Blood Pressure Management in Acute Ischemic Stroke

Kimberly Clark, PharmD, BCCCP Clinical Pharmacy Specialist – Critical Care, Greenville Health System

Adjunct Assistant Professor, South Carolina College of Pharmacy

Objectives

• Define acute hypertensive response and its impact on patient outcomes

• Review the guideline recommendations for blood pressure (BP) management in acute ischemic stroke (AIS)

• Examine newly published literature • Compare available antihypertensive agents

Acute Hypertensive Response

• Profound BP elevations are common during the acute phase of stroke even among patients without a prior history of hypertension

• In the US National Hospital Ambulatory Medical Care Survey, 76.5% of patients with AIS had systolic blood pressure (SBP) ≥ 140 mm Hg on arrival

Circulation 2015;133:e38-e360.

BP Effect on Outcomes

Stroke 2002;33:1315-1320.

Why Not Treat?

• BP typically decreases spontaneously during AIS, starting within 90 minutes after onset of stroke symptoms

• Lowering BP in patients with hypertension might reduce blood flow from collateral vessels to the ischemic penumbra and lead to loss of neurons

Stroke 2013;44:870-947.

Acute Ischemic Stroke (non-tPA)

AHA/ASA 2013 Guideline Recommendation

Do not lower blood pressure during the initial 24 hours of acute ischemic stroke unless the

blood pressure is >220/120 mm Hg or there is a concomitant specific medical condition that would benefit from blood pressure lowering

Stroke 2013;44:870-947.

Acute Ischemic Stroke and tPA AHA/ASA 2013 Guideline Recommendation

To limit the risk of ICH: • Blood pressure should be lowered to

<185/110 mmHg prior to fibrinolytic therapy with tPA

• Once tPA is given, the blood pressure must be maintained <180/105 mmHg for at least the first 24 hours

Stroke 2013;44:870-947.

CATIS China Antihypertensive Trial in Acute Ischemic Stroke

• Randomized, controlled, single blind trial • Multicenter – 26 hospitals across China • Inclusion

– ≥ 22 years old – Ischemic stroke, confirmed by CT or MRI, within 48 hours of symptom onset – Elevated SBP between 140 mmHg and 220 mmHg

• Exclusion – Hemorrhagic stroke – Severe heart failure, acute myocardial infarction or unstable angina, atrial

fibrillation, aortic dissection, cerebrovascular stenosis – SBP ≥ 220mmHg or DBP ≥ 120mmHg – Resistant hypertension – Treated with IV thrombolytic therapy (i.e. tPA) – Deep coma – Pregnant

JAMA. 2014;311:479-489.

Intervention

• Antihypertensive treatment group – Lower SBP by 10%-25% within the first 24 hrs – BP < 140/90 mmHg within 7 days and for remainder of

hospitalization – Protocol did not require the use of specific

antihypertensive medications • For all patients

– On admission, home antihypertensive medications were held

– At discharge, patients were prescribed antihypertensive medications according to clinical guidelines

JAMA. 2014;311:479-489.

Baseline Characteristics Treatment (n=2038) Control (n=2033)

Age, years 62 62

Male (%) 65 63

Time from onset to randomization, hrs, mean (SD)

15 (13) 15 (13)

History of HTN (%) 79 79

Current use of BP meds (%) 50 48

BP at entry, mmHg Systolic Diastolic

167 97

166 97

NIHSS score, median 4 (2-7) 4 (3-8)

Stroke subtype (%) Thrombotic Embolic Lacunar

77 5

21

79 5

19 JAMA. 2014;311:479-489.

BP Reduction

JAMA. 2014;311:479-489.

Outcomes Treatment (n=2038) Control (n=2033) p-Value

Primary Outcome Death or major disability at 14 days or discharge

34% 34% 0.98

Secondary Outcomes

Death or major disability at 3 months

25% 25% 0.93

Modified Rankin Scale at 14 days or discharge

2 (1-3) 2 (1-3) 0.70

Modified Rankin Scale at 3 months

1 (1-3) 1 (1-3) 0.52

Recurrent stroke 1.4% 2.2% 0.07

Vascular events 2.4% 3.0% 0.28

JAMA. 2014;311:479-489.

Subgroup Analysis

JAMA. 2014;311:479-489.

Subgroup Analysis

JAMA. 2014;311:479-489.

Author’s Conclusion

Unless a patient’s SBP is ≥ 220 mmHg or DBP ≥ 120 mmHg, the decision to lower blood pressure with antihypertensive treatment in patients with AIS does not improve or worsen outcome and therefore should be based on individual clinical judgment

JAMA. 2014;311:479-489.

