The relationship between blood pressure (BP) control and short and long term outcomes in patients with acute ischemic stroke (AIS) is highly complex and not well understood with conflicting data. More than half of ischemic stroke patients had systolic blood pressure (SBP) above 160 mmHg within the first 48 hours of symptom onset in the International Stroke Trial (IST) [1] . However, the IST evaluation demonstrated a U-shaped relationship between SBP at both 14-day and 6 month outcomes. The most interesting was an increased risk of death at 14 days by 17.9% for every 10 mmHg SBP less than 150 mmHg compared to a 3.8% increased risk of death with each 10 mmHg increase above 150 mmHg (3.6% vs. 1.1% for 6 month death or dependency) [1] . On the other hand, recurrent AIS within 14-days was directly associated with increased SBP, which independently predicted the likelihood of AIS in a multivariate analysis [1] .

Currently, the evidence does not support aggressive management of BP during AIS as a global strategy [2] . Although significantly elevated BP in AIS is deleterious, rapid reduction of SBP has been associated with a higher mortality [3] with cerebral hypoperfusion and increased cardiac events [4] . Reducing diastolic BP (DBP) by >20% also significantly increases the risk of death [5] . Citing conflicting evidence, the 2013 ACC/AHA Guidelines for the “Early Management of Patients with Acute Ischemic Stroke” did not specify BP targets and suggest using “best clinical judgment” and “to initially lower the SBP by 15% and monitor for neurological deterioration related to the (blood) pressure lowering” [2] .

An important component of BP is the difference between SBP and DBP, or the pulse pressure (PP) [6] . Increased PP above a population norm has been associated with inferior outcomes in AIS [7] [8] [9] [10] [11] , especially when PP exceeds 70 mmHg [7] . With the varying components of BP and the diversity of findings among the clinical trials of BP in AIS, the optimal approach to BP management in AIS remains unclear. Likewise, the choice of antihypertensive treatment in AIS and during follow-up has not been well established [12] . Angiotensin converting enzyme inhibitors (ACEI) were demonstrated to prevent recurrent strokes [13] and improve hospital [14] and follow-up survival [15] . Some studies suggested benefit with angiotensin II receptor blocker (ARB) [16] [17] [18] [19] ; while calcium channel blocker (CCB) [5] [20] and beta-adrenergic blocker (BB) [21] [22] [23] therapies failed to show consistent reduction in mortality and prevention of recurrent stroke.

The effects of anti-hypertensive therapy on outcomes in patients with AIS and widened pulse pressure (WPP) have not been well studied previously. In this observational study, we examined whether treatment of hypertension modulates adverse effects of WPP in ischemic stroke. We have chosen to define WPP as a value of ≥70 mmHg as this cut point has been shown to be associated with poorer outcomes in previous studies [7] .

After inclusion and exclusion criteria were applied a total of 322 patients were identified for the study cohort (Table 1). The population was 43.8% female and the average age was 66.5 years. Table 1 also contains baseline demographic parameters for the cohort with baseline pulse pressure (PP) ≥ and <70. Patients with a PP ≥ 70 were older than those with PP < 70 (73.7 vs. 62.8 years, p < 0.001). Patients with PP ≥ 70 were more likely to have a history of hypertension (83.5 vs. 68.1%, p = 0.003), and PAD (67% vs. 54.6%, p = 0.031). The difference in PP between the two groups was driven by SBP. The first recorded SBP was 175.5 in patients with PP ≥ 70 and 133.7 in PP < 70 (p < 0.001); there was no difference between groups in first recorded DBP. The first recorded PP (in mmHg) was 49.8 and 89.6 in patients with PP < 70 and ≥70, respectively (p < 0.001). Patients with PP ≥ 70 were more likely to be placed on an ACEI/ARB or BB as compared to those with PP < 70 (53.9 vs. 31.9%, p < 0.001). Patients with PP ≥ 70 were less likely to be on monotherapy with BB therapy or not treated with BB at all.

Regarding the choice of antihypertensive class―ACEI/ARB or BB―patients in either of these two classes were similar in baseline comorbidity profile except for having a history of coronary artery disease without prior revascularization, which was more common in BB group (Table 2).

