efficiency
Save time and labor
Reduce wastage
Provide safe alternative to after-hours compounding
Support dosage standardization
Promote achievement of key clinical benchmarks


Door-to-Dose
Optimization of patient outcomes
Abbreviations: TJC, The Joint Commission; ASHP, American Society of Health-System Pharmacists; IV, intravenous.
IV Treatment of Acute Hypertension Is a Vital Consideration
in Neuroemergencies
Abbreviations: AIS, acute ischemic stroke; ICH, intracerebral hemorrhage; IV, intravenous; aSAH, aneurysmal subarachnoid
hemorrhage; SBP, systolic blood pressure.
References: 1. Jauch EC et al. Stroke. 2013;44(3):870-947. 2. Antihypertensive Treatment of Acute Cerebral Hemorrhage
(ATACH) Investigators. Crit Care Med. 2010;38(2):637-648. 3. Connolly ES et al. Stroke. 2012;43(6):1711-1737.
Key Considerations for Choosing an Antihypertensive
Agent in Acute Stroke
Abbreviations: AIS, acute ischemic stroke; BP, blood pressure; ICH, intracerebral hemorrhage; aSAH, aneurysmal
subarachnoid hemorrhage.
.
What the Guidelines State…
12
Abbreviations: AHA, American Heart Association; ASA, American Stroke Association; aSAH, aneurysmal subarachnoid hemorrhage;
BP, blood pressure; DBP, diastolic blood pressure; IV, intravenous; SBP, systolic blood pressure.
References: 1. Connolly ES et al. Stroke. 2012;43(6):1711-1737. 2. Jauch EC et al. Stroke. 2013;44(3):870-947. 3. CARDENE I.V.
(nicardipine hydrochloride) Premixed Injection Prescribing Information. Cary, NC: Cornerstone Therapeutics Inc.; 2013.
What the Guidelines State…
13
Abbreviations: AHA, American Heart Association; ASA, American Stroke Association; ATACH, Antihypertensive
Treatment of Acute Cerebral Hemorrhage trial; BP, blood pressure; ICH, intracerebral hemorrhage.
Reference: Morgenstern LB et al. Stroke. 2010;41(9);2108-2129.
“Time Is Brain” in Acute Ischemic Stroke
Extensive Neural Circuitry Loss Occurs During Every
Minute of a Typical Large Vessel, Supratentorial AIS
*Stereological measurement of brains from across the human lifespan has demonstrated that the neocortex loses ≈31 million
neurons per year in normal aging. Values are based on estimated loss.
Abbreviation: AIS, acute ischemic stroke.
Reference: Saver JL. Stroke. 2006;37(1):263-266.
BP Management Is a Key Component for Patients Being
Considered for tPA Therapy




Door-to-tPA treatment in ≤60 minutes is the standard of care1
 Gently bring BP to <185/110 mm Hg to qualify for tPA therapy1
 Maintain BP at <180/105 mm Hg after tPA is administered1
“Controlled blood pressure lowering during acute stroke can best be achieved
with intravenous antihypertensive therapies. A single optimal medication to lower
the blood pressure in all patients with acute stroke has not been determined,
and an individualized approach is best”1
Treating emergent elevated BP is a major consideration for improving rapid triage
and management of patients2
Acute treatment of hypertension has not been shown to improve stroke outcomes
Abbreviations: BP, blood pressure; tPA, tissue plasminogen activator.
References: 1. Jauch EC et al. Stroke. 2013;44(3):870-947. 2. Shulkin DJ et al. Popul Health Manag. 2011;14(6):267-275.
Summary of Key Treatment in AIS
Intervention
Eligible for Thrombolysis
No Eligible for Thrombolysis
First 24 hours From Symptom Onset
Initial Evaluation
Airway Protection with RSI
BP Control
ABC, NIHSS, GCS
Etomidate 0.2-0.3 mg/kg IV; Lidocaine 1-2 mg/kg; Rocuronium 0.61.2 mg/kg IV
Maintain < 180/105 mm Hg
Avoid hypotension
IV Fluids
Maintain < 220/120 mm Hg
Avoid hypotension
O.9% NaCl
Dysphagia screening
Yes before any medication or food is given
Antiplatelet
NO
ASA 325 mg
DVT Prophylaxis
Mechanical devices only
LMWH
Temperature
Maintain core body temperature < 37.2°C with APAP or external
cooling devices
Blood Glucose
Maintain 140-180 mg/dL
Statins
Jauch EC, et al. Stroke 2013; 44(3):870-947
YES
Summary of Key Treatment in AIS
Intervention
Recommendation
Beyond 24 Hours From Symptom Onset
IV Fluids
0.9% NaCl
BP Control
Initiate long-term antihypertensives; reduce 15% of initial value
Manage Cerebral Edema
Head elevation (30°-45°); Osmotic therapy (mannitol 1 gm/kg IV bolus
then 0.25-1 gm/kg OR 3% NaCl 250-300 mL bolus OR 23.4% NaCl 30 mL
bolus); Sedation/Analgesia
Temperature
Maintain core body temperature < 37.2°C with APAP or ibuprofen or
external cooling devices
Blood Glucose
Maintain 140-180 mg/dL
DVT Prophylaxis
LMWH
Statins
YES
Antithrombic Therapy
Antiplatelet (ASA, clopidogrel, or Aggrenox) or Anticoagulant (Warfarin
or TSOAC)
Jauch EC, et al. Stroke 2013; 44(3):870-947
Aggressive BP Lowering and rt-PA
Therapy


