Overuse of antihypertensives in patients with acute ischemic stroke.

Background: The Stroke Council of the American Heart Association/American Stroke Association (AHA/ASA) recommends conservative management of hypertension (HTN) during acute ischemic stroke (AIS), although clinicians often manage blood pressure more aggressively. Our hypothesis was that aggressive management of HTN in patients with AIS is associated with hypotensive events and worsened neurologic outcomes.

Methods: The study was a retrospective, observational cohort of patients who were admitted to the hospital with AIS. Classification of neurologic outcomes was based on nurses' neurologic assessments and were categorized as "worsened," "stayed the same," or "improved." The accuracy of these assessments was verified by review of physician's progress notes. Management of arterial HTN was recorded in all patients.

Results: Fifty medical records of patients with AIS who met inclusion criteria were reviewed. While only 22% of patients met the AHA/ASA criteria for hypertension treatment, 98% of the cohort were given antihypertensive therapy. Relative hypotension occurred in 64% of treated patients. Absolute hypotension associated with antihypertensive medications was uncommon but did occur in 2 of 15 patients who experienced neurologic worsening (13%), in 1 of 28 (3%) of patients who stayed the same, and in none of those who improved. Blood pressure was reduced excessively in all 11 of the patients who met AHA/ASA guidelines for treatment.

Conclusions: Adherence to AHA/ASA guidelines for HTN management during AIS was poor. Initiation or intensification of antihypertensive drugs was not associated with worsened neurologic outcomes. Furthermore, relative hypotension, absolute hypotension and excessive reductions in blood pressure were not associated with worsened neurologic outcomes.

Key Words: hypertension, hypotension, acute ischemic stroke, antihypertensives, neurologic outcomes

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The majority of patients with acute ischemic stroke (AIS) present with elevated blood pressure. (1-3) Proper management of arterial hypertension during AIS is a matter of controversy and confusion for clinicians and some evidence suggests that antihypertensive therapy aggravates ischemia and worsens outcomes. (4-8)

The Stroke Council of the American Heart Association/American Stroke Association (AHA/ASA) has published guidelines addressing the management of arterial hypertension during acute ischemic stroke (AIS). (9,10) For patients who are not going to receive thrombolysis and do not have concomitant noncerebral hypertensive organ damage (aortic dissection, pulmonary edema, hypertensive encephalopathy, acute myocardial ischemia, acute renal failure), the guidelines suggest withholding blood pressure treatment unless the systolic blood pressure is >220 mm Hg or the diastolic blood pressure is > 120 mm Hg. The guidelines suggest a relatively conservative 10 to 15% per day reduction in blood pressure. (9,10)

It has been our observation that patients presenting with AIS commonly receive antihypertensive medications even for modest blood pressure elevations. Since this practice is inconsistent with AHA/ASA guidelines, and may be associated with worsened neurologic outcomes, we sought to examine the practice of treating arterial hypertension in patients with AIS at our institution.

Materials and Methods

The study was a retrospective cohort of consecutive patients with a principle discharge diagnosis of AIS who were admitted to Methodist Healthcare University Hospital, a 600-bed community-based teaching hospital in Memphis, TN. The protocol was reviewed and approved by the hospital's institutional review board and the requirement for informed consent was waived. Medical records with the following ICD-9 codes between May 2004 and February 2005 were obtained: 433.0 Basilar Artery Occlusion, 433.1 Carotid Artery Occlusion, 433.2 Vertebral Artery Occlusion, 433.3 Multi Precerebral Occlusion, 433.8 Precerebral Occlusion Not Elsewhere Classified, 433.9 Precerebral Occlusion Not Otherwise Specified, 434.1 Cerebral Embolism, and 434.9 Cerebral Artery Occlusion Not Otherwise Specified. Patient records from the hospital's Health Information Management and Patient Financial Services were reviewed for the following exclusion criteria: Patients less than 18 years of age, AIS unable to be validated by chart review, IV or intra-arterial thrombolysis performed or concomitant diagnosis of acute renal failure, hypertensive encephalopathy, aortic dissection, pulmonary edema, acute myocardial infarction or hypertensive emergency. The coding for AIS was considered to be correct if the patient had signs, symptoms and/or radiographic abnormalities consistent with AIS and if the diagnosis was documented by the attending physician.

Information collected from the chart included patient demographics, nurses' neurologic assessments for extremity strength, systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements at hospital admission and for 96 hours following admission, antihypertensive drug use before and during hospitalization, and mortality. At least five blood pressures were collected, including the lowest and highest daily reading and those at times closest to 800, 1,600 and 2,400. The lowest and highest mean arterial pressure (MAP) was calculated using the following formula: MAP = [(2 X DBP) + SBP]/3.