Overall in-hospital mortality was 5.3%. The average length of follow-up data was 49.7 months. Mortality during follow up for the overall cohort was 28.2% (Table 1). There was no difference between PP groups for in-hospital mortality. Follow-up mortality was significantly higher among those with a baseline PP > 70 (37.4 vs. 23.2%, p = 0.009) (Table 1). On univariate analysis, older age, the

Abbreviations: SD―standard deviation; SBP―systolic blood pressure; DBP―diastolic blood pressure; BB―beta-adrenergic blockers; ACEI―angiotensin converting enzyme inhibitors; ARB―angiotensin receptor blockers; IV―intravenous; HTN―hypertension; Rx―therapy.

Abbreviations: OR―odds ratio; ACEI―angiotensin converting enzyme inhibitors; ARB―angiotensin receptor blockers; CAD―coronary artery disease; CABG―coronary artery bypass graft surgery; PCI―percutaneous coronary intervention; TIA―transient ischemia attack.

presence of CAD without prior revascularization, presence of PAD, having a creatinine > 2 mg/dl or being on hemodialysis, having a Glasgow Coma Scale score > 9, PP > 70, requiring intravenous anti-hypertensive therapy during the hospitalization, and being on a BB based anti-hypertensive regimen were all significantly associated with increased follow-up mortality. In-hospital mortality was non-significantly lower for patients treated with ACEI/ARB compared to those not treated with ACEI/ARB (3.7% vs. 8.6%); follow up mortality was similar between the anti-hypertensive therapy groups (27.4% vs. 24.2%, p = 0.150). Looking at various combinations of ACEI/ARB and BB based therapy, being on an ACEI/ARB based therapy without BB was associated with lowest in-hospital and follow up mortality (2.5% and 16%, respectively, p = 0.003) (Table 3).

After adjustment for covariates in multivariate analysis (Table 4), PP > 70 was not independently associated with an elevated odds ratio (OR) of in-hospital or follow-up mortality. However, choice of antihypertensive therapy remained important in determining outcomes; there were also some subtle differences in the effects of antihypertensive therapy choice based on baseline PP. Being on an ACEI or ARB based antihypertensive regimen was associated with a lower probability of in-hospital mortality in both PP groups. When BB therapy was included in antihypertensive therapy with ACEI/ARB, the lowering of in-hospital mortality was attenuated in the PP > 70 group, but not in the PP < 70 group. Follow-up

Abbreviations: CAD―coronary artery disease; HTN―hypertension; Rx - therapy; IV―intravenous; ACEI―angiotensin converting enzyme inhibitor; ARB―angiotensin receptor blockers.

*) compared to outcomes in patients without CAD; †) compared to outcomes in patients with Glasgow Coma Scale <9; ††) compared to outcomes in patients not on ACEI or ARB or BB; Abbreviations: OR―odds ratio; IV―intravenous; HTN―hypertension; Rx―therapy; ACEI―angiotensin converting enzyme inhibitors; ARB―angiotensin receptor blockers; BB―beta blockers.

mortality was not influenced by choice of antihypertensive therapy (ACEI/ARB, BB, both ACEI/ARB and BB, or neither ACEI/ARB or BB) in the PP > 70 group (Table 4). Among patients with PP < 70, being on an ACEI/ARB based therapy without a BB was associated with a significantly lower follow-up mortality (OR 0.07, 95% confidence interval 0.01 - 0.477, p = 0.0066).

In this retrospective cohort of patients admitted with a diagnosis of AIS, PP was not independently associated with short or long term mortality, but the use of an ACEI or ARB based antihypertensive regimen was associated with lower in-hospital among patients with PP <70 or ≥70. ACEI/ARB without BB was associated with lower follow-up mortality only those patients with baseline PP < 70.

