Time to blood pressure control before thrombolytic therapy in patients with acute ischemic stroke: comparison of labetalol, nicardipine, and hydralazine.
Background: Elevated blood pressure is common in patients with acute ischemic stroke. Thrombolytic therapy is contraindicated in patients with a systolic blood pressure greater than 185 mmHg or diastolic blood pressure greater than 110 mmHg. Elevated blood pressure can lead to a delay in thrombolytic therapy, which is associated with increased morbidity. There is currently insufficient evidence to support the use of a specific antihypertensive agent in this setting. Objective: This study aimed to compare the effects of labetalol, nicardipine, or hydralazine on time to target blood pressure before alteplase administration in patients with acute ischemic stroke. Methods: A retrospective chart review was conducted to identify patients who received labetalol, nicardipine, or hydralazine to treat elevated blood pressure (systolic blood pressure > 185 or diastolic blood pressure >110) before intravenous alteplase therapy for ischemic stroke. Data collection included time to blood pressure control, door-to-needle time, total dose administered, and use of additional antihypertensive agent(s). Results: Most patients in this study received labetalol (25/29). Median time to blood pressure control was 10, 22, and 15 minutes in the labetalol, nicardipine, and hydralazine groups, respectively. Among patients who received labetalol, the average time to blood pressure control was 10 minutes longer in those who received 10 mg initially versus those who received 20 mg. Patients who required higher total doses of labetalol tended to achieve blood pressure control more slowly, had longer door-to-needle times, and required additional antihypertensive agents. Conclusions: Adequate initial dosing of antihypertensive treatment has the potential to reduce time to blood pressure control and possibly time to alteplase therapy. The optimal antihypertensive regimen for controlling blood pressure before alteplase therapy remains unclear.
Keywords: alteplase, antihypertensive, blood pressure, hydralazine, ischemic stroke, labetalol, nicardipine, stroke, thrombolytic
Elevated blood pressure, defined as a systolic blood pressure (SBP) greater than 140 mmHg, affects approximately 80% of patients in the setting of acute ischemic stroke (Britton, Carlsson, & de Faire, 1986; Wallace & Levy, 1981). Furthermore, in a large randomized trial of almost 20,000 patients with ischemic stroke, over 50% had an SBP of 160 mmHg or greater (International Stroke Trial Collaborative Group, 1997). Despite its overwhelming prevalence, management of elevated blood pressure in the patient with acute ischemic stroke remains controversial. Elevated blood pressure in this patient population has been associated with poor outcomes, including neurological deterioration and death (Castillo et al., 2004). Conversely, lowering the blood pressure with antihypertensive agents may also worsen neurological function by reducing cerebral perfusion. Guidelines from the American Heart Association/American Stroke Association (AHA/ASA) acknowledge this conundrum and suggest a more conservative approach to the hypertensive patient with stroke. The AHA/ASA recommend withholding administration of antihypertensive agents unless the diastolic blood pressure PBP) is >120 mmHg or the SBP is >220 mmHg in patients not receiving thrombolysis (Jauch et al., 2013).
In patients with stroke who are eligible for treatment with intravenous (IV) alteplase, the recommended threshold for administration of antihypertensives is lower than that of other patients with stroke. Alteplase, a recombinant form of tissue plasminogen activator, is contraindicated in patients who have an SBP > 185 mmHg or a DBP >110 mmHg (Activase [package insert], 2002). Deviation from alteplase treatment protocols has been associated with increased mortality (Graham, 2003; Katzan et al., 2003). Thus, it is recommended to treat hypertension in alteplase candidates who exhibit blood pressure greater than 185 mmHg systolic or 110 mmHg diastolic. If blood pressure cannot be reduced below these thresholds, alteplase should not be administered. Furthermore, such blood pressure reduction must be accomplished in a timely manner. The recommended treatment window for alteplase is up to 3-4.5 hours after the onset of stroke symptoms with a goal door-to-needle time of 1 hour (Del Zoppo, Saver, Jauch, Adams, & AHA Stroke Council, 2010). The importance of early alteplase administration has been shown by evidence of worsened outcomes when thrombolytic therapy is delayed (Marler et al., 2000).
The AHA/ASA guidelines list the following antihypertensive regimens as treatment options before alteplase: labetalol 10-20 mg IV over 1-2 minutes, nicardipine 5 mg/h infusion titrated to desired blood pressure, or other agents (e.g., hydralazine, enalaprilat) when appropriate. Although these options are listed in the aforementioned guidelines, the authors state that there is a lack of data to support the use of any specific antihypertensive agent in the patient with acute ischemic stroke. Guidelines from the European Stroke Organization provide similar recommendations with regard to blood pressure thresholds for treatment; however, they do not recommend specific antihypertensive agents (European Stroke Organisation Executive Committee & Writing Committee, 2008).