We defined absolute hypotensive events as at least one episode of SBP < 90 or MAP < 60 mm Hg in a patient treated with antihypertensives. Relative hypotension was defined as at least one episode of SBP < 120 or MAP < 85 mm Hg in a patient treated with antihypertensives. The analysis of absolute and relative hypotensive events was performed on the lowest and highest recorded blood pressures each day. Excessive reduction of MAP was defined as more than a 30% relative reduction over 72 hours in patients treated with antihypertensive medications.

All neurologic assessments for extremity strength were collected during the first 96 hours. These were routinely performed by nurses at least every 8 hours and categorized as "strong," "fair," "weak" or "no movement." We categorized neurologic status as "worsened" if the nurses' neurologic assessment indicated a decrease in strength by at least two units (ie, from strong to weak or from fair to no movement) along with corroborating data from physician's notes. Neurologic status was classified as "stayed the same" if no such change was noted and was classified as "improved" if the nurses' neurologic assessment indicated an increase by at least two units (ie, from weak to strong or from no movement to fair) along with corroborating data from physician's notes. The study population was divided into these three categories by one investigator, and antihypertensive treatments were recorded by another investigator who was "blinded" to the neurologic category of the patient.

Patients who were not treated with an antihypertensive medication at home but who were prescribed a new antihypertensive after admission were labeled as having therapy "initiated." If medication from home was continued after admission, they were labeled as having therapy "continued." Those who had their home antihypertensive medication continued and who received at least one additional medication after admission were labeled as having therapy "intensified."

Since the AHA/ASA consensus is that antihypertensives should be withheld unless the DBP is >120 or SBP is >220 mm Hg, the use of antihypertensive drugs in patients with lower blood pressures was deemed inappropriate. Data was assessed for an association between neurologic worsening and relative or absolute hypotensive events or excessive reduction in MAP. All associations were assessed for statistical significance with the Fisher's exact test using software supplied by www.graphpad.com. The cutoff alpha value for significance was set at P < 0.05.

Results

Of 261 patients who were screened, 211 met one or more of the exclusion criteria, leaving 50 charts for review. The patients were primarily elderly and African-American with hypertension and diabetes mellitus (Table 1). While only 22% (n = 11) of patients met AHA/ASA criteria for antihypertensive therapy, 98% of the population were treated (Table 2). Only 18% of patients (n = 9) were normotensive, and the remaining 60% (n = 30) of patients had arterial hypertension with SBP in the 140 to 219 range or DBP between 90 to 120 mm Hg. Of the 39 patients (78%) who did not meet AHA/ASA criteria for treatment, 97% received antihypertensive therapy during the first 96 hours. All 11 patients who met AHA/ASA criteria for antihypertensive treatment had their blood pressure lowered excessively with a [greater than or equal to]10% reduction in MAP per day.

Nurses' neurologic assessments, along with physician's progress notes, indicated that 14% (n = 7) improved, 56% (n = 28) stayed the same, and 30% (n = 15) worsened. Absolute hypotension occurred in none of the patients who improved and occurred in one (3.6%) patient who stayed the same and in two (13.3%) patients whose neurologic status worsened (P = 0.211). In one of the two patients with absolute hypotension who worsened, the antihypertensive medicine was administered after the decline in neurologic function had already occurred, ruling out a causal relationship. Relative hypotension was common and occurred in 6 of 7 (86%) of those who improved, 18 of 28 (64%) of those who stayed the same, and 8 of 15 (53%) of those who worsened. Excessive reductions in MAP were seen in approximately 60% of all patients, with no differences between patients who improved, stayed the same or worsened. The average reduction in MAP over 3 days in those treated with antihypertensives was approximately 45 mm Hg.

Only 2 patients (4%) had antihypertensive medication discontinued upon admission, while almost 70% of patients who were taking antihypertensive medication at home had therapy either continued or intensified after admission (Table 3). We found no association between initiation or intensification of antihypertensive therapy and neurologic worsening. At discharge, 46% of patients were transferred to a nonacute care facility, 48% were discharged home, and 6% had died during hospitalization.

Discussion

Antihypertensive agents were initiated, continued, or intensified in 90% of those admitted with AIS, apparently without regard to AHA/ASA treatment guidelines. Blood pressure reduction was also much more aggressive than recommended by AHA/ASA. However, we did not find an association between antihypertensive use or hypotensive events and neurologic worsening in patients with AIS. It is possible that our method of defining neurologic worsening was not sensitive enough to detect minor changes in clinical status that might be caused by hypotensive events. However, we felt that our criteria for worsening or improving reduced the risk of incorrectly assigning a patient to the wrong category. Furthermore, we examined at least five blood pressures per patient daily for 96 hours following admission, thereby reducing the likelihood of overlooking significant hypotensive events related to antihypertensive medication.

