Anti-Arrhythmics - What Good Are They?

/

Last week we had our first Journal Club of the year and had an excellent discussion of the evidence surrounding the use of amiodarone, lidocaine, and procainamide for ventricular dysrhythmias.  Take a listen to the podcast below and read up on the details of the papers below that!

Ortiz M et al. Randomized Comparison of Intravenous Procainamide vs. Intravenous Amiodarone for the Acute Treatment of Tolerated Wide QRS Tachycardia: the PROCAMIO Study. Eur Heart J 2016. PMID: 27354046

Study Design

Prospective, Randomized- open label, Multicenter Clinical trial comparing use of IV amiodarone vs IV procainamide for treatment of stable wide complex tachycardia

Methods

Enrolled patients into open label 1:1 randomization if they fit into the following criteria: Regular wide complex tachycardia (QRS>120), SBP> 90, Age>18

Excluded:        

  • Poor Hemodynamic tolerance
  • Evidence of hypoperfusion
  • Evidence of SVT? (per physician assessment)
  • Prior treatment w/ amiodarone or procainamide
  • Drug contraindications
  • Did not consent

Measured blood pressure every 3 minutes. EKG performed before initiating treatment, then every 10 minutes and upon rhythm change.

Initial EKG was reviewed by electrophysiologist to confirm VT. (88% procainamide, 93% amiodarone, p= 0.49)

Enrollment

Enrolled 74 patients over 6 years of which 62 were analyzed. Study was stopped early due to poor enrollment.

Groups

  • IV procainamide 10mg/kg over 20min
  • IV amiodarone 5mg/kg over 20 min

Outcomes

Primary - Adverse Cardiac events within study period (40min)

  1. Clinical signs of peripheral hypoperfusion,
  2. Heart failure signs: dyspnea at rest and/or orthopnea associated with signs of pulmonary congestion (presence or increase of rales and/or decrease in blood oxygen saturation),
  3. Severe hypotension defined as systolic blood pressure ≤70 mmHg if the pre-treatment systolic pressure was ≤100 mmHg or systolic blood pressure ≤80 mmHg if the pre-treatment systolic pressure was .100 mmHg,
  4. Tachycardia acceleration of 20 bpm of its mean value, and
  5. Appearance of fast polymorphic VT.

 Secondary: Resolution of arrhythmia within study period (40min).  Adverse Cardiac events within observation period (24h)

Results

Total patients

  • Procainamide n=33
  • Amiodarone n=29

Primary outcome: MACE over 40min (p=0.006)

  • Procainamide n=3 (9%) - Severe Hypotension n=3
  • Amiodarone n= 12 (41%) -  Severe Hypotension n=7, Hypoperfusion n=3 Pulmonary Edema n=2

Secondary Outcome: Tachycardia resolution over 40 min (p=0.026)

  •             Procainamide n= 22 (67%)
  •             Amiodarone n=11 (38%)

Secondary Outcome: MACE over 24 hours (p=0.24)

  •             Procainamide n=6 (18%)
  •             Amiodarone n=9 (31%)

Discussion

This trial had a strong study design as a multicenter, prospective RCT comparing IV amiodarone vs procainamide for treatment of stable wide complex tachycardia. It also had well defined inclusion/exclusion criteria and endpoints. We felt that the outcomes measured were relevant to clinical practice, and set out to answer the appropriate clinical question. However, despite its methods, this study is plagued by limitations which hinder the results from being readily incorporated into everyday practice.

As the authors found out, stable wide complex tachycardia is a rare disease process. This resulted in a very low sample size of 74 enrolled patients, and resulted in an even smaller 62 being analyzed. This was at odds with the authors’ own power calculations which called for 302 patients to detect a 15% difference between the two groups (based on prior observational studies). Given the small sample size, we found that this study has a high fragility index. This alone limits the validity of the results, despite having achieved statistical significance in several of the outcome findings.

Next, the dosing regimen for amiodarone is quite high. At 5mg/kg, an average 70kg individual would receive 350mg of amiodarone over 20 minutes. This is well above the ACLS guideline of 150mg. Procainamide did not suffer from the same increased dosing, at 10mg/kg actually falling under the ACLS recommended 17mg/kg which may have led to increased MACE in the amiodarone group. Though the authors claim that increased amiodarone dosing should also have led to more efficacy in the amiodarone group, this is unsupported by evidence.

There were also some slight differences in the demographics of each group which are suspect for the open label nature of the study possibly affecting medication choice. The subgroup analysis, while an interesting discussion, is even further underpowered than the primary study, in addition to suffering from typical subgroup biases.

Clinical Impact

This study asked an interesting question- should we be using amiodarone first line for wide complex tachycardia? We feel that while the study was flawed, it does raise a reasonable suspicion that the days of dogmatic use of amiodarone may be numbered. While it is a bit of a stretch to conclude procainamide should be first line instead, it may be worthy of consideration as another tool in your armamentarium of antiarrhythmics. Still, all of these patients are quick to decompensate, so you will want to prepare for the worst- always keep the defib pads on the patient and have a backup plan in place!

Further Reading

Kudenchuk, P. J., Brown, S. P., Daya, M., Rea, T., Nichol, G., Morrison, L. J., et al. (2016). Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. New England Journal of Medicine, 374(18), 1711–1722. http://doi.org/10.1056/NEJMoa1514204

Methodology

Multi-center, randomized, double-blind, placebo-controlled trial with 1:1:1 allocation of amiodarone, lidocaine, and placebo

    There was adequate concealment and randomization.