Evaluation of 178 patients treated with IV rt-PA w/in 3 hrs of symptom
onset
28.1% received antihypertensives






52% received standard lowering with labetalol boluses
48% received aggressive lowering with nicardipine or nicardipine + labetalol
Patients requiring antihypertensives had increased baseline NIHSS,
increased baseline blood glucose, and history of HTN
After controlling predictors of outcome use of aggressive lowering was
not associated with poor outcome
Aggressive lowering had significantly reduced LOS (4 vs. 7 days)
Time to rt-PA from symptom onset and ED arrival was significantly longer
in aggressive treatment group (~10-20 min)

Hypothesized to be due to wait time for the nicardipine to be prepared
Martin-Schild et al. Arch Neurol 2008;65:1174-1178
ADJUSTED RISK OF DEATH
Blood Pressure Variation Linked to Mortality
1.0
0.8
0.6
0.4
0.2
0.0
High
Low
–0.2
–0.4
30
40
50
60
70
80
90 100
110 120
130 140
150 160 170
DBP (mm Hg)
Wide fluctuation of blood pressure in
the first 3 hours of the ED stay in
patients with AIS appears to be
associated with an increased risk of
death at 90 days
Stead LG et al. Neurology 2006;66:1878-1881
ADJUSTED RISK OF DEATH
 Mortality Risk With DBP <70 and >105 mm Hg
1.0
0.8
0.6
0.4
0.2
0.0
High
Low
–0.2
–0.4
70
80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280
SBP (mm Hg)
Stead LG et al. Neurology. 2005;65:1179
 Mortality Risk With SBP <155 and >220 mm Hg
Large Retrospective Studies in AIS Focus on Minimizing
BP Variability



Blood pressure variability was associated with hemorrhagic transformation
after AIS, independent of thrombolysis (N=792)1
Systolic blood pressure variability was associated with symptomatic ICH
and death in thrombolysis-treated AIS patients (N=527)2
Blood pressure variability in the subacute phase of ischemic stroke was
associated with poor 3-month outcomes (N=2271)3
Abbreviations: AIS, acute ischemic stroke; BP, blood pressure; ICH, intracerebral hemorrhage.
References: 1. Ko Y et al. Stroke. 2010;41(11):2512-2518. 2. Endo K et al. Stroke. 2013;44(3):816-818.
3. Kang J et al. Neurology. 2012;79(20):2018-2024.
Early Hemorrhage Growth in Patients with
ICH

