Effect of Blood Pressure During the Acute Period of Ischemic Stroke on Stroke Outcome

Subjects and Methods

The sample used for the analysis comprises the intention-to-treat group with ischemic stroke in the GAIN International Trial. GAIN International was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial conducted to test the effectiveness of gavestinel for acute stroke treatment. The trial was approved by the regulatory and ethics committees of each participating institution. Written or witnessed verbal informed consent was obtained from all patients. The trial included previously independent patients >18 years of age who presented within 6 hours of acute stroke symptoms. Subjects had to have limb weakness (with at least a drift within 10 seconds for the arm or 5 seconds for the leg; if mild, arm and leg both had to be affected). Inclusion criteria tolerated a wide range of BP but excluded malignant hypertension (DBP >130 mm Hg). Other exclusion criteria were previously reported.¹¹

Standard stroke care was accompanied by gavestinel or placebo administration. Gavestinel did not show any superiority over placebo on stroke outcome and did not significantly alter BP.¹¹ Therefore, both treatment groups were combined for our analysis. Management of BP was at the discretion of physicians. According to the trial protocol, BP measurements were taken at baseline, 30 minutes, and 4, 12, 12.25, 60, and 60.25 hours after the start of the loading infusion of the randomized treatment.

As measures of BP, we looked at baseline MAP, weighted average MAP, and substantial increase or decrease (by >30%) from baseline MAP. The weighted average MAP is an area under the curve describing MAP over the course of the measurement divided by duration of the measurement period (up to 60.25 hours). Medications prescribed to the patients at any time from the start of the study drug infusion to day 7 (or hospital discharge if earlier) were recorded. We identified drugs that potentially affect BP. CCBs, BBs, ACE inhibitors, diuretics, dipyridamole, and nitrates were classified as drugs that decrease BP.

The primary outcomes were those of the GAIN International statistical analysis plan: mortality, Barthel Activities of Daily Living Index¹³ at 7 days (or at hospital discharge if earlier), 1 and 3 months (trichotomized as dead or 0 to 55 versus 60 to 90 versus ≥95), National Institutes of Health Stroke Scale (NIHSS)¹⁴ at 7 days and 1 and 3 months (dichotomized as dead or ≥2 versus 0 to 1), and modified Rankin Scale^15,16 at 1 and 3 months (dichotomized as dead or ≥2 versus 0 to 1). Secondary outcome measures were NIHSS score change from baseline at 7 days, 1 month, and 3 months (dichotomized at the median; dead was excluded from analysis) and hemorrhagic transformation of the stroke and progression of the stroke by day 7 recorded as events common to stroke patients.

Results

We included 1455 patients in the analysis. Baseline characteristics of the sample and groups of patients subdivided by quartiles of weighted average MAP are presented in Table 1. MAP declined gradually (Figure 1). However, the behavior of BP in individual patients was more variable. A 30% decrease and a 30% increase from baseline MAP occurred in 11% and 6% of patients, respectively.

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Figure 1. Quartiles of MAP over time. ▪, Lower quartile; , median; ▴, upper quartile.

Multivariate ordinal logistic regression identified baseline variables that were associated with weighted average MAP level (Table 1). History of hypertension (odds ratio [OR], 2.44; 95% confidence interval [CI], 2.01 to 2.96), increased alcohol consumption (OR, 1.67; 95% CI, 1.21 to 2.29), age (OR, 1.18; 95% CI, 1.09 to 1.28 per decade), and baseline NIHSS score (OR, 1.02; 95% CI, 1.01 to 1.04 per point) predicted higher weighted average MAP. Previous myocardial infarction (OR, 0.65; 95% CI, 0.50 to 0.86) and partial anterior circulation infarction by OCSP classification (OR, 0.80; 95% CI, 0.66 to 0.98) predicted lower MAP.

Overall, 1842 prescriptions of drugs that affect BP were used in the study sample during the recording period of 7 days or discharge from hospital (if earlier). We found that 29% of patients received at least 1 diuretic; 21%, at least 1 CCB; 20%, at least 1 BB; 19%, at least 1 ACE inhibitor; 14%, dipyridamole; and 7%, at least 1 nitrate. Only 0.5% of patients received at least 1 drug that increases BP.

Primary Outcomes

Baseline MAP and a 30% decrease from baseline MAP were not associated with primary outcomes after correction for baseline factors (baseline NIHSS score, age, sex, treatment group, time to treatment, stroke risk factors, and stroke subtype by OCSP). Elevated weighted average MAP was associated with poor outcome assessed by mortality at 3 months, Barthel Index, and NIHSS score at 1 month (Table 2). A 30% increase from baseline MAP was associated with poor Barthel Index at 1 and 3 months, poor NIHSS score at 1 and 3 months, and poor outcome by Rankin Scale score at 1 month. Univariate Kaplan-Meier curves of groups stratified by weighted average MAP quartiles (Figure 2) showed that patients with MAP <95 mm Hg fared better than all others (log-rank test, P<0.0004).

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TABLE 2. Statistically Significant Associations Between Primary Outcomes and BP Variables

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Figure 2. Kaplan-Meier curves of groups stratified by weighted average MAP quartiles. —, Lower quartile; – – – –, lower quartile to median; —•—, median to upper quartile; —••—, upper upper quartile.

Treatment with at least 1 diuretic was associated with mortality (hazard ratio [HR], 1.72; 95% CI, 1.33 to 2.17) and with poor Barthel Index at 3 months (OR, 1.43; 95% CI, 1.10 to 1.87) after correction for baseline factors and BP variables. Treatment with dipyridamole was associated with survival (HR, 0.46; 95% CI, 0.28 to 0.75) and good Barthel Index at 3 months (OR, 0.69; 95% CI, 0.50 to 0.97). Treatment with at least 1 drug that increases BP was associated with mortality (OR, 3.05; 95% CI, 1.04 to 8.99).