A widened PP has been demonstrated in multiple analyses to be associated with a higher cardiovascular burden. Widened PP has been shown to correlate and associate with worse CV outcomes [31] [32] . The current analysis confirms that a widened PP is associated with increased mortality (p = 0.020), however this did not persist when adjusted for multiple comorbidities. The only other analysis of PP on AIS outcomes demonstrated a significant association with weighted average PP (over 60 hours) on 3 month outcomes in the Glycine Antagonist in Neuroprotection International Trial; however, as with the current analysis, the baseline PP was not associated with follow-up outcomes after adjusting for comorbidities [7] . The association of average PP over the course of hospitalization with outcomes deserves further evaluation.

In contrast, choice of antihypertensive therapy remained significantly associated with outcomes with some notable differences based on baseline PP categorization. Regardless of baseline PP, being on an ACEI/ARB based antihypertensive therapy is associated with favorable in-hospital outcomes during AIS and including BB into the regimen attenuates the benefit. For long term mortality outcomes, ACEI/ARB based therapy was found to be beneficial in patients with PP < 70, with attenuation, again, from addition of BB. There was a reduction in mortality with ACEI/ARB based therapy, without BB, among patients with PP ≥ 70 however it did not meet statistical significance (OR 0.363, p = 0.054).

The Scandinavian Candesartan Acute Stroke Trial (SCAST) randomized patients with acute stroke (the majority of whom, ~85%, had AIS) to initial treatment with Candesartan or placebo for hypertension management. This was not a BP target study and no data on PP was provided. The investigators found no significant difference in the primary outcome at 6 months or 3 years [33] . A direct comparison between a randomized study and a retrospective study is not possible however the current analysis may suggest that PP may be an important consideration when analyzing the effect of antihypertensive therapy on AIS outcomes.

BB, on the other hand, were not associated with improved short and long term outcomes and attenuated some of the benefit seen with ACEI/ARB therapy. BB has been relegated to second line therapy in hypertension in general [27] . In regards to AIS, most of the data on BB therapy has been derived from retrospective studies. A recent analysis by Koton and colleagues looked at pre-stroke use of BB for hypertension management and post stroke outcomes [34] . These investigators found no effect on outcomes (stroke severity, recurrent stroke, or mortality) with the use of BB for pre-stroke hypertension therapy. Phelan and colleagues found a decrease in the in-hospital mortality in patients with AIS who had their home BB therapy continued during the first 3 days of AIS versus patients in whom BB therapy was discontinued [35] . This was despite a higher comorbid profile among patients on BB therapy [35] . Similarly, Tziomalos found worse in-hospital outcomes in patients treated with BB prior to AIS, than in those not treated with BB [36] . In contrast to our findings, Tziomalos and colleagues did not find a beneficial effect of ACEI or ARB therapy [36] . Similarly, Sykora and colleagues found improved in-hospital and 3-month AIS outcomes with the use of BB pre-stroke [37] . One important distinction from the current analysis is the duration of follow up; in our study, the duration of follow-up was significantly longer. In addition, distinctions in patient populations by PP have not been previously reported. Given the disparate findings among data sets, a well-designed randomized controlled trial examining the role of BB therapy in improving post stroke outcomes may be warranted.

Several important limitations of the current analysis need to be acknowledged. The choice of antihypertensive therapy was left to the discretion of the provider and thus introduces indication bias that cannot be adequately addressed in the current format. In addition, there is no means to know how patients were treated after the point of discharge. Addition or subtraction of hypertensive medications may have led to muted effects seen in the various subgroup analyses. Finally, our study contained modest sample size and follow up period as a larger sample size with longer follow up would be beneficial in studying this matter.

Despite these limitations, the current analysis revealed important distinctions within patients who have suffered AIS. ACEI/ARB based antihypertensive management appears to provide the most favorable short and long term outcomes in patients with AIS. This seems to be most prominent among patients with AIS and PP < 70 at presentation. Future randomized controlled trials of patients with AIS should look at antihypertensive classes and PP interactions.

Lavelle, M., Mathew, R.O., Arora, J., Murthy, A., Du, L., Bulibek, B., Sidhu, M. and Torosoff, M. (2017) Interaction between Antihypertensive Therapy Class and Pulse Pressure on Outcomes Following Acute Ischemic Stroke. International Journal of Clinical Medicine, 8, 543-555. https://doi.org/10.4236/ijcm.2017.810051