SGEM#116: Paramedics’ Got a Squeeze Box – Remote Ischemic Conditioning

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Date: April 15th, 2015

Guest Skeptics: Clay Odell. Clay is a paramedic and Executive Director of Upper Valley Ambulance, a regional EMS system covering nine communities in rural New Hampshire and Vermont. He’s been involved in EMS for over 30 years in a variety of roles including urban paramedic, flight paramedic, an emergency nurse, and Chief of the State EMS Office in New Hampshire. Clay is very interested in EBM for EMS and says he’s trying really hard to learn, but continues to procrastinate about actually taking a statistics course again.

Previous EMS/Pre-hospital Episodes on the SGEM:

SGEM#54: Baby It’s Cold Outside (Pre-Hospital Therapeutic Hypothermia in Out of Hospital Cardiac Arrest)
SGEM#59: Can I get a witness (Family Members Present During CPR)
SGEM#96: Machine Head (NIPPV for Out of Hospital Respiratory Distress)

Case: Your rural EMS unit is dispatched to a call for a 65-year-old man with chest pain. On scene a 12 lead ECG is acquired in six minutes, revealing ST elevation in V3 through V6. The patient is given 324 mg of chewable aspirin, sublingual nitroglycerin which reduces his 9/10 chest pressure, oxygen by nasal cannula at 2 lpm to maintain his SaO2 above 94%. The patient is removed from the second floor of his home by stairchair, placed on the stretcher, loaded into the ambulance and transport is initiated to the closest PCI center. The EMS provider calls the hospital with a STEMI alert with a 30 minute ETA. Enroute the patient is monitored, serial 12 lead is done, another nitro is given when chest discomfort returns, but otherwise you settle in for the ride. You recall reading an article in a journal recently about remote ischemic conditioning, which is done by inflating a BP cuff on the patient’s arm to 200 mmHg for 5 minutes, then release the pressure for 5 minutes, and repeat three more times. The article said this technique reduces myocardial damage from reperfusion injury after the PCI. It’s not in your protocols so you call online medical control to discuss it.

Pickard et al Basic Res Cardiol 2015

Background: The phenomenon of ischemic preconditioning was reported almost 30 years ago in experiments done on dogs. These early studies looked at limiting infarct size. The technique involved a series of alternating periods of ischemia of a coronary artery with reperfusion sessions to render the myocardium more resistant to a subsequent ischemia event.

When a coronary vessel is occluded during an MI, myocardial cells distal to the occlusion suffer from ischemic injury. A reperfusion injury has been described once the flow has been restored via PCI that may increase the infarct size.

Unlike the dog experiments, the remote ischemic conditioning (RIC) involves placing a blood pressure cuff on an extremity. It typically is on the arm and inflated to 200 mmHg for 5 minutes, then released. This pattern is repeated three more times.

The exact mechanism behind remote ischemic conditioning (RIC) is not known. It is thought to be a neuroal and hurmoral interaction mediating the protective effect.

RIC has been investigated in a number of large cardiac surgery and PCI trials. These have reported benefit in improving cardiac markers and limiting infarct size.

Clinical Question: Does pre-hospital remote ischemic conditioning performed on STEMI patients decrease myocardial reperfusion injury and improve their long-term outcome?

Reference: Sloth et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. European Heart Journal (2014)

Population: Adults with symptoms <12hrs and STEMI on ECG.
- Exclusion Criteria – diagnosis not confirmed upon hospital arrival, history of previous myocardial infarction, previous coronary artery bypass grafting (CABG), and chest pain > 12 hours prior to admission. (Parent trial excluded LBBB, fibrinolytic treatment in previous 30 days, left main stem stenosis, severe heart failure needing mech ventilation, and intra-aortic balloon pump)
Intervention: Remote ischemic conditioning by inflating a blood pressure cuff on the patient’s arm to 200 mmHg for 5 minutes, followed by release of pressure for 5 minutes. Performed a total of 4 times prior to PCI.
Comparison: Usual care
Outcome:
- Primary endpoint was MACCE (Major Adverse Cardiac and Cerebrovascular Events) that included a composite of all-cause mortality, myocardial infarction, readmission for heart failure and ischemic CVA/TIA.
- Secondary endpoints were the individual components of the MACCE.
- On the ClincalTrial.gov website they did not mention the components of the MACCE as secondary outcomes. They only mentioned LV-function and remodeling measured by ECHO.

Author’s Conclusions: Remote ischemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infarction.

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the ED. No, it focused on prehospital patients being transported by EMS to a PCI center.
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Yes
The patients in both groups were similar with respect to prognostic factors. Patients in the intervention arm were more likely to have preexisting hypertension than the control arm, otherwise they were similar
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. No. Patients and clinicians were aware, outcome assessors were not
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. Unsure

Key Results: There were 333 patients with suspected STEMI randomized into the trial. Only 251 met trial criteria after randomization and these patients has a per protocol analysis performed. The 82 patients excluded were: Diagnosis of MI not confirmed (34), previous CABG (4), CP>12hrs (4) and previous MI (41).