In consideration of the restricted time window available for alteplase treatment as well as the potential for improved patient outcomes with earlier alteplase administration, it would be valuable to determine if the required blood pressure targets could be attained more rapidly with the use of specific antihypertensive agents. This study aimed to compare the antihypertensive effects of labetalol, nicardipine, and hydralazine in this patient population. The study was conducted at an 851-bed tertiary care hospital located in Florida. The hospital has been accredited by The Joint Commission (TJC) as a Primary Stroke Center since 2008 and operates a specially trained team that responds to patients with potential stroke arriving at the emergency department. This team evaluates approximately 30 patients with stroke per month on average.
The primary objective of this study was to compare the effects of labetalol, nicardipine, and hydralazine on time to target blood pressure before alteplase administration in patients with acute ischemic stroke. This parameter was measured as the time from the first dose of the initial antihypertensive agent until target blood pressure (defined as SBP <180 mmHg and DBP <110 mmHg) was reached. Secondary measures included door-to-needle time (defined as time from arrival to start of alteplase administration, in minutes), percentage of patients with door-to-needle time of <60 minutes, total antihypertensive dose required, and frequency of use of additional antihypertensive agents to achieve target blood pressure. Safety measures were also assessed, including the incidence of SBP < 140 mmHg, bradycardia (heart rate [HR] < 60 beats per minute), and tachycardia (HR > 100 beats per minute).
This study was a retrospective chart review and received approval from the study site's institutional review board. Patients who received alteplase for acute ischemic stroke between October 2004 and September 2012 were eligible for inclusion if they had an elevated blood pressure (defined as SBP > 185 mmHg or DBP > 110 mmHg) before IV alteplase administration and received labetalol, nicardipine, or hydralazine as the initial antihypertensive treatment. For patients who received multiple antihypertensive agents, stratification into a study group was determined by the agent that was administered first. Patients were excluded if an antihypertensive other than labetalol, nicardipine, or hydralazine was administered first.
Data were collected for the following parameters: patient age, gender, all anti hypertensive agent(s) and dose(s) administered before alteplase administration, all blood pressure and HR measurements taken before alteplase administration (including time of measurements), time of first dose of antihypertensive, time of initial alteplase bolus, and baseline National Institute of Health Stroke Scale score.
Statistical analyses of the results were performed with the Kruskal-Wallis test for nonparametric data. A Tukey's honestly significant difference test was utilized for the post hoc analysis. For outcomes that compared categorical data, statistical significance was assessed with the chi-square test.
Baseline characteristics are shown in Table 1. There were 29 patients included in the primary outcome analysis. Most (86%) patients received labetalol as the initial antihypertensive agent. Table 2 shows the results of the primary and secondary outcome measures. The median time to blood pressure control was 10,22, and 15 minutes in the labetalol, nicardipine, and hydralazine groups, respectively. Of note, alternative antihypertensive agents (other than the initial agent) were used in 12% of patients in the labetalol group. The patient who received hydralazine initially also received a subsequent dose of labetalol.
Safety measures are shown in Table 3. Hypotension (systolic BP < 140 mmHg) was observed in 16% of patients in the labetalol group and 33% in the nicardipine group as well as in the patient who received hydralazine. Bradycardia was seen in 8% of labetalol patients and 33% of nicardipine patients, and 8% of patients who received labetalol also experienced tachycardia. Overall, the three antihypertensive agents that were studied appeared to be well tolerated.
A subgroup analysis was performed on the group of patients who received labetalol. It was observed that 64% (16/25) of patients who received labetalol were given an initial dose of 10 mg with half of these patients requiring additional labetalol doses. In patients who received an initial labetalol dose of 20 mg, only one required an additional dose. On average, the time to blood pressure control was approximately 10 minutes longer in patients who received 10 mg initially versus those who received 20 mg. The rate of adverse effects was similar for both groups.
A subgroup analysis was also performed to assess differences based on cumulative labetalol doses (Table 4). Patients who required lower amounts of labetalol tended to have faster times to blood pressure control. Patients who required only 10-mg labetalol or less achieved blood pressure control in a median of 5.5 minutes versus 59 minutes for patients who required more than 20 mg (p = .0108). The median door-to-needle time was shorter in patients who required less labetalol (57 vs. 95 minutes, p = .0503). Additional antihypertensive agents other than labetalol (nicardipine, enalaprilat) were also required for two of the four patients who received more than 20-mg labetalol total.