N=103 patients scanned
within < 3 hrs of onset

38% significant hematoma
growth




(> 33% increase in volume)
26% in 1hr of baseline scan
12% between 1-20hr scan
ICH growth associated with
clinical NIHSS deterioration
2.0 hours
after onset
6.5 hours
after onset
NIHSS, National Institutes of Health Stroke Scale
Brott T et al. Stroke. 1997;28:1-5
Proportion of Patients (%)
Timing of Hematoma Expansion
40
35
30
25
20
15
10
5
0
0-3 Hr
3–6 hr
6–12 hr
Time
Kazui S et al. Stroke. 1996;27:1783
12–24 hr 24–48 hr
Elevated SBP May Predispose to Hematoma
Enlargement
SBP >200 mm Hg
50
% of Patients
40
30
20
10
0
Hematoma
Enlargement
Kazui S et al. Stroke. 1996;27:1783
No Hematoma
Enlargement
Intensive BP Lowering Following ICH
INTERACT
ATACH
N
404
60
Treatment Groups
Intensive = SBP<140
Guideline = SBP<180
Tier 1 = SBP 170-200
Tier 2 = SBP 140-170
Tier 3 = SBP 110-140
Time to Intervention
w/in 6 hrs of symptom onset
& SBP 150-220 at baseline
w/in 6 hrs of symptom onset & SBP
≥ 170 at baseline
BP Lowering Therapy
Variable; at discretion of
individual investigators
Nicardipine infusion
Outcome
RR hematoma growth 36%
lower in the intensive group
Safety endpoints not below
prespecified thresholds; 3 month
mortality lower than expected
Anderson CS, et al. Lancet Neurol 2008; 7:391-99
Qureshi AI. Crit Care Med 2010:38 (2) [epub]
Achieved BP Target & Hematoma
Growth – INTERACT
Absolute Increase in Hematoma Volume
Proportional Increase in Hematoma Volume
Maximum reduction in hematoma growth
occurred in 1/3 of patients with lowest ontreatment SBP (median = 135 mm Hg)
Intensive BP reduction to goal SBP 130-140
is likely to provide maximum protection
against hematoma growth
Arima H et al. Hypertension 2010;56:852-858
INTERACT 2

International (21 countries), multicenter,
prospective, randomized, open-treatment, blinded
end-point trial comparing intensive (SBP < 140 mm
Hg) to guideline based treatment
 N=
2839 enrolled within 6 hours of symptom onset
with SBP 150-220 mm Hg
Anderson et al. NEJM 2013;368:2355-2365
INTERACT 2

BP Agents used in trial

Mean SBP Achieved
1 hour: Intensive = 150 mm Hg vs Guideline= 164 mm Hg
 6 hours: Intensive = 139 mm Hg vs Guideline = 153 mm Hg

Anderson et al. NEJM 2013;368:2355-2365
INTERACT 2 - Outcomes
Ordinal analysis
of the primary
outcome, there
were significantly
better functional
outcomes among
patients assigned
to intensive
treatment than
among patients
assigned to
guidelinerecommended
treatment
Anderson et al. NEJM 2013;368:2355-2365
INTERACT 2 and BP Variability
• SBP variability In
hyperacute/acute
period predicts
poor outcome
• Strongest
predictor were
max SBP and SD of
SBP
• Benefits of early
treatment to
reduce SBP < 140
mm Hg may be
enhanced by
smooth and
sustained control
trying to avoid
peaks in SBP
Manning et al. Lancet Neurology 2014; 13:364-373
Intensive BP Lowering Following ICH
INTERACT
ATACH
N
404
60
Treatment Groups
Intensive = SBP<140
Guideline = SBP<180
Tier 1 = SBP 170-200
Tier 2 = SBP 140-170
Tier 3 = SBP 110-140
Time to Intervention
w/in 6 hrs of symptom onset
& SBP 150-220 at baseline
w/in 6 hrs of symptom onset & SBP
≥ 170 at baseline
BP Lowering Therapy
Variable; at discretion of
individual investigators
Nicardipine infusion
Outcome
RR hematoma growth 36%
lower in the intensive group
Safety endpoints not below
prespecified thresholds; 3 month
mortality lower than expected
Anderson CS, et al. Lancet Neurol 2008; 7:391-99
Qureshi AI. Crit Care Med 2010:38 (2) [epub]
ATACH Study
SBP reduction ≥60
mmHg
All Subjects
N=32
SBP reduction <60
mmHg
RR
(95% CI)
N=28
Hematoma
expansion
(increase of >33%)
19.4%
33.3%
0.58
(0.24, 1.42
Relative edema
expansion
(increase of >40%)
42.9%
57.7%
0.74
(0.43, 1.27)
Death or disability
(mRS 4-6)
32.1%
52.0%
0.62
(0.32, 1.19)
Qureshi AI, et al. Arch Neurol. 2010;67(5):570-576.
ATACH Study
SBP reduction ≥60
mmHg
SBP reduction <60
mmHg
Subjects treated
within 3 hours of
symptom onset
N=11
N=9
Hematoma
expansion (increase
of >33%)
18.2%
37.5%
0.48
(0.10, 2.26)
Relative edema
expansion (increase
of >40%)
30.0%
37.5%
0.80
(0.22, 2.94)
Death or disability
(mRS 4-6)
12.5%
42.9%
0.29
(0.04, 2.21)
Qureshi AI, et al. Arch Neurol. 2010;67(5):570-576.
RR
(95% CI)
ATACH Study