Critique Strengths • Meets statistical power • Only ischemic stroke

patients • Discontinued home

medications in both groups

• Not limited to a single medication or combination

• Well separated BP levels

Limitations • All Chinese patients • Low median NIHSS score • Did not repeat neurologic

function tests or brain imaging within the first 24 hrs

JAMA. 2014;311:479-489.

ENCHANTED ENhanced Control of Hypertension aNd Thrombolysis strokE stuDy

• International (mostly China), multicenter, prospective, randomized, open-label trial with blinded outcome evaluation

• Intervention – Conventional guideline-directed: SBP <180 mg (since all patients

received tPA) – Early and intensive: SBP 130-140 mmHg within 1 hr (maintained

for 72 hrs) • Primary outcome

– Combined endpoint of death and disability (defined by the modified Rankin Scale) at 90 days

• Sample size – 2,800

• Study to be completed in 2018 World Stroke Organization 2015;10:778–788.

Acute Ischemic Stroke (non-tPA)

AHA/ASA 2013 Guideline Recommendation

Do not lower blood pressure during the initial 24 hours of acute ischemic stroke unless the

blood pressure is >220/120 mm Hg or there is a concomitant specific medical condition that would benefit from blood pressure lowering

Stroke 2013;44:870-947.

Additional Guideline Recommendations

• Reasonable to temporarily discontinue or reduce home antihypertensive medications at the onset of AIS

• Reasonable to initiate long-term antihypertensive therapy after the initial 24 hours from stroke onset but an optimal long-term antihypertensive therapy has not been definitively established

• Controlled blood pressure lowering can best be achieved with intravenous antihypertensive therapies but a single optimal medication has not been determined Stroke 2013;44:870-947.

IV Antihypertensive Therapies

Stroke 2013;44:870-947.

Labetalol (Trandate)

• MOA: Non-selective beta-blocker with alpha blocker properties Alpha to beta ratios vary by route (1:7 IV, 1:3 PO)

• Dosing – Continuous infusion: 0.5–3 mg/min

(300 mg max per 24hrs) – IV bolus: 20–80 mg IV every 15 min

• Caution: asthma, acute heart failure • Adverse effects: bronchospasm, HF exacerbation,

bradycardia/heart block, volume overload

Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 9, 2016

Nicardipine (Cardene)

• MOA: Dihydropyridine calcium channel blocker; results in vasodilation (arteries > veins)

• Dosing – Continuous infusion: 5-15 mg/hr

• Caution: angina/myocardial infarction, acute heart failure, aortic stenosis

• Adverse effects: Reflex tachycardia, headache, flushing, volume overload

Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 9, 2016

Labetalol vs. Nicardipine

• Prospective, randomized, single-center study • Inclusion

– > 18 years old – Admitted for primary ICH, SAH, or AIS

• Exclusion – Traumatic etiology – History of intracranial neoplasm – Received IV antihypertensive medication within 24 hrs – Imminent brain death – Acute myocardial infarction or bradycardia

Neurocrit Care 2013;19:41-47.

Intervention

• Labetalol – IV bolus starting at 20 mg – Repeat dosing every 15 min up to a maximum

cumulative dose of 300 mg/day • Nicardipine

– IV infusion starting at 5 mg/hr – Titrated every 15 min by 2.5 mg/hr until therapeutic

response achieved or max rate of 15 mg/hr • BP monitoring

– Every 15 min until goal achieved – Hourly thereafter for 24 hr period

Neurocrit Care 2013;19:41-47.

Outcomes

Outcome Labetalol (n=28) Nicardipine (n=26) p-Value

Goal BP achieved (%) 61 100 <0.001

Time to goal, min 90 (30-900) 30 (15-120) 0.001

Time at goal (%) 36 (13-72) 89 (80-100) <0.001

Number adjustments to reach goal

2 (1-5) 0 (0-1) <0.001

Number adjustments to maintain goal

4 (2-8) 3 (0-5) 0.05

Hypotension (%) 4 4 1.000

Bradycardia (%) 14 0 0.065

Reflex tachycardia (%) 4 12 0.277

Neurocrit Care 2013;19:41-47.

Author’s Conclusion

• Nicardipine provides better BP control than labetalol over the first 24 h in acutely hypertensive stroke patients

Neurocrit Care 2013;19:41-47.

Critique

Strengths • 24 hr evaluation period • Studied guideline

recommended therapies

Limitations • Compared IV bolus to

infusion • Not designed to look at

clinical outcomes

Neurocrit Care 2013;19:41-47.

