PDF: MR-ASAP
(2022)Objective
To evaluate whether transdermal glyceryl trinitrate (GTN) 5mg applied in the ambulance within 3 hours of symptom onset improves functional outcome at 90 days in patients with presumed acute stroke.
Study Summary
• No blood pressure-lowering effect was detected at hospital admission despite median prehospital SBP of 175–180 mmHg
• Trial terminated early after DSMB safety signal: 7-day mortality in ICH patients was 34% (GTN) vs 10% (control), aOR 5.91 (95% CI 0.78–44.81)
• Prespecified subgroup: possible harm at lower prehospital SBP (<177 mmHg) vs possible benefit at higher SBP (>176 mmHg), p-interaction 0.004
Intervention
Transdermal glyceryl trinitrate (GTN) 5mg patch applied for 24 hours by paramedics in the ambulance within 3 hours of stroke symptom onset
Inclusion Criteria
Adults ≥18 years with a probable diagnosis of acute stroke as assessed by a paramedic in the prehospital setting; Face-Arm-Speech-Time (FAST) test score of 2 or 3; systolic blood pressure ≥140 mmHg; treatment could be started within 3 hours of symptom onset; transported by participating ambulance services in the Netherlands
Study Design
Arms: Glyceryl trinitrate 5mg transdermal patch for 24h (n=170) vs Standard care (n=155)
Patients per Arm: 170 GTN, 155 control (325 modified ITT; 380 randomized)
Outcome
• Target population (ischemic stroke/TIA/ICH, n=286): adjusted common OR 0.92 (95% CI 0.59–1.43)
• 7-day mortality: GTN 9% vs control 3%, aOR 3.43 (95% CI 0.96–12.24)
• ICH subgroup 7-day mortality: 12/35 (34%) vs 2/21 (10%), aOR 5.91 (95% CI 0.78–44.81)
Bottom Line
Prehospital GTN does not improve functional outcomes in unselected patients with presumed acute stroke and carries a safety signal in those with ICH. GTN should not be used in the prehospital stroke setting outside of research. A prespecified subgroup interaction with prehospital systolic BP warrants hypothesis-generating follow-up but is insufficient to support clinical use.
Major Points
- GTN did not improve the primary outcome (mRS at 90 days) in either the total population (adjusted common OR 0.97) or the target population of stroke/TIA/ICH (adjusted common OR 0.92)
- No blood pressure-lowering effect of GTN was detected at hospital admission, despite a median prehospital SBP of 175–180 mmHg
- The trial was prematurely terminated on DSMB advice after a signal of harm in ICH patients: 7-day mortality was 34% (GTN) vs 10% (control), aOR 5.91
- A prespecified interaction between prehospital systolic BP and GTN effect (p=0.004) suggests possible harm in lower-BP patients and possible benefit in higher-BP patients, but this is exploratory
- Combined with RIGHT-2, MR ASAP provides consistent evidence against prehospital GTN for unselected stroke patients
Study Design
- Study Type
- Multicenter, randomized, open-label, blinded endpoint (PROBE design), phase 3 trial
- Randomization
- Yes
- Blinding
- Open-label treatment allocation; independent blinded endpoint assessment (PROBE design); blinded adjudication of mRS outcomes and neuroimaging
- Sample Size
- 380
- Follow-up
- 90 days
- Centers
- 18
- Countries
- Netherlands
Primary Outcome
Definition: Modified Rankin Scale (mRS) score at 90 days, analyzed as ordinal shift (adjusted common odds ratio via multivariable ordinal logistic regression)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Median mRS 2 (IQR 1–4), n=148 | Median mRS 2 (IQR 1–4), n=170 | 0.97 (0.65–1.47) | Not reported (CI only) |
Limitations & Criticisms
- Trial terminated prematurely at 325 patients (target 1400) on DSMB advice — underpowered to detect small effects or definitively confirm ICH harm
- 14% of patients did not provide deferred consent; withdrawal was more frequent in the control group, potentially introducing selection bias
- Open-label treatment allocation may have introduced performance bias, despite blinded endpoint assessment
- 43 patients (28%) in the GTN group had documented early patch removal within the 24-hour window, reducing treatment fidelity
- Marked baseline imbalance in prehospital SBP (175 vs 180 mmHg) and history of hypertension (52% vs 63%), which may have confounded the SBP subgroup interaction
- No blood pressure-lowering effect was demonstrated at hospital admission, making it unclear whether GTN was pharmacologically active during the prehospital window
- Heterogeneous population (ischemic stroke, ICH, TIA, mimics) limits interpretation — prehospital diagnosis of stroke type is inherently imprecise
- The SBP interaction is exploratory and hypothesis-generating; the trial was not powered to confirm differential effects by blood pressure level
Citation
Lancet Neurol 2022;21:971-981