SGEM#269: Pre-Hospital Nitroglycerin for Acute Stroke Patients?

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Date: September 25th, 2019

Reference: Bath PM et al. Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomized, sham-controlled, blinded, phase 3 trial. The Lancet March 2019.

Guest Skeptic: Clay Odell is a Paramedic/RN for New London Hospital EMS in New Hampshire, USA which provides 9-1-1 coverage and Mobile Integrated Healthcare for seven rural communities. He’s been involved in EMS for over 30 years in a variety of roles and is a strong advocate for evidence-based EMS protocols.

Case: Your ambulance responds to a 9-1-1 call for a 75-year-old male experiencing abrupt onset of left sided weakness. You arrive to find the patient awake and alert, with a facial droop, slurred speech and left-sided arm drift (FAST-ED score = 3). He has a history of hypertension. His vital signs are heart rate 90 beats per minute, blood pressure 162/96 mmHg, respiratory rate 14 breaths per minute, SpO2 96% on room air, capillary blood glucose 120 mg/dl (6.7 mmol/L). His 12-lead ECG shows a normal sinus rhythm without ST abnormality or ectopy. While preparing for transport you contemplate administering nitroglycerin due to the likelihood of stroke.

Background: We have covered stroke many times on the SGEM (SGEM#29: Stroke Me, Stroke Me; SGEM#70: The Secret of NINDS; SGEM Xtra:Thrombolysis for Acute Stroke; SGEM Xtra: No Retreat, No Surrender; and SGEM Xtra: The Walk of Life). This episode will not debate the use of tPA for acute ischemic stroke. Rather we will be discussing whether lowering the blood pressure of a patient suspected of having a stroke in the pre-hospital setting will have a net beneficial patient-oriented outcome (POO).

Hypertension is common in acute stroke and is a predictor of poor outcome [1]. There is still some controversy on whether or not it is beneficial to lower the blood pressure in these cases [2].

Previous studies suggested that Nitric Oxide (NO) donors, such as transdermal glyceryl trinitrate (GTN – also known as nitroglycerin), reduced blood pressure, improved cerebral blood flow and reduced stroke lesion size if administered early [3 and 4].

There have been five randomized trials looking at nitroglycerin with four not showing superiority for functional outcome. One phase 2 trial done in the pre-hospital setting (RIGHT: Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial) did suggest a benefit to nitroglycerine [5].

The RIGHT study was a subgroup analysis of the ENOS (Efficacy of Nitric Oxide in Stroke) that looked at nitroglycerin within 6 hours of stroke. It too failed to demonstrate a statistical benefit [6].

However, a SRMA of individual patient data in these five trials suggested that earlier administration of nitroglycerin was associated with better outcomes in both ischemic and intracerebral hemorrhage stroke. It also was associated with lower mortality, disability, cognitive impairment, mood disturbance and poor quality of life (QOL) [7].

The conclusion to the RIGHT study was that a larger trial is needed to determine if nitroglycerin improves survival with good neurologic outcome.

Clinical Question: Does early administration of glyceryl trinitrate (nitroglycerin) by paramedics in the pre-hospital setting improve neurologic outcome in patients with presumed acute stroke?

Population: Adult patients who called emergency services for presumed stroke within 4 hours of onset of symptoms and a FAST score of 2 or 3, systolic blood pressure of equal or greater than 120 mmHg
- Exclusions: Nursing home patients, Glasgow Coma Scale <8, hypoglycemia or witnessed seizure, life expectancy < 6 months, known to have taken PDE5 inhibitor in the previous days and sensitivity to the Transidermal-Nitro patch or DuoDERM hydrocolloid dressing.
Intervention: Application of a 5.0 mg Transidermal-Nitro patch
Comparison: Application of a sham DuoDERM hydrocolloid dressing
Outcome:
- Primary Outcome: Functional outcome measured by Modified Rankin Scale (mRS) at 90 days.
- Secondary Outcomes: Barthel Index, cognition, quality of life and mood.
- Safety Outcomes: All-cause mortality, cause specific mortality,hypotension or hypertension occurring during the first 4 days.

Authors’ Conclusions: “Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting.”

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. No
The patients were adequately randomized. Yes
The randomization process was concealed. Unsure
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They enrolled 1,149 patients into RIGHT-2. The median time to randomization was 71 minutes. The cohort had slightly more men and the mean age was in the early 70’s. Ischemic strokes were diagnoses in 52%, intracerebral hemorrhage in 13%, TIAs in 9% and stroke mimics in 26%.

The mean change in blood pressure after the initial treatment was 5.8 mmHg systolic and 2.6 mmHg diastolic compared to the sham group. This drop in blood pressure represents a disease-oriented outcome (DOO) or surrogate outcome.

No statistical difference in functional outcome.

Primary Outcome: Functional outcome measured by Modified Rankin Scale (mRS) at 90 days.
- Odds Ratio 1.04 (95% CI; 0·84 to 1·29) p=0·69
Secondary Outcomes: There were no statistically differences between groups.
Safety Outcomes:There were no statistical difference between the two groups (ex: in mortality or serious adverse events). The nitroglycerine group did have more hypotension at day 4.

