CATIS-2: Intensive vs. Standard Blood Pressure Reduction in Acute Ischemic Stroke (2022)

“Among patients with acute ischaemic stroke who received intravenous thrombolysis, intensive blood pressure reduction did not significantly improve functional outcome at 90 days compared with the guideline-recommended standard blood pressure reduction.”

  • The CATIS-2 Collaborative Group

1. Publication Details

  • Trial Title: Intensive blood pressure reduction in acute ischaemic stroke (CATIS-2): a randomised, multicentre, open-label, blinded-endpoint trial
  • Citation: The CATIS-2 Collaborative Group. Intensive blood pressure reduction in acute ischaemic stroke (CATIS-2): a randomised, multicentre, open-label, blinded-endpoint trial. Lancet. 2022;400(10362):1513-1522. DOI: 10.1016/S0140-6736(22)01997-6
  • Published: October 29, 2022, in The Lancet
  • Author: The CATIS-2 Collaborative Group
  • Funding: The Ministry of Science and Technology of the People’s Republic of China.

2. Keywords

  • Ischemic Stroke, Blood Pressure, Hypertension, Antihypertensive Therapy, Thrombolysis, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute ischemic stroke who are eligible for intravenous thrombolysis and have elevated systolic blood pressure (Population), does a strategy of intensive blood pressure reduction (Intervention) compared to the guideline-recommended standard blood pressure reduction (Comparison) improve the rate of favorable functional outcome at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: For patients with acute ischemic stroke receiving thrombolysis (t-PA), guidelines recommend maintaining a systolic blood pressure (SBP) of <180 mm Hg to reduce the risk of hemorrhagic transformation. However, the optimal blood pressure target within this safe range was unknown.
  • Knowledge Gap: It was a major clinical question whether a more aggressive, intensive blood pressure reduction strategy would be superior to the standard approach. The potential benefit of reducing bleeding risk had to be weighed against the potential harm of reducing cerebral perfusion to the ischemic penumbra.
  • Proposed Hypothesis: The authors hypothesized that an intensive blood pressure reduction strategy would be superior to a standard reduction strategy in improving functional outcomes at 90 days.

5. Study Design and Methods

  • Design: A large, multicenter, prospective, randomized, open-label, blinded-endpoint trial (used to test the effectiveness of interventions).
  • Setting: 97 academic and community hospitals in China.
  • Trial Period: Enrollment ran from September 2016 to May 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with acute ischemic stroke who were treated with intravenous alteplase within 4.5 hours of symptom onset and had a systolic blood pressure between 140 mm Hg and 220 mm Hg.
    • Exclusion Criteria: Included patients with a clear indication for more aggressive blood pressure lowering (e.g., aortic dissection) or those with severe heart failure.
  • Intervention: An intensive blood pressure reduction strategy, with a target SBP of 130-140 mm Hg within 1 hour.
  • Control: A standard blood pressure reduction strategy, with a target SBP of 140-180 mm Hg, as recommended by guidelines.
  • Management Common to Both Groups: All patients received intravenous alteplase and standard medical care for acute ischemic stroke.
  • Power and Sample Size: The authors calculated that a sample size of 966 patients would provide 80% power to detect a 7% absolute difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: A favorable functional outcome at 90 days, defined as a modified Rankin Scale (mRS) score of 0 or 1.
    • Secondary Outcomes: Included the distribution of mRS scores, 90-day mortality, and the incidence of symptomatic intracranial hemorrhage.

6. Key Results

  • Enrollment and Baseline: 961 patients were randomized (484 to the intensive group and 477 to the standard group). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. A favorable functional outcome occurred in 314 of 484 patients (65%) in the intensive group and in 309 of 477 patients (65%) in the standard group (p=0.97).
  • Secondary Outcomes: There were no significant differences between the groups in the overall distribution of mRS scores or in 90-day mortality.
  • Adverse Events: The incidence of symptomatic intracranial hemorrhage was low and similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients with a favorable outcome between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.97 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design with blinded outcome assessment provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of a large number of diverse hospitals make the findings highly generalizable to a broad population of patients with acute ischemic stroke receiving thrombolysis.
  • Statistical Power: The large sample size provided definitive power to confidently rule out a modest but clinically important benefit of the intervention.
  • Patient-Centered Outcomes: The primary outcome of 90-day functional status is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of patients with acute ischemic stroke who are receiving thrombolysis.
  • Other: The blood pressure difference achieved between the two groups was modest in the first 24 hours.

10. Conclusion of the Authors

  • The authors concluded that among patients with acute ischemic stroke who received intravenous thrombolysis, intensive blood pressure reduction did not significantly improve functional outcome at 90 days compared with the guideline-recommended standard blood pressure reduction.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against a strategy of more aggressive blood pressure lowering in stroke patients receiving thrombolysis. It supported the current, more conservative guideline recommendations.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute ischemic stroke receiving thrombolysis and with a SBP < 220 mm Hg.
    • Actionable Intervention: The results support the current guideline recommendation of targeting a SBP between 140 and 180 mm Hg.
  • What This Trial Does NOT Mean: This trial does NOT mean that blood pressure control is not important during thrombolysis. It only suggests that a more aggressive target (<140 mm Hg) is not superior to the standard target.
  • Implementation Caveats: The key takeaway is that the current guideline-recommended blood pressure targets are evidence-based and appropriate.

12. Context and Related Studies

  • Building on Previous Evidence: The CATIS-2 trial (2022) was a direct follow-up to the original CATIS trial (2014), which had studied blood pressure management in patients not receiving thrombolysis. CATIS-2 addressed the specific population that was excluded from the first trial.
  • Influence on Subsequent Research: The definitive neutral result of this large trial will be highly influential in shaping international stroke guidelines, reinforcing the current, more conservative blood pressure targets for patients receiving thrombolysis.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: Future research may focus on identifying if there are specific subgroups of stroke patients who might still benefit from more intensive blood pressure control, or on the optimal blood pressure management during and after mechanical thrombectomy.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and important clinical dilemma in the acute management of stroke patients receiving thrombolysis.
  • Methods: The very large, multicenter, randomized controlled trial design with blinded outcome assessment was of high quality. The main methodological weakness is the open-label design, but the primary outcome was objective and adjudicated by a blinded committee.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of a more intensive blood pressure reduction strategy.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that was practice-affirming, providing strong evidence to support the current, less aggressive standard of care.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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