Pharmacotherapy considerations on intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a particularly devastating kind of stroke, with a mortality rate of about 40%....
Abdelwahab Ward, BS Pharm, PharmD

Overview

Intracerebral hemorrhage (ICH) is a particularly devastating kind of stroke, with a mortality rate of about 40%. But there are things that can be done (or avoided) to improve outcomes. The chart below presents those relating to pharmacotherapy. Recent guidelines on ICH management from the American Heart Association/American Stroke Association are available at http://stroke.ahajournals.org/content/46/7/2032.full.pdf...

Clinical questions should be in your mind?

  1. How do you manage patients taking an anticoagulant?
  2. How do you manage patients taking antiplatelets?
  3. What VTE prophylaxis is recommended?
  4. How should blood pressure be managed?
  5. If fever develops, is therapeutic cooling recommended?
  6. Should corticosteroids be used to treat elevated intracranial pressure (ICP)?
  7. What quality measures pertain to ICH?

Suggested approach

How do you manage patients taking an anticoagulant?

Correct INR quickly in warfarin patients. 4-factor PCC (e.g., Kcentra) reverses INR faster than FFP, but has not been compared to 3-factor PCC (e.g., Bebulin VH) in an RCT. FFP poses risks of fluid overload, infection, and transfusion and allergic reactions, and requires thawing and cross-matching, which are time-consuming. Vitamin K 5 to 10 mg IV should be used as an adjunct for warfarin reversal. Recombinant factor VIIa is generally not recommended because it does not replace all the vitamin K-dependent clotting factors. For patients taking a DOAC, consider reversal with activated PCC (FEIBA NF) or a PCC. Wait at least four weeks to restart anticoagulation in most patients. Consider restarting earlier in patients with mechanical heart valves.

How do you manage patients taking antiplatelets?

Assess need for antiplatelet. Consider restarting aspirin within a few days, if indicated. Antiplatelet monotherapy does not seem to increase risk of rebleed.

What venous thromboembolism (VTE) prophylaxis is recommended?

Intermittent pneumatic compression is recommended, starting on hospital day 1. Graduated compression stockings don’t work in these patients. Low-dose subcutaneous heparin or low-molecular-weight heparin can be considered in patients who are immobile 1 to 4 days post-stroke, if bleeding has stopped.

How should blood pressure be managed?

Reduce SBP to < 180 mmHg. Current guidelines recommend a goal of < 140 mmHg. INTERACT2 suggests reducing SBP to < 140 mmHg (intensive treatment) improves functional recovery (i.e., lower modified Rankin score with intensive treatment p=0.04), but not the combined primary outcome of death or severe disability, compared to a target of < 180 mmHg (standard treatment), in patients with a mean baseline SBP of 179 mmHg (150 to 220 mmHg). In INTERACT2, one third of patients achieved their SBP goal within 1 hr, and 50% of patients achieved SBP goal within 6 hr. Mean SBP was 150 mmHg in the first h in the intensive treatment group, and 164 mmHg in the standard-treatment group. Over 40% of patients were randomized and treated 4 or more hrs after symptom onset.

BUT a subsequent study (ATACH-2, published after the guidelines) suggests lowering SBP to a range of 110 to 139 mmHg (intensive treatment) doesn’t improve risk of death or disability, or improve functional recovery, compared to a target of 140 to 179 mmHg (standard treatment) in patients with baseline SBP > 180 mmHg (mean around 200 mmHg), and may increase the risk of acute renal failure. In this study, most patients in the intensive group achieved a goal of < 140 mmHg (mean minimum SBP 129 mmHg) within 2 hr. Mean minimum SBP was 141 mmHg in the first 2 hr in the standard treatment group. All patients were randomized and treated within 4.5 hr of symptom onset. Therefore, SBP reduction was faster and greater than in INTERACT2. Despite a paucity of evidence in patients presenting with SBP > 220 mmHg, guidelines state it is reasonable to consider aggressive blood pressure reduction in such patients, with close monitoring.

Individualize choice of agent. Nicardipine may improve cerebral perfusion. Compared to labetalol, nicardipine seems to be more effective and easier to titrate, with similar safety. Consider a starting dose of nicardipine 5 mg/hr, increased by 2.5 mg/hr every 15 min if needed, to a max of 15 mg/hr. Labetalol can be added if necessary. Avoid clinically significant hypotension. Nitroprusside and nitroglycerin can reduce cerebral blood flow. Consider long-term BP goal of < 130/80. In the Secondary Prevention of Small Subcortical Strokes study, a SBP goal of < 130 mmHg was associated with a lower risk of ICH (not the primary outcome) after lacunar stroke vs a SBP goal of 130 to 149 mmHg (HR 0.37, p=0.03).

If fever develops, is therapeutic cooling recommended?

Fever is associated with poor prognosis. Treatment has not been shown to improve outcomes but is reasonable. Hypothermia is experimental and is not recommended in practice.

Should corticosteroids be used to treat elevated intracranial pressure (ICP)?

Corticosteroids increase complications and do not improve outcomes.

What quality measures pertain to intracerebral hemorrhage (ICH)?

Measures include Inpatient Stroke Core Measures. VTE prophylaxis started on the day of or the day after admission. Provided stroke education. Assessed for rehabilitation services

Comprehensive Stroke Center Additional Core Measures. Severity measurement performed prior to surgical intervention, or within 6 hours of admission if not undergoing surgical intervention. The ICH score is externally validated and often used. Get an ICH score calculator at http://www.mdcalc.com/intracerebral-hemorrhage-ich-score/. Use of procoagulant reversal agent in patients with INR > 1.4. For details, see The Joint Commission’s Specifications Manual for National Hospital Inpatient Quality Measures (https://www.jointcommission.org/specifications manual for national hospital inpatient quality measures.aspx) and their Comprehensive Stroke Performance Measurement Implementation Guide (http://www.jointcommission.org/assets/1/6/CSTK-Manual-Mar2015.pdf), which meets the standards for comprehensive stroke centers.

References

  1. Hemphill, J.C., Greenberg, and others (2015). Guidelines for the Management of Spontaneous Intracerebral Hemorrhage. Stroke, 46(7), pp.2032–2060.
  2. The Joint Commission. Disease-specific care certification program. Comprehensive stroke performance measurement implementation guide. January 2015. http://www.jointcommission.org/assets/1/6/CSTK_Manual_Mar2015.pdf
  3. Manning L, Robinson TG, Anderson CS. Control of blood pressure in hypertensive neurological emergencies. Curr Hypertens Rep. 2014 Jun;16(6):436.
  4. SPS3 Study Group, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507-515.
  5. Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013;368(25):2355-2365.
  6. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016;375(11):1033-1043.

Abdelwahab Ward, BS Pharm, PharmD