Additional Intravenous Options

Drug Onset / Duration Dose Adverse Effects / Precautions

Enalaprilat (Vasotec)

30 min; 12–24 hrs 0.625–1.25 mg IV every 4–6 hrs

Renal insufficiency/failure, hyperkalemia CI: Pregnancy, renal artery stenosis (Note: long half-life)

Hydralazine (Apresoline)

10 min; 1–4 hrs 5–20 mg IV every 4–6 hrs Reflex tachycardia, headache, flushing Caution: Angina/MI, aortic dissection

Sodium nitroprusside (Nipride)

Immediate / 2–3 min after stopped

0.25–10 mcg/kg/min Cyanide/thiocyanate toxicity, methemoglobinemia CI: Renal, hepatic failure

Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 9, 2016

Transitioning to Oral Therapy Drug Dose Adverse Effects / Precautions

Amlodipine (Norvasc)

5-10 mg PO daily Reflex tachycardia, nausea, vomiting, headache, flushing Caution: Angina/MI, acute HF, increased ICP

Lisinopril (Zestril)

10-40 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis

Candesartan (Atacand)

16-32 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis

Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 9, 2016

Transition Tips • Study Objective – Identify treatment options to reduce

time on IV nicardipine while providing optimal blood pressure management

• Patient Population – 50% were stroke patients • Results

– Trend toward improved transitioning with amlodipine • Shortest time from start of oral agent to nicardipine discontinuation • Fewest number of agents required during transition • Fewest nicardipine transition failures

– Multiple antihypertensives required for optimal transitioning • 94% required ≥ 2 antihypertensive agents

– Oral antihypertensives added early in nicardipine therapy • Possibly associated with decreased ICU length of stay and medication

cost

Take Home Points

• The majority of patients with AIS have an elevated BP on arrival

• Based on recent literature and guideline recommendations, there is no clinical benefit of lowering BP during the initial 24 hours of AIS (non-tPA) unless the BP is >220/120 mm Hg

• Nicardipine may provide a more rapid and consistent BP lowering effect in stroke patients

Blood Pressure Management in Acute Ischemic Stroke

Kimberly Clark, PharmD, BCCCP Clinical Pharmacy Specialist – Critical Care, Greenville Health System

Adjunct Assistant Professor, South Carolina College of Pharmacy kbclark@ghs.org

Hemorrhagic Stroke AHA/ASA 2015 Guideline Recommendation

• High SBP is associated with greater hematoma expansion, neurological deterioration, and death and dependency

• Acute lowering of SBP to 140 mm Hg is safe and can be effective for improving functional outcome

• May be reasonable to consider aggressive reduction of BP with a continuous intravenous infusion and frequent BP monitoring

Stroke 2015;46:2032-2060.

Aneurysmal Subarachnoid Hemorrhage AHA/ASA 2012 Guideline Recommendation

• The magnitude of blood pressure control to reduce the risk of rebleeding has not been established, but a decrease in SBP <160 mmHg is reasonable

Stroke. 2012;43:00-00.

Chronic Management AHA/ASA 2014 Guideline Recommendation

• Initiation of BP therapy is indicated for previously untreated patients with ischemic stroke or TIA who, after the first several days, have an established BP ≥140/90 mmHg

• Optimal drug regimen to achieve the recommended level of reductions is uncertain because direct comparisons between regimens are limited

• Available data indicate that diuretics or the combination of diuretics and an angiotensin-converting enzyme inhibitor (ACEI) is useful

Stroke. 2014;45:00-00.

Oral Options Drug Dose Adverse Effects / Precautions

Lisinopril (Zestril)

10-40 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis

Candesartan (Atacand)

16-32 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis

Hydrochlorothiazide 25-50 mg PO daily Hypokalemia, hypercalcemia, photosensitivity Caution: Gout, sulfa allergy

Amlodipine (Norvasc)

5-10 mg PO daily Reflex tachycardia, nausea, vomiting, headache, flushing Caution: Angina/MI, acute HF, increased ICP

Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; September 9, 2016

Blood Pressure Variability (BPV)

• Meta-Analysis of 7 studies: Systolic BPV was significantly associated with poor functional outcome (death or disability): pooled odds ratio per 10 mm Hg increment, 1.2; confidence interval (1.1–1.3)

• Retrospective observational study of 1161 AIS patients: Odds of early neurological deterioration increased 14–21% with each increase of one standard deviation in the BPV

• Prospective study of 608 AIS patients: No association between BPV and in-hospital outcomes

Stroke. 2015;46:2482-2490 Journal of Hypertension. 2015;33:2099–2106

American Journal of Hypertension. 2016;29:841-846