PDF: INTERACT2
(2013)Objective
Determine whether early intensive blood pressure lowering improves outcomes in patients with acute spontaneous intracerebral hemorrhage (ICH).
Study Summary
• In patients with spontaneous ICH and elevated systolic BP (150–220 mm Hg) within 6 hours of onset, intensive BP lowering to <140 mm Hg was safe and showed a modest improvement in functional outcomes, though it did not significantly reduce the primary composite outcome of death or major disability.
Intervention
International, multicenter, randomized, open-label trial with blinded outcome assessment. N=2839 patients randomized to intensive treatment (target SBP <140 mm Hg within 1 hour) vs. guideline-recommended treatment (target <180 mm Hg). Follow-up at 90 days.
Study Design
Arms: Array
Outcome
• Primary outcome (mRS 3–6): 52.0% (intensive) vs. 55.6% (standard); OR 0.87 (95% CI 0.75–1.01); p=0.06
• Ordinal mRS shift: OR 0.87 (95% CI 0.77–1.00); p=0.04
• Mortality: 11.9% vs. 12.0% (p=0.96)
• Serious adverse events: 23.3% vs. 23.6%
• Quality of life better in intensive group (EQ-5D utility score 0.60 vs. 0.55; p=0.002)
• Hematoma growth not significantly different (mean increase 2.5 mL vs. 5.5 mL; p=NS)
• Ordinal mRS shift: OR 0.87 (95% CI 0.77–1.00); p=0.04
• Mortality: 11.9% vs. 12.0% (p=0.96)
• Serious adverse events: 23.3% vs. 23.6%
• Quality of life better in intensive group (EQ-5D utility score 0.60 vs. 0.55; p=0.002)
• Hematoma growth not significantly different (mean increase 2.5 mL vs. 5.5 mL; p=NS)
Bottom Line
Intensive SBP lowering to <140 mm Hg within 6 hours of ICH onset was safe and associated with improved functional outcomes, though it did not significantly reduce death or major disability.
Major Points
- INTERACT2 was the first large randomized trial of acute BP management in intracerebral hemorrhage, establishing that targeting SBP <140 mmHg within 6 hours of ICH onset is SAFE and probably beneficial — transforming ICH management from permissive hypertension to early aggressive BP control.
- Primary outcome (death or major disability mRS ≥3 at 90 days): 52.0% intensive vs 55.6% standard (OR 0.87, 95% CI 0.75–1.01, p=0.06) — narrowly missed statistical significance by the conventional dichotomous analysis, but the trend was consistent and clinically meaningful.
- Pre-specified ordinal shift analysis of the full mRS distribution showed SIGNIFICANT benefit: common OR 0.87, p=0.04 — demonstrating that intensive BP lowering shifted outcomes favorably across the disability spectrum, not just at the death/disability threshold.
- 2,839 patients across 144 hospitals in 21 countries. Predominantly Asian (68% Chinese) — the largest ICH trial at the time, though subsequently surpassed by INTERACT3 and ATACH-2.
- BP achieved: median SBP 139 mmHg (intensive) vs 153 mmHg (standard) at 1 hour — a 14 mmHg difference. Intensive arm reached target <140 mmHg within 1 hour in 33.4% of patients, highlighting the practical difficulty of achieving rapid BP control.
- No increase in adverse events: SAEs were 23.6% vs 23.3% (p=0.83), renal events 0.6% vs 0.3% (p=0.12) — directly addressing the longstanding fear that aggressive BP lowering would cause perihematomal ischemia or renal failure.
- Hematoma growth: absolute hematoma growth was numerically smaller in the intensive group (1.6 vs 2.8 mL), though not statistically significant — mechanistically supporting the theory that early BP control limits hemorrhage expansion.
- Median time to randomization was 4 hours — leaving a window where some hematoma expansion may have already occurred. Earlier BP lowering (within 1–2 hours) might show greater benefit, as tested in subsequent trials.
- Set the standard of care: AHA/ASA 2015 ICH guidelines gave intensive BP lowering to SBP <140 mmHg a Class IIa recommendation based primarily on INTERACT2, making it the de facto approach in most stroke centers worldwide.
- Followed by ATACH-2 (2016) which tested SBP <140 vs <180 using IV nicardipine — found NO benefit but MORE renal events, suggesting there may be a 'floor effect' where additional BP lowering beyond a certain point is harmful. INTERACT2's less aggressive approach (targeting <140 within 1 hour) appears to be the sweet spot.
Study Design
- Study Type
- Open-label, randomized, controlled trial with blinded endpoint assessment
- Randomization
- Yes
- Blinding
- Endpoint-assessor blinded
- Sample Size
- 2839
- Follow-up
- 90 days
- Centers
- 144
- Countries
- Australia, China, UK, Vietnam, India, South Korea, Pakistan, Chile, Mexico, Brazil, and others
Primary Outcome
Definition: Death or major disability (modified Rankin score ≥3) at 90 days
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 55.6% | 52.0% | 0.87 (0.75–1.01) | 0.06 |
Limitations & Criticisms
- Primary endpoint narrowly missed significance (p=0.06) by dichotomous analysis — this 'near-miss' left room for skeptics to argue the benefit was not proven. However, the pre-specified ordinal analysis was significant (p=0.04), and most subsequent guidelines accepted the totality of evidence.
- Open-label design — physicians knew the BP target, potentially influencing overall care intensity and outcome assessment. PROBE design (blinded endpoint assessment) mitigated this, but treatment contamination (standard arm patients receiving more aggressive BP treatment than protocol) was documented.
- 68% Chinese enrollment — may limit generalizability. Chinese patients may have different ICH etiology (more hypertensive vasculopathy), response to antihypertensives, and background care practices than Western populations.
- Moderate BP difference achieved: 14 mmHg at 1 hour (139 vs 153 mmHg) — the standard arm was treated more aggressively than protocol required (<180 target), narrowing the between-group difference and potentially diluting the treatment effect.
- No specific antihypertensive protocol — flexible agent choice improves generalizability but introduces heterogeneity. Different agents (nicardipine vs labetalol vs urapidil) have different hemodynamic profiles and may affect perihematomal perfusion differently.
- 90-day follow-up only — long-term functional recovery after ICH often continues beyond 3 months. Longer follow-up might have shown different results.
- Did not assess hematoma expansion by serial imaging in all patients — the mechanistic link between BP lowering and reduced expansion was inferred but not directly proven in this trial.
- Excluded GCS ≤5 patients — the most severe ICH patients, who have the highest mortality and might theoretically benefit most (or least) from BP control, were not studied.
- Subsequently challenged by ATACH-2 (2016): same BP target (<140 mmHg) but with mandatory IV nicardipine and faster BP reduction — showed NO benefit and MORE renal events, raising questions about whether speed/method of BP lowering matters as much as the target itself.
Citation
Anderson CS et al. N Engl J Med. 2013;368(25):2355-2365.