Does intensive blood pressure reduction reduce recurrent stroke risk in patients with a history of stroke or TIA?

• Quality of evidence: moderate
• Applicability of the evidence to Finnish population: good

Table 1. Description of the included studies

Reference	Study type	Population	Intervention and comparison	Outcomes	Risk of bias
RCT=randomized controlled trial; SR=systematic review; MA=meta-analysis
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	MA	Patients with prior stroke or transient ischemic attack from 10 RCTs across multiple countries	More intensive vs less intensive blood pressure lowering	Primary outcome: Recurrent stroke; Secondary outcomes: major cardiovascular events, ischemic stroke, hemorrhagic stroke, fatal/disabling stroke, myocardial infarction, death from cardiovascular causes, death from any cause, heart failure	Moderate

Table 2. Additional comments for included studies

Reference

Comments

«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1

This meta-analysis investigated whether more intensive blood pressure (BP) lowering is more effective than less intensive treatment in preventing recurrent strokes among patients with a history of stroke or transient ischemic attack (TIA). The study synthesized data from ten randomized controlled trials published between 1980 and 2022, encompassing a total of 40,710 patients. Eligible studies were randomized trials that included patients with prior stroke or TIA, compared more intensive versus less intensive BP-lowering strategies—either through antihypertensive drugs versus placebo or lower versus higher BP targets—and reported recurrent stroke as an outcome. Studies were required to report the magnitude of systolic BP reduction between groups and have a minimum treatment duration of one year. Trials were excluded if they were published before 1980, used only non-pharmacological interventions, compared different antihypertensive drugs, had paradoxical BP outcomes (i.e., higher BP in the intensive group), enrolled patients within three days of stroke, or included a significant proportion of patients with end-stage kidney disease. Among the 10 included trials, 6 compared antihypertensive drug(s) to placebo or no antihypertensive therapy, and 4 trials compared a lower BP target to higher BP target. The mean baseline BP was 146 mmHg and diastolic BP was 85 mmHg across all trials. The magnitude of BP reduction varied across studies. On average, the differential SBP reduction between the more intensive and less intensive groups was 6.7 mmHg, and the differential diastolic BP reduction was 2.8 mmHg. The meta-regression analysis revealed a log-linear relationship between the magnitude of BP reduction and the risk of recurrent stroke. For example, a 5 mmHg greater systolic BP reduction was associated with an RR of 0.90, and a 10 mmHg reduction with an RR of 0.67. Similarly, a 3 mmHg greater diastolic BP reduction was associated with an RR of 0.84, and a 5 mmHg reduction with an RR of 0.60. These findings suggest that greater BP reductions are associated with proportionally greater reductions in stroke risk. For the primary outcome, recurrent stroke, number needed to treat (NNT) is 58 in 3 years. For major cardiovascular events, NNT is 61 in 3 years. The quality of the included studies was assessed using the Cochrane Risk of Bias tool. All studies were randomized. However, allocation concealment and blinding varied. Some studies were double-blinded (particularly those comparing drugs to placebo), while others—especially those comparing BP targets—were open-label, introducing potential performance bias. Blinding of outcome assessment was inconsistently reported, which may have led to detection bias, particularly in trials where stroke was not the primary outcome. Attrition bias appeared minimal, as sensitivity analyses showed that removing individual trials did not significantly alter the overall results. Selective outcome reporting was not evident, and the primary and secondary outcomes were consistently documented across studies. Publication bias was assessed using the trim-and-fill method, and no major asymmetry was found, suggesting low risk of bias from unpublished negative studies. The analysis was conducted at the trial level, not the individual patient level, which limited the ability to explore subgroups such as patients with baseline systolic BP below 140 mmHg. There was substantial heterogeneity among the included trials, likely due to differences in BP reduction magnitude and study design. Additionally, two large trials (PRoFESS and PROGRESS) contributed more than half of the total patient population, which may have disproportionately influenced the pooled results. The definition of BP reduction varied across studies, with some reporting mean differences over time and others using single time-point comparisons. Target BPs in the intervention group were also defined differently between those included studies that compared intensive vs. less intensive BP targets, e.g. systolic BP <120 mmHg; systolic BP <125 mmgHg; systolic BP <130 mmHg; systolic BP <130 mmHg or a 10 mmHg reduction if baseline systolic pressure was <140 mmHg mmHg; or BP 120/80 mmHg. Furthermore, in several trials, stroke was not the primary endpoint, which could affect the accuracy of event reporting.

Results

Table 3. Primary outcome: Recurrent stroke

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I=intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	10 studies; patients (I: 20344 / C: 20366)	Mean 2.8 years (range 1–4 years)	1704 (8.4%)	2061 (10.1%)	RR: 0.83 (95% CI: 0.78–0.88)
Level of evidence: moderate

Table 4. Secondary outcome: Major cardiovascular events

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I=intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	9 studies; I: 19582 / C: 19608	Mean 2.8 years (range 1–4 years)	2348 (12.0%)	2679 (13.7%)	RR: 0.88 (95% CI: 0.83–0.92)
Level of evidence: moderate

Table 5. Secondary outcome: Ischemic stroke

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I= intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	6 studies; I: 16134 / C: 16189	Mean 2.8 years (range 1–4 years)	1217 (7.5%)	1403 (8.7%)	RR: 0.88 (95% CI: 0.83–0.92)
Level of evidence: moderate

Table 6. Secondary outcome: Hemorrhagic stroke

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I= intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	6 studies; I: 16134 / C: 16189	Mean 2.8 years (range 1–4 years)	114 (0.7%)	212 (1.3%)	RR: 0.54 (95% CI: 0.43–0.68)
Level of evidence: moderate

Table 7. Secondary outcome: Fatal or disabling stroke

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I= intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	6 studies; I: 8537 / C: 8539	Mean 2.8 years (range 1–4 years)	253 (3.0%)	334 (3.9%)	RR: 0.76 (95% CI: 0.64–0.89)
Level of evidence: moderate

Table 8. Secondary outcome: Myocardial infarction

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I=intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	9 studies; I: 20344 / C: 20366	Mean 2.8 years (range 1–4 years)	365 (1.8%)	409 (2.0%)	RR: 0.89 (0.78–1.03)
Level of evidence: moderate

Table 9. Secondary outcome: Death from cardiovascular cause

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I= intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	9 studies; I: 19711 / C: 19736	Mean 2.8 years (range 1–4 years)	629 (3.2%)	728 (3.7%)	RR: 0.86 (0.78–0.96)
Level of evidence: moderate

Table 10. Secondary outcome: Death from any cause

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I=intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	10 studies; I: 20344 / C: 20366	Mean 2.8 years (range 1–4 years)	1511 (7.4%)	1554 (7.6%)	RR: 0.97 (95% CI: 0.91–1.04)
Level of evidence: moderate

Table 11. Secondary outcome: Heart failure

Reference	Number of studies and number of patients (I/C)	Follow-up time	Absolute number of events (%) I	Absolute number of events (%) C	Relative effect (95% CI)
I= intervention; C=comparison; CI=confidence interval; RR=relative risk
«Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):5»1	2 studies; I: 10779 / C: 10816	Mean 2.8 years (range 1–4 years)	126 (1.2%)	120 (1.1%)	1.05 (0.82–1.35)
Level of evidence: low

References

1. Hsu CY, Saver JL, Ovbiagele B, ym. Association Between Magnitude of Differential Blood Pressure Reduction and Secondary Stroke Prevention: A Meta-analysis and Meta-Regression. JAMA Neurol 2023;80(5):506-515 «PMID: 36939729»PubMed