Primary Outcome MACCE Per Protocol Analysis:
- 13.5% RIC vs. 25.6% control
- HR 0.49 (0.27-0.89) p=0.018
Secondary Outcomes
- All cause mortality HR 0.32 (0.12-0.88) p=0.027
- Myocardial infarction HR 0.69 (0.28-1.71) p=0.423
- Readmission HR 0.54 (0.16-1.85) p=0.327
- CVA/TIA HR 0.72 (0.16-3.23) p=0.670

SGEM Commentary: This study was a long-term followup to a study by Botker et al published in the Lancet 2010. It looked at these same 251 patients who either received the RIC procedure or the control group, and looked at the short term outcome differences in post-PCI myocardial damage as measured by single photon emission CT.

They were pleased with their outcomes and went on to follow these patients through Danish nationwide medical registries up to five years after their MI, looking to see if there were any differences in Major Adverse Cardiac or Cerebrovascular Events (MACCE).

We identified five issues with the study:

Per-Protocol vs. Intention to Treat Analysis:Both are tools to investigate the data and have strengths and weaknesses. Intentions to treat analysis tend to be a better method because it is not biased by non-compliant patients, dropouts and cross overs.
- Per-protocol analysis excludes patients who deviated from the protocol and only includes those who received the treatment. Doing a per-protocol analysis can introduce attrition bias. This is a form a bias in which those groups of patients being compared no longer have similar characteristics. It tends to be a lower form of evidence but better demonstrates the effects of a treatment when used in an optimal manner. These types of per protocol analyses can be helpful in interpreting non-inferiority trials.
- They did both a per-protocol and intention to treat analysis but highlight only the per protocol results. This makes me skeptical of the results because if you look at the ITT for the primary composite outcome of MACCE the HR is not nearly as robust and barely meets statistical significance. HR 0.62 (0.39-0.99) p=0.45
- The authors say they focused on the per protocol analysis because the parent trial showed benefit in myocardial salvage index per protocol. For more information on ITT vs. Per protocol check out this review by Dr.Gupta.
Where was the Benefit?
- Their secondary outcomes were the components of the MACCE composite outcome. Only the all-cause mortality showed significant reduction in HR. Interestingly when they broke this down into subgroup analysis for cardiac mortality vs. non-cardiac mortality the benefit was seen in the later.
- Cardiac mortality HR 0.39 (0.08-2.00) p=0.258
- Non Cardiac Mortality HR 0.28 (0.08-1.03) p=0.056
- The RIC intervention that was to decrease cardiac badness (death) did not seem to be superior to control. However, there were very few events in both groups that make the results difficult to interpret.
- The ITT analysis on all cause mortality showed no statistical difference HR 0.51 (0.25-1.07) p=0.074
Not Blinded:
- This was not a blinded trial for the providers or the participants. Only the outcome assessors were blinded to treatment group. This could have introduced bias into the experiment. The EMS personal may have treated the intervention group differently even if on a subtle level.
- They could have attempted to blind the trial. An automatic BP cuff that automatically inflated to either 200mm Hg for temporary ischemia or a value significantly less. They could have even asked the paramedics and patients post intervention which “arm” of the trial they thought they were randomized. This would have confirmed the blinding was maintained.
Time to Complete:
- This has the potential to slow things down in the filed for a time dependent emergency. The protocol called for 5min of inflation followed by 5min deflation. This was done for four cycles taking 40 minutes in total.
- Sixteen of the 251 (6%) could not complete the four cycles of inflation/deflation because the transportation time was insufficient. They continued the procedure in hospital while the patients were getting primary PCI.
- So the question becomes can you apply these results to your practice environment. It may depend on how long your transportation times are and this could, if proven to be of benefit, may play a greater role in rural/remote areas with longer transport times.
External Validity:
- This study was done in Denmark where the EMS system could be substantially different than in North America. In addition to the transport times what level of training do their EMS providers have compared to ours? What can be provided in the pre-hospital setting?

Clay Odell

Comment on authors’ conclusion compared to SGEM Conclusion: The authors’ conclusion that RIC “seemed” to show improvement in long-term clinical outcomes in patients with STEMI gives them some wiggle room. We would agree there “seemed” to be some benefit if you used the per protocol analysis but there did not seemed to be benefit if you used the ITT analysis, considered the lack of blinding and the other limitations mentioned.

SGEM Bottom Line: The technique has promise as it is cheap and can be done by all levels of EMS provider. However, there needs to be a large multicentred trial using RIC showing improved patient oriented outcomes before this becomes a routine treatment in the pre-hospital setting for STEMI patients.

Case Resolution: You discuss the recommendation with your EMS medical director via cell phone. You and the doctor decide not to perform the procedure, but agree to meet and review the literature to see if the procedure should be considered for inclusion in statewide protocols.

Clinically Application: None at this time.

What do I tell my patient? You are having a heart attack and we are taking you to the hospital as fast and safely as we can.

Keener Contest: Last weeks winner was Nathan Green from San Francisco. He knew that Claudius Amyand, famous for having done the first recorded appendectomy in 1735, was also famous for having a hernia named after him.

Listen to the podcast for this weeks keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct response will win a cool skeptical prize.