1. Enrollment/Randomization: We are unsure if consecutive patients were randomized due to the possible lack of concealment. Ambulance stations were randomized with blocks of four packs (two active and two control). Paramedics got an envelope at the beginning of their shift and returned unopened ones at the end of their shift. They did not mention if the envelopes were opaque. Even if the envelopes were opaque there is recent evidence of paramedics opening trial envelopes until they found the intervention group. It is possible that paramedics could have known which treatment group they had at the start of their shift and returned it unopened.

2. Blinding: This trial was not completely blinded. Paramedics and treating clinicians knew which group patients were assigned. The patients and outcome assessors were unaware of group allocation. However, there is no confirmation in the study that blinding was maintained. Unmeasured factors in the management of the patient could be possible. In addition, if the patient knew which group they were assigned and the study hypothesis that could have introduced bias favoring the intervention. It would have been easy to ask participants at the end of the study which group they thought they were assigned.

3. Outcome Assessment: The primary outcome was the mRS. The reliability of the mRS is only moderate in trained clinicians and its validity has been questioned [8 and 9]. This trial outcome assessment was done by telephone with a trained blinded assessor. If the patient could not be reached by phone, a questionnaire was mailed for the patient to complete. No information could be found on how many patients had to fill out the questionnaire and how many patients were interviewed over the phone.

4. Intervention: The study design was for four placements of the active or sham patch. However, there was significant falloff following the initial treatment. While there was 99% adherence to protocol by paramedics, only 55% of the subjects received a second treatment (in the hospital), and less than 50% got all four intended treatments.

Even the fall in blood pressure for the 99% who received the first treatment was lower than prior studies. It is possible with a larger dose of nitroglycerine dropping the blood pressure greater and better adherence to treatment protocols that a benefit could be demonstrated.

5. ITT vs. mITT: They divided the study up into two cohorts. Cohort 2 included all the patients and represents a true ITT. The primary outcome was no statistical difference. Cohort 1 removed all the patients with TIAs (9%) or stroke mimics (26%) for a total of 35%. The remaining 65% of patients were analyzed as a from modified ITT of the targeted disease (ischemic or hemorrhagic stroke). This mITT also failed to superiority of nitroglycerine.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors’ conclusions about lack of efficacy but are not sure why they needed to include the statement about feasibility.

SGEM Bottom Line: Very early application of transdermal nitroglycerin by paramedics in the pre-hospital setting cannot be recommended at this time in patients with a suspected stroke.

Case Resolution: An intravenous line is established in the patient’s right forearm and he is transported to the closest hospital with stroke care capability.

Clay Odell

Clinical Application: This is another example of pre-hospital treatment not resulting in a patient-oriented outcome (POO). Other examples include IV fluids (SGEM#246) and IV antibiotics (SGEM#207) in septic patients and therapeutic hypothermia (SGEM#183), endotracheal intubation (SGEM#247) and epinephrine (SGEM#238) for OHCA. We need to focus on things that have been proven to make a difference in the pre-hospital setting by paramedics like high-quality CPR and early defibrillation.

What Do I Tell My Patient? It looks like you might be having a stroke. We are going to monitor you closely and transport you to the hospital emergency department where they will assess you and treat whatever is causing your weakness.

Keener Kontest: Last weeks’ winner was Eliyahu Simcha Rosenberg an EMT from Israel. He knew Gene Glass is credited with coining the term “meta-analysis” and published one of the first SRMA in 1979 on the inverse relationship between class size and pupil academic achievement?

List to the SGEM podcast to hear this weeks’ question. If you think you know the answer, send an email to TheSGEM@gmail.com with keener in the subject line. The first correct answer will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

Appleton et al. Blood pressure management in acute stroke. Stroke and Vascular Neurology 2016
Bath et al. Blood Pressure in Acute Stroke To Treat or Not to Treat: That Is Still the Question. Stroke 2018
Willmot et al. A systematic review of nitric oxide donors and L-arginine in experimental stroke; effects on infarct size and cerebral blood flow. Nitric Oxide. May 2005
Maniskas et al. Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke. J Neurointerv Surg. January 2018
Ankoleker et al. Feasibility of an ambulance-based stroke trial, and safety of glyceryl trinitrate in ultra-acute stroke: the rapid intervention with glyceryl trinitrate in Hypertensive Stroke Trial (RIGHT, ISRCTN66434824). Stroke November 2013
Woodhouse et al. Effect of Hyperacute Administration (Within 6 Hours) of Transdermal Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome After Stroke: Subgroup Analysis of the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Stroke November 2015
Bath et al. Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials. Stroke Res Treat 2016
Wilson et al. Reliability of the Modified Rankin Scale Across Multiple Raters Benefits of a Structured Interview. Stroke 2005
Zhao et al. The modified Rankin Scale in acute stroke has good inter-rater-reliability but questionable validity. Cerebrovasc Dis January 2010