Although several antihypertensive agents have been studied in the setting of acute ischemic stroke, available evidence is limited to small studies, which typically had inconclusive and/or conflicting results. A Cochrane review assessing the use of vasoactive agents in patients with acute ischemic stroke found that beta-blockers, oral calcium-channel blockers (CCBs), and nitric oxide donors all significantly reduced blood pressure in the early treatment period (less than 24 hours; Geeganage & Bath, 2010). A blood-pressure-lowering effect was also seen for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and IV CCBs. However, the small number of participants in these trials limited the ability to show statistical significance. Other studies have shown blood pressure reduction in patients with acute ischemic stroke who received angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or nitrates, without the reduction in cerebral perfusion that has been seen with beta-blockers and CCBs (Bath, 2004). One small, randomized controlled trial did show a significant reduction in blood pressure with labetalol or lisinopril over placebo in patients with acute ischemic stroke (Potter et al., 2009). However, up to 43% of patients receiving active treatment did not meet the SBP target (145-155 mmHg or reduction of 15 mmHg) within 4 hours. In addition, the average time to treatment was approximately 20 hours. Thus, it is unclear if the blood pressure thresholds for alteplase administration would have been met within the required treatment window.
The importance of early administration of alteplase has been well established. The National Institute of Neurological Disorders and Stroke t-PA Stroke Study showed that earlier treatment of stroke led to improved outcomes (Marler et al., 2000). Furthermore, it was shown that patient recovery rates decrease as the delay to alteplase infusion increases from 15 to 30, 45, and 60 minutes. Several of the core metrics that are used by the AHA/ASA to measure quality of care in stroke centers assess timeliness of treatment (Leifer et al., 2011). Core Metric 2 evaluates the percentage of patients with ischemic stroke who are eligible for alteplase and receive it within the appropriate time window. Core Metric 3 assesses the percentage of patients treated with alteplase who receive it within 60 minutes of arrival (door-to-needle time [less than or equal to] 60 minutes). In addition, the AHA has launched a national campaign aimed at achieving this door-to-needle time. Evidence from the Get With The Guidelines-Stroke national United States registry, which includes data from over 25,500 patients who were treated with alteplase, found a 17% reduction in the unadjusted in-hospital mortality rate when door-to-needle time was <60 minutes as compared with >60 minutes (8.6% vs. 10.4%, respectively; Fonarow et al., 2011). Furthermore, for every 15-minute reduction in door-to-needle time, there was a 5% lower odds of risk-adjusted in-hospital mortality. In addition to the AHA/ASA Core Metrics, TJC also evaluates various components of stroke care. One key component is the STK-4 performance measure, which assesses the percentage of patients with acute ischemic stroke who arrive at the hospital within 2 hours and receive alteplase within 3 hours of time last known well (TJC, 2015). Overall, these quality measures emphasize the importance of early administration of alteplase.
This is the first study, to the authors' knowledge, that has evaluated the efficacy of antihypertensive agents specifically for the acute period before alteplase administration in patients with ischemic stroke. Labetalol was the most widely used antihypertensive agent in this study. The reason for the disproportionate use of labetalol versus other antihypertensives is unclear but may be secondary to physician preference. Labetalol was found to result in a faster time to blood pressure control as compared with nicardipine or hydralazine; however, this study was not powered to detect a statistical difference. Although most patients who received labetalol were given an initial dose of 10 mg, the average patient required approximately 20 mg total. Notably, the time to blood pressure control was faster when patients received an initial labetalol dose of 20 mg versus 10 mg. These results indicate that adequate initial dosing of antihypertensives may limit the need for subsequent doses and could potentially reduce the time required to achieve blood pressure control and thus alteplase door-to-needle times.
Another key finding of this study was that patients who received an initial labetalol dose of 20 mg had a similar rate of adverse events versus those who received 10 mg. This is particularly important with regard to hypotension because this can lead to decreased cerebral perfusion. Several studies have shown that larger reductions in blood pressure are associated with neurological deterioration and increased mortality (Castillo et al., 2004; Sandset et al, 2012). Our study suggests that the 20-mg dose of labetalol may lead to faster control of blood pressure without increasing the risk of hypotension.