Inclusion criteria: >18 yo, non traumatic out-of-hospital cardiac arrest AND shock-refractory Vfib or VTac, and with IV or IO access

Exclusion criteria: already received open-label IV lidocaine or amiodarone or had known hypersensitivity

Data Analysis

Pre-specified that the primary outcome would be looked at in a per-protocol population (must actually meet inclusion criteria and have confirmed Vtac or Vfib on prehospital ECG)

Outcomes

Primary: Survival to hospital discharge in amiodarone patients vs placebo (powered study to detect 6.3% difference in survival)

Secondary

  • Survival to hospital discharge with favorable neurologic status (Rankin less than or equal to 3)
  • #of Defibrillations after trial drug
  • ROSC at time of hospital arrival
  • Survival to hospital admission

Subgroups (pre-specified) - Witnessed cardiac arrest (none, bystander, EMS), bystander CPR, route of administration

Results

Per-Protocol Patient Group Characteristics 

  • Amiodarone - 974 patients
  • Lidocaine - 993 patients
  • Placebo - 1059 patients

Generally well matched in terms of known prognostic factors.  There was slightly more EMS witnessed arrest, bystander-initiated PAD shock, and decreased time to first EMS arrival in the amiodarone group as compared to the lidocaine or placebo arms.

Primary Outcome

Survival to Hospital Discharge - Absolute difference 3.2% (-0.4% to 7.0, p=0.08)

  • Amiodarone - 24.4%
  • Lidocaine - 23.7%
  • Placebo - 21%

Secondary Outcomes of Interest

Survival to discharge with favorable neurologic outcome

  • Amiodarone - 18.8%
  • Lidocaine - 17.5%
  • Placebo - 16.6%

ROSC at ED arrival

  • Amiodarone - 35.9%
  • Lidocaine - 39.9%
  • Placebo - 34.6%

Survival to Hospital Admission - 6% difference between Amiodarone and Placebo (p=0.01)

  • Amiodarone - 45.7%
  • Lidocaine - 47%
  • Placebo - 39.7%

Discussion

Take a listen to the podcast for a more complete version but the tl:dl version breaks down something like this:

This was a well conducted study, methodologically only limited by it’s use of a per-protocol analysis of the data and large numbers of drop out from each group as compared to the intention-to-treat group.  That said, the per-protocol groups were well matched for known prognostic factors and our confidence in point-estimate effect given by this trial is high.

Strictly speaking, amiodarone and lidocaine don’t improve survival to discharge from the hospital but do result in better survival to hospital admission.  This isn’t the final word on this subject.  Because they improve survival to hospital admission, as in-hospital patient treatments continue to improve, anti-arrhythmic medications may be found, in the future, to improve survival to discharge.

Helpful FOAMed Links

Ageliki Laina et al. Amiodarone and cardiac arrest: Systematic Review and meta-analysis. International Journal of Cardiology. 2016. PMID: 27434349

Study Design

This is a meta-analysis and systematic review that included 4 randomized control studies and 6 retrospective observational studies.  The researches were trying to determine outcomes in cardiac arrest in patients that received amiodarone vs placebo, amiodarone vs lidocaine and amiodarone vs nifekalant.

Methods

The researchers searched MEDLINE via PUBMED and the Cochrane Library from 1940 to March 2016 without language restrictions.  They initially identified 1663 studies but included 10 total studies that included RCT and observational studies.  5326 patients were included in those 10 studies.

Outcomes

Primary outcomes included:

  1. ROSC
  2. Survival to ICU for OHCA
  3. 24 hour survival for IHCA
  4. Survival to hospital discharge
  5. Neurologic outcome at the time of discharge

Results

1.  7 studies were included in the primary outcome analysis of ROSC obtained after cardiac arrest with the initial rhythm of ventricular tachycardia or pulseless ventricular fibrillation prior to hospital admission. When all of the studies were included in the analysis, amiodarone actually seemed to decrease the incidence of ROSC by 22%. The researchers did so a sub-analysis that only included randomized control studies that did show a statistically significant improvement in ROSC prior to hospital admission.

2.  6 studies were included in the primary analysis of survival to hospital admission for patients that suffered out of hospital cardiac arrest (OHCA). Amiodarone was shown to improve the incidence of survival to hospital admission compared to other interventions (placebo, lidocaine, nifekalant)

3.  Survival at 24 hours for patients with in-hospital cardiac arrest (IHCA) was included in only 3 studies. There was no improvement in survival noted at 24 hour post ROSC in patients that received amiodarone. No subgroup analyses were included due to such a small population size in this primary outcome.

4.  The largest amount of patients were included in the primary outcome of survival to hospital discharge. 9 of the 10 studies included this as a primary outcome. When the data was analyzed, there appeared to be no improvement in survival to hospital discharge in patients that received amiodarone. In the discussion section, the researchers did note that survival to hospital discharge actually improved in the amiodarone group when they included only RCT data.

5.  The last primary outcome looked at neurologic outcome at the time of hospital discharge. Amiodarone was not associated with improved neurologic status at the time of hospital discharge. There were very limited studies so no further analyses were completed.

Further Reading