Discussion

The original exclusion and inclusion criteria¹¹ need to be taken into account when the results of this study are generalized to hospital-based common practice. Our sample includes previously independent patients >18 years of age within 6 hours of stroke onset. It excludes very mild and very severe patients (patients were required to have limb weakness and symptoms that were neither rapidly improving nor thought likely to resolve completely within 24 hours and could not be obtunded or were otherwise unconscious). Patients with other severe diseases were also excluded (severe congestive heart failure, malignant hypertension, and known history of significant renal or hepatic impairment).

In addition to history of hypertension,^4,18 we have identified age, baseline NIHSS score, and increased alcohol consumption as predictors of higher weighted average MAP. Partial anterior circulation infarction and previous myocardial infarction were associated with lower average MAP.

Casual BP measurements carry limited prognostic significance compared with beat-to-beat measurements.¹⁹ This underscores the limitation of studies that have addressed the value of single measurements of BP after stroke in predicting outcome. Our analysis, however, could rely on repeated BP measurements at fixed intervals and was able to consider the effects of both a longer course of BP (weighted average MAP) and BP fluctuations (a 30% increase and decrease from baseline MAP). In this study, all analyses were corrected for atrial fibrillation, which may contribute to BP instability. Other strengths of this study are the high quality of the data and the detailed recording of demographic and clinical information, which allows correction for stroke prognostic factors.

Our findings do not support the hypothesis of a J-shaped relationship between poor outcome and BP^8,9,20 because the difference between the linear models (presented) and generalized additive models (which allows any shape of relationship) of baseline MAP and weighted average MAP on stroke outcome was not significant (analysis of variance, P>0.05). However, it cannot be excluded that patients with low BP were treated before the baseline measurement of BP or that they were simply excluded from the trial and therefore we fail to show a negative effect of low values of initial BP on stroke outcome, although this is an unlikely scenario. Similarly the actual relationship between high BP and poor outcome may also have been somewhat underestimated in this study because our sample excluded patients with extremely high BP (DBP >130 mm Hg).

Our observational study cannot prove causality regarding the associations of marked (>30%) changes with primary and secondary outcome variables because it is not clear whether BP alterations led to poor outcome or if they occurred secondary to some other predictor of poor outcome. In addition, progression of stroke or hemorrhagic transformation could have preceded some of the measurements of BP because these events were recorded at day 7 without their time of onset specified. Therefore, the events themselves may have affected the course of BP. At any rate, this study suggests that sharp fluctuations in BP (both increasing and decreasing) should be avoided in clinical practice and may constitute the focus of future drug trials assessing the impact of BP modulation. Our study also clearly indicates that patients with lower BP over the first 2.5 days have better outcome.

Drugs that decrease BP may not have been prescribed to patients with the prime aim of reducing BP but rather to treat other conditions. Our findings may also be biased toward overuse of drugs that decrease BP because we did not count intravenous fluid infusions as a result of methodological constraints of measuring their impact. Again, the associations presented in this study are important for illustrating BP treatment in acute stroke care in the context of a randomized clinical trial and aspects that should be addressed by future studies.

Diuretic prescription did not necessarily cause poor stroke outcome but rather may have been the consequence of a poor health status leading to more aggressive treatment. Therefore, we have corrected for all known and available events common to stroke that occurred during the first 7 days. Nevertheless, diuretics remained significant predictors of mortality (HR, 1.33; 95% CI, 1.03 to 1.73). Therefore, the question of adverse effect of diuretics on stroke outcome (possibly because of dehydration) remains unanswered, and further investigation of the matter is needed.

The association between mortality and drugs that increase BP can likely be explained by treatment of hypotension that occurs before death. The association between hemorrhagic transformation and BB and CCB, although strong, should also not be overinterpreted because of the relatively small number of events (n=71).

The beneficial effect of dipyridamole treatment is worth mentioning. This effect was not necessarily related to a reduction in BP but could also be the consequence of the antiplatelet activity of this drug. Although dipyridamole and aspirin are considered a first-line therapy for secondary prevention of stroke,²¹ the use of dipyridamole was low (14%). The association can be explained in part by the facts that dipyridamole was prescribed to patients with milder stroke and that we may have failed to correct for all prognostic factors. Because dipyridamole is usually prescribed together with aspirin (8% of patients were prescribed both), the beneficial effect of dipyridamole may be due to the correlation with aspirin. If corrected for aspirin, all presented ORs and HRs were still significant with the trend of their increase by 0.03 to 0.01. Therefore, these data suggest that dipyridamole has an independent beneficial effect on stroke outcome, and its use in this indication should be further explored.

Ongoing clinical trials such as Efficacy of Nitric Oxide in Stroke (ENOS)²² and Intravenous Magnesium Efficacy in Acute Stroke (IMAGES)²³ may provide additional observational and experimental data on the role of BP in acute stroke care. However, to resolve the controversy of BP management in acute stroke care, there is a need for a randomized clinical trial that will investigate the different patterns of BP management and demonstrate a cause-effect relationship between BP and stroke outcome. Analysis from observational studies such as ours will clearly be helpful when such trials are planned.

In conclusion, data from well-conducted clinical trials provide a valuable source of information for investigating the natural history of stroke and its association with BP. There is no evidence to conclude that a single casual MAP measurement at baseline is associated with ischemic stroke outcome. However, variables that describe the course of BP over the first 60 hours (higher weighted average MAP and a 30% increase from baseline MAP) have a marked and independent relationship with poor outcomes from ischemic stroke at 1 and 3 months.