There were some limitations in this study that should be taken into consideration when assessing the results. Despite an 8-year study period, only a small number of patients were eligible for inclusion. Although there were an adequate number of patients who received labetalol to allow for subgroup analyses, the sample size of patients who received nicardipine or hydralazine was insufficient to provide power for statistical comparison. Finally, inclusion of patients who required life-sustaining procedures or treatments may have skewed the time to treatment. Several patients had significant delays in door-to-needle time because of reasons other than elevated blood pressure (e.g., required intubation).
Control of blood pressure before alteplase therapy in patients with acute ischemic stroke remains a challenge in patient care. Unfortunately, there is still a paucity of data to determine which antihypertensive agent is preferred in this setting. The results of our study suggest that adequate initial dosing of labetalol 20 mg may provide a more rapid time to blood pressure control when compared with labetalol 10 mg, with the same rate of adverse effects. In addition, most patients in our study who received labetalol 10 mg initially went on to require further antihypertensive treatment, whereas those who received 20 mg did not. Overall, further studies are warranted to determine the effects of labetalol, nicardipine, and hydralazine on blood pressure control in a larger sample of patients with acute ischemic stroke. Optimal dosing regimens should also be further investigated.
Questions or comments about this article may be directed to Courtney McKay, PharmD, firstname.lastname@example.org. She is the Surgical Intensive Care Unit Clinical Pharmacist at Bellevue Hospital Center, New York, NY, andAssistantClinical Professor at St. John's University, Queens, NY.
A. Brad Hall, PharmD, is the Director of PCY-2 Emergency Medicine Pharmacy Residency and Emergency Medicine Clinical Pharmacist, Lakeland Regional Medical Center, Lakeland, EL.
Jennifer Cortes, PharmD BCPS, is the Medical Critical Care Clinical Pharmacy Specialist, Memorial Hermann Medical Center, Houston, TX.
The authors declare no conflicts of interest.
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TABLE 1. Baseline Characteristics Labetalol Nicardipine Hydralazine Parameter (N = 25) (N = 3) (N = 1) Mean age in years (range) 67 (42-93) 65 (41-80) 55 Gender (% male) 12 (48%) 1 (33%) 0 (0%) Mean NIHSS score at baseline 6.6 12 (a) 13 Severe HTN at baseline (SBP > 5 (20%) 2 (67%) 0 (0%) 220 mmHg or DBP > 120 mmHg) Note. NIHSS = National Institute of Health Stroke Scale; HTN = hypertension; SBP = systolic blood pressure; DBP = diastolic blood pressure. (a) Baseline NIHSS not available for one patient. TABLE 2. Results of Efficacy Outcome Measures Labetalol Nicardipine Hydralazine Parameter (N = 25) (N = 3) (N = 1) Median time to BP control 10 (2-90) 22 (10-30) 15 in minutes (range) Median door-to-needle time 74 (39-218) 91 (75-112) 34 in minutes (range) Door-to-needle time 40 0 100 [less than or equal to] 60 minutes (%) Mean initial dose 12 mg 5 mg/hr 5 mg administered Mean total dose required 19 mg N/A 5 mg Use of alternative anti 12 0 100 hypertensive agents (%) Note. BP = blood pressure; N/A = not applicable. TABLE 3. Results of Safety Outcome Measures Labetalol Nicardipine Hydralazine Parameter (N = 25) (N = 3) (N = 1) Hypotension (SBP < 140 mmHg) 4 (16%) 1 (33%) 1 (100%) Bradycardia (HR < 60 bpm) 2 (8%) 1 (33%) 0 Tachycardia (HR > 100 bpm) 2 (8%) 0 0 Note. SBP = systolic blood pressure; HR = heart rate; bpm = beats per minute. TABLE 4. Subgroup Analysis of Cumulative Labetalol Dosage Labetalol [less than or equal Labetalol = Labetalol > to] 10 mg 20 mg 20 mg p Parameter (N = 10) (N = 11) (N = 4) Value Median time to BP 5.5 (2-33) 15 (5-53) 59 (14-90) .0108 control in minutes (range) Median door-to-needle 57 (39-93) 80 (58-174) 95 (60-218) .0503 time in minutes (range) Door-to-needle time 6 (60%) 3 (27%) 1 (25%) .2491 [less than or equal to] 60 minutes Use of alternative 0 1 (9%) 2 (50%) -- antihypertensive agents Adverse effects 3 (30%) 5 (45%) 0 -- Note. BP = blood pressure.
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|Title Annotation:||Pharmacology Update|
|Author:||McKay, Courtney; Hall, A. Brad; Cortes, Jennifer|
|Publication:||Journal of Neuroscience Nursing|
|Date:||Dec 1, 2015|
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