The consistent favorable direction of these
associations support further studies to evaluate the
efficacy of aggressive pharmacological SBP reduction
with adequately powered randomized controlled
design
ATACH II Primary Hypothesis

Intensive SBP reduction (SBP≤140 mmHg, intensive
treatment) using IV nicardipine with treatment
initiated within 3h of onset of ICH and continued for
the next 24h reduces the likelihood of death or
disability at 3m after ICH (defined by mRS score of 4-6)
by 10% or greater (absolute difference) compared with
standard SBP reduction (SBP≤180 mmHg, standard
treatment)
Qureshi AI, et al. Arch Neurol. 2010;67(5):570-576.
Study Population

Inclusion Criteria



Admission to ED with documented evidence of acute unremitting focal
neurological deficits
Hypertension that required treatment based upon current practice
Exclusion Criteria







Age < 18 years
Brainstem herniation or immanent brain death
Traumatic brain injury
History of intracranial neoplasm
Acute myocardial infarction
Severe aortic stenosis
Bradycardia at time of randomization (defined as heart rate <50 bpm)
Drug Regimens
Nicardipine
•Infusion started at 5
mg/hr
•Titrated by 2.5 mg/hr
every 15 minutes until a
therapeutic response is
achieved or a maximal
rate of 15 mg/hr is
reached
Labetalol
•20 mg IVP over 1-2
minutes
•May repeat dose 20mg
or 40mg per physician
discretion every 15
minutes up to a
maximum cumulative
dose of 300 mg/day
Study Outcomes

Primary Outcomes


Time to target blood pressure/ % of time at goal BP
Secondary Endpoints






Number of doses of labetalol administered
Number of dosing changes with nicardipine
Treatment failures (i.e. Failed to reach target BP; additional
antihypertensive agents needed or “rescue” therapy)
Extension of hemorrhage
Hospital and intensive care unit lengths of stay
Incidence of adverse events during the study period



Hypotension, defined as SBP <90 mmHg
Bradycardia, defined as HR <50 bpm
Tachycardia, defined as HR >120 bpm
24-Hour BP Control
P<0.05
Significantly less variation in BP in nicardipine group compared to labetalol group
Blood Pressure Endpoints
Variables
Goal BP Achieved n(%)
Within 60 minutes
Time to Goal BP (min) median (IQR)
% Time Spent within Goal BP (% of 24 hr)
median (IQR)
Labetalol
(n=22)
15 (68.2%)
7 (32%)
90 (30-900)
45.7 (24.774.9)
Nicardipine
(n=25)
25 (100%)
22 (88%)
30 (15-120)
88.5 (79.398.2)
P-value
<0.001
0.026
<0.001
Medication Related Endpoints
Variables
Nicardipine
(n=25)
-----------
P-value
Total dose to achieve goal (mg)
Labetalol
(n=22)
50 (10-280)
Average rate to achieve goal (mg/hr)
-----------
5 (2.5-15)
NA
Number dose adjustments to reach goal BP
2 (1-10)
0 (0-4)
<0.002
0 (0%)
<0.001
Additional anti-HTN agents (“Rescue Therapy”) 16 (73%)
NA
n(%)
Total dose during 24-hr (mg)
Max rate during 24-hr (mg/hr)
145 (40-320)
-----------
Data presented as median (IQR) unless otherwise noted
-----------
8 (2.5-15)
NA
NA
Patients Requiring “Rescue” Therapy
Variables
Labetalol (n=16)
Time additional agent added (hr)
16 (6-23.5)
Achieved goal with additional agent n(%)
16 (100)
Time goal achieved with additional agent (min)
60 (15-82.5)
Agent Added: n(%)
Nicardipine
Enalaprilat
Hydralazine
Clonidine
Total number of additional agents added
14(87.5)
4 (25)
1(2.1)
1 (2.1)
1 (1-3)
Data presented as median (IQR) unless otherwise noted
Adverse Events
Variables n(%)
Labetalol
(n=22)
Nicardipine
(n=25)
P-value
Hypotension (SBP<90 mmHg)
1 (4.5%)
1 (4.0%)
1.000
Bradycardia (HR<50 bmp)
2 (9.1%)
0
0.214
3 (12.0%)
<0.002
Reflex tachycardia (HR>120 bpm) 1 (4.5%)
24 Hour HR Profile
P<0.001
Summary


Limited evidence to guide practice in managing
acute BP
We should focus on minimizing BP variability while
still achieving target BP