We identified 4 distinctive categories of SBP trajectory: the Low SBP, Moderate SBP, Persistently high SBP, and Slowly dropping SBP groups. Longitudinal changes in the mean SBP in the study subjects overall were similar to that of previous findings, in that more than 80% of patients with acute ischemic stroke had elevated SBP above 140 mmHg early after ischemic stroke;15 this largely stabilized by 24 hours after stroke onset 7,11. Using the BP trajectory model, we were able to find distinguishable patterns that could not be detected by observing the overall group mean of SBP. Furthermore, we observed that distinct patterns were associated with differences in clinical outcomes.
The most noteworthy category among the 4 SBP trajectory groups was the Slowly dropping SBP Group. Compared to the Moderate SBP Group, the Slowly dropping SBP Group had markedly higher SBP (approximately 180 mmHg at stroke onset), which decreased slowly during the first month, and finally reached a level of 120‒130 mmHg; the SBP level at 30 days after the index stroke was similar to that in the Moderate SBP Group. However, the risk of the primary outcome was higher in the Slowly dropping SBP Group than in the Moderate SBP Group, despite the similarity in SBP levels after the first month. This result is concordant with the findings from previous studies focusing on BP trajectories in a more acute stroke time period. Our prior study showed that SBP during the first 24 hours after stroke onset had distinct trajectory groups, and patients who were classified by categories as having SBP above 150 mmHg at 24 hours had a higher risk of adverse events, including mortality 8. Additionally, a secondary analysis of the CATIS trial about the SBP trajectories during the first week after stroke onset showed a similar result, in that patients with SBP above 160 mmHg had the highest risk of adverse events.9 Interestingly, in the latter study, patients who initially had a high SBP (approximately 180 mmHg), but which rapidly dropped to 140 mmHg (within 3 days), had a lower risk of mortality than those whose SBP remained high. In our study, the Slowly dropping SBP Group and Persistently high SBP Group may have been comparable to those with high early SBPs in these prior studies.
One possible explanation for the poor outcome in ischemic stroke patients with higher SBP at baseline is that high SBP is a marker of elevated sympathetic activity, which may lead to subsequent cardiovascular complications, and consequently makes an individual more prone to comorbidities, such as infection 12,13. However, in the Slowly dropping SBP Group, more than one-third of the patients who were diagnosed with hypertension before the index stroke were not on antihypertensive medications at stroke onset. This implies undertreatment of hypertension in this patient group. Uncontrolled and sustained high BP throughout the lifetime is also known to result in poor outcomes. Previous studies analyzing the long-term BP trajectory in the general population consistently showed that those with higher BP have a higher risk of adverse events than those who are normotensive. BP trajectory groups with a high BP level show a higher risk of mortality 2,5,6,14; cardiovascular events, such as stroke 4,6, myocardial infarction 4, heart failure 14, and atrial fibrillation 15; and also subclinical markers, such as increased carotid intima-media thickness or left ventricular mass index 3.
BP drop during the early stage of ischemic stroke is known to result in subsequent neurological deterioration by decreasing cerebral perfusion 16, and current practice guidelines mention that initiating BP-lowering therapy within the first 48 or 72 hours of onset may have no benefit 17. However, eventually lowering SBP to guideline-based levels (e.g., < 140 mmHg or < 130 mmHg) in patients with stroke or transient ischemic attack is recommended to prevent subsequent cardiovascular events 18. It is not clear when to begin lowering of BP or how quickly target BP levels should be reached in patients with acute ischemic stroke. There have been several clinical trials, such as the CATIS, ENOS, and SCAST trial, all of which failed to show a benefit in the primary outcome endpoint with more intensive BP-lowering therapy in patients with acute stroke 19–21. Our study results imply that the BP trajectory immediately after the acute stage of ischemic stroke is a potential target for BP-lowering interventions. More than half of the Slowly dropping SBP Group received no antihypertensive medication or only one medication at 30 days after stroke onset (Fig. 4). Intense treatment, particularly during the first 30 days after stroke onset, might improve outcomes in these patients. This area of research needs to be explored further, as physicians may feel that clinical equipoise exists in relation to when and how much to lower BP after stroke; this may explain, at least in part, the finding of no or only 1 antihypertensive medication being prescribed at 30 days in our Slowly dropping SBP Group.
It is interesting to note that the Low SBP Group did not have an evidently lower risk of mortality than the Moderate SBP Group (Table 2 and Supplemental Table 4). This result supports the findings from previous observational studies that there may be a “J-shaped” association between BP and outcomes 22,23. About 30% of the Low SBP Group were classified as having cardioembolic stroke and about 25% had atrial fibrillation (Table 1). These findings might explain both the low SBP and poor outcome in these patients, as atrial fibrillation results in decreased cardiac contractility and is associated with cardiovascular comorbidities, such as myocardial infarction and heart failure 24,25. Our data showed that the Low SBP Group were more likely to have atrial fibrillation and coronary heart disease and to present with more severe neurologic deficits at arrival, all of which could increase mortality (Supplemental Table 7).
Our study had several limitations. First, as we included patients who had SBP measurements taken at no fewer than 2 of 7 time-points, there might be a potential selection bias. On the other hand, only 2 measurements are not adequate for estimating BP trajectories. We intended to maximize the inclusion of such patients to minimize possible selection bias and performed a sensitivity analysis with subjects with 3 or more SBP measurements, which demonstrated the robustness of our study results. Second, although we were able to find associations between 1-year SBP trajectories and outcomes, we cannot conclude that there is a causal relationship between our main outcome findings and SBP trajectory results. However, we analyzed SBP data that were obtained before outcome events, in order to maintain the temporal relationships between SBP measurements and outcome events. Third, all the centers participating in the CRCS-K registry are academic hospitals, and therefore the generalizability of the study results to the entire stroke population might be limited. However, the age and sex distributions of the CRCS-K registry subjects are similar to those of the ischemic stroke population in South Korea 26. Forth, BP measurement protocol and device were not standardized between centers. Although we tried to consider the center effect using the Shared Frailty Model, this heterogeneity should be noted.
In conclusion, SBP trajectory in acute ischemic stroke patients were categorized into four distinct groups and patients in the Slowly dropping SBP group had poor outcome after index stroke event. While only small proportion of patients used antihypertensive agents despite high SBP during the early period in this group, meticulous BP management in these patients might be a potential target for improving outcome.