Level of Systolic Blood Pressure Within the Normal Range and Risk of Recurrent Stroke

1. Level of Systolic Blood Pressure Within the Normal Range and Risk of Recurrent Stroke Ovbiagele B, Diener H-C, Yusuf S, et al., PROFESS Investigators. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA. 2011;306(19):2137–2144. Ryan Mullins MS-III Mercer University School of Medicine Dr. Rahimi- RTR Medical Group Savannah, GA 12/7/2011

2. Funding • Boehringer-Ingelheim provided grant monies and materials to execute PROFESS trial, which is the basis of this post hoc observational analysis

3. Question/Objective • “To assess the association of maintaining low-normal vs high-normal SBP levels with risk of recurrent stroke.”

4. Design • Study was a post hoc observational analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial. • PROFESS trial included 20,330 patients who had recently had a non-cardioembolic ischemic stroke. Patients were enrolled from September 2003 through July 2006 from 695 centers in 35 countries. • PROFESS used 2x2 factorial design to compare (acetylsalicylic acid + ER dipyridamole) to clopidogrel and compare telmisartan to placebo in the prevention of recurrent stroke. • Patients were evaluated at the time of discharge from the hospital (qualifying stroke) or in a clinic visit at one week; then at 1, 3, and 6 months; then every 6 months after. Minimum expected follow-up was 18 months. • BP was measured twice, with at least two minutes between measurements, using Omron sphygmomanometer, and measurements were averaged.

5. Design • PROFESS trial did not find any evidence that (acetylsalicylic acid + ER dipyridamole) was superior to clopidogrelor that telmisartanwas superior to placebo in the prevention of recurrent stroke. • Since there were no significant differences found in PROFESS trial, THIS study combined and included all data from enrolled patients of PROFESS trial in the analyses for THIS study following the intention-to-treat principle.

6. Design • Patients from PROFESS trial were divided into 5 groups based on mean SBP: very low-normal (<120 mm Hg), low-normal (120-<130 mm Hg), high-normal (130-<140 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg). • Mean follow-up and reduction from baseline SBP was measured for patients using all but their baseline measurements until they died, experienced an outcome, or were censored. • The group with mean SBP within the high-normal range was the reference group. • Tests for interaction of baseline features including hxof diabetes, sex, age, stroke before qualifying stroke, small vessel stroke subtype, large vessel stroke subtype, and treatment assignment (from PROFESS) were performed. • Significance level for this study was a P<.05 using a 2 sided test. • Based on comparisons with reference group @ α level of .05, >80% power to detect a 20% risk reduction in recurrent strokes for the low-normal, high, and very high SBP groups, and >70% power for the very low-normal SBP group.

7. Patients/Setting • Patients in stable condition aged ≥55, or those aged 50-54 with at least two additional vascular risk factors, who experienced a non-cardioembolic ischemic stroke within 120 days prior to randomization. • PROFESS trial enrolled 20,330 patients from 695 centers in 35 countries

8. Inclusions/Exclusions • Inclusions • None observed other than those listed previously. • Exclusions • Patients excluded if they had a primary hemorrhagic stroke, severe disability after the qualifying stroke, C/I to any of the drugs used in the study, or other factors making them unsuitable for randomization. • Two patients without BP measurements during trial.

9. Main Outcome • The primary outcome was first recurrence of stroke of any type. • The secondary outcomes fatal stroke, MI, death from a vascular cause, death from any cause, and a composite of stroke, MI or vascular death.

10. Results

11. Results Ovbiagele, B. et al. JAMA 2011;306:2137-2144

12. Conclusion • The conclusion, based on this post hoc observational analysis, was as follows: In patients with recent non-cardioembolic ischemic stroke, mean SBP levels in the very low-normal (<120 mm Hg), high (140-<150 mm Hg), and very high (≥150 mm Hg) were associated with increased risk of recurrent stroke when compared to high-normal (130-<140 mm Hg) SBP levels.

13. Comment • “There were significant interactions between some variables and mean SBP on outcome in this study, including the association of older age with more events in the low-normal SBP level group.” • This study was a post hoc observational analysis of a completed randomized control trial. As such, the possibility that unmeasured confounding might explain some of the findings cannot be excluded. • The number of patients in the very low-normal group was less than half the number of patients in all other groups. • Qualifying event for this study was a non-cardioembolic ischemic stroke, so these findings may not be applicable to cardioembolic ischemic stroke. • “In conclusion, these data are hypothesis generating and the notion that aggressively and consistently lowering BP levels within the normal range in the short term to longer term after an index ischemic stroke is not beneficial remains unproven, and will require the conduct of dedicated clinical trials comparing intensive with usual BP reduction in the stable follow-up period after a stroke.”

14. Comments • In the study, there were 631 patients without postbaseline SBP measurements prior to the outcome. For these patients, their baseline values were used. However, as one can see, baseline values were often inconsistent with mean SBP groups.

15. References • Ovbiagele B, Diener H-C, Yusuf S, et al., PROFESS Investigators. Level of systolic blood pressure within the normal range and risk of recurrent stroke. JAMA. 2011;306(19):2137–2144.