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 NIHSS score, median 4 (2-7) 4 (3-8) Stroke subtype (%) Thrombotic Embolic Lacunar 167 97 77 5 21 JAMA. 2014;311:479-489. 166 97 79 5 19
BP Reduction JAMA. 2014;311:479-489.
Outcomes Primary Outcome Death or major disability at 14 days or discharge Secondary Outcomes Death or major disability at 3 months Modified Rankin Scale at 14 days or discharge Modified Rankin Scale at 3 months Treatment (n=2038) Control (n=2033) p-value 34% 34% 0.98 25% 25% 0.93 2 (1-3) 2 (1-3) 0.70 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 Number adjustments to maintain goal 2 (1-5) 0 (0-1) <0.001 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) Hydralazine (Apresoline) Sodium nitroprusside (Nipride) 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) 10 min; 1 4 hrs 5 20 mg IV every 4 6 hrs Reflex tachycardia, headache, flushing Caution: Angina/MI, aortic dissection 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) Lisinopril (Zestril) Candesartan (Atacand) 5-10 mg PO daily Reflex tachycardia, nausea, vomiting, headache, flushing Caution: Angina/MI, acute HF, increased ICP 10-40 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis 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 angiotensinconverting enzyme inhibitor (ACEI) is useful Stroke. 2014;45:00-00.
Oral Options Drug Dose Adverse Effects / Precautions Lisinopril (Zestril) Candesartan (Atacand) 10-40 mg PO daily Renal insufficiency/failure, hyperkalemia, cough, angioedema CI: Pregnancy, renal artery stenosis 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