Reasons for nonadherence to the guidelines are unclear. Physicians may feel uncomfortable withholding antihypertensives until the blood pressure exceeds 220/120 mm Hg in patients with AIS. Furthermore, the guidelines are "Grade C" recommendations based on consensus, rather than strong data, so clinicians may not have confidence in them.

One limitation of our study is that "excessive" blood pressure lowering could have been due to the natural history of arterial hypertension in patients with AIS, since blood pressure generally falls in the first hours to days after an AIS. Also, our system for categorizing neurologic worsening and improvement has not been validated. The strength of our data is that we carefully excluded all patients who had a clear indication for hypertension treatment, such as those with hypertensive encephalopathy or other hypertensive emergencies.

Conclusion

Our data suggests that hypertension in AIS is treated more aggressively than national guidelines recommend, but we did not confirm that this practice is harmful. The use of antihypertensive medications in AIS should be evaluated in a large, prospective randomized trial to determine their effect on neurologic and other outcomes.

References

1. Wallace JD, Levy LL. Blood pressure after stroke. JAMA 1981;246:2177-2188.

2. Britton M, Calson A, de Faire U. Blood pressure course in patients with acute stroke and matched controls. Stroke 1986;17:861-864.

3. Rose JC, Mayer SA. Optimizing blood pressure in neurological emergencies. Neurocrit Care 2004;3:287-299.

4. Lindenaeur PK, Mathew MC, Ntuli TS, et al. Use of antihypertensive agents in the management of patients with acute ischemic stroke. Neurology 2004;63:318-323.

5. Oliveira-Filho J, Silva SCS, Trabuco SS, et al. Detrimental effect of blood pressure reduction in the first 24 hours of acute stroke onset. Neurology 2003;61:1047-1051.

6. Lanvin P. Management of hypertension in patients with acute stroke. Arch Intern Med 1986;146:66-68.

7. Fischberg GM, Lozano E, Rajamani K, et al. Stroke precipitated by moderate blood pressure reduction. J Emerg Med 2000;19:339-346.

8. Britton M, de Faire U, Helmers C. Hazards of therapy for excessive hypertension in acute stroke. Acta Med Scand 1980;207:253-257.

9. Adams HP Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the stroke council of the American Stroke Association. Stroke 2003;34:1056-1083.

10. Adams H, Adams R, Del Zoppo G, et al, Stroke Council of the American Heart Association; American Stroke Association. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke 2005;36:916-923.

While we have the gift of life, it seems to me that only tragedy is to
allow part of us to die--whether it is our spirit, our creativity, or
our glorious uniqueness.
--Gilda Radner

Matthew Underwood, PharmD, Bob L. Lobo, PharmD, Christopher Finch, PharmD, and James Wang, MD

From the Department of Pharmacy, Methodist LeBonheur Healthcare University Hospital, Memphis, TN.

Reprint requests to Bob Lobo, PharmD, Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN. 38104. Email: [e-mail]

Accepted May 10, 2006.

RELATED ARTICLE: Key Points

* The Stroke Council of the American Heart Association/American Stroke Association has published guidelines (Grade C, Level 5) addressing the proper management of hypertension in patients with acute ischemic stroke.

* This retrospective, observational cohort of patients with acute ischemic stroke documented poor compliance with the guidelines for treating blood pressure in acute ischemic stroke.

* There was no association between antihypertensive treatment that resulted in hypotension and adverse neurologic outcomes.

Table 1. Baseline characteristics of total patient population (n = 50)

Characteristic                            Result

Age (average)                              68 years
Length of stay (average)                    8.4 days
Male                                       46%
White                                      22%
African American                           76%
Hispanic                                    2%
Hypertension                               84%
Diabetes mellitus                          54%
Coronary artery disease                    28%
Heart failure                              10%
End-stage renal disease                    10%
Combined morbidity                         28%
Atrial fibrillation on electrocardiogram    4%
Systolic (average)                        168 mm Hg
Diastolic (average)                        84 mm Hg
Mean arterial pressure (average)          111.4 mm Hg
Heart rate (average)                       79.2 bpm

Table 2. Adherence to AHA/ASA criteria for blood pressure treatment
during acute ischemic stroke

Acute ischemic stroke patient population (n = 50)     Result

Blood pressure medication use during first 96 hours    98%
* Patients meeting ASA criteria for treatment          22%
  -- Proportion treated                               100%
  -- Proportion with [less than or equal to] 10% MAP    0%
     decrease per day
* Patients not meeting ASA criteria for treatment      78%
  -- Proportion treated                                97%
  -- Proportion that were not treated                   3%

ASA, American Stroke Association; AHA, American Heart Association; MAP,
mean arterial pressure.

Table 3. Antihypertensive drug management during the first 96 hours

Antihypertensive management  n   %

Discontinued                  2   4
Continued                     5  10
Intensified                  29  58
Initiated                    11  22
Unknown                       3   6