a b s t r a c t

Background: With recent negative studies of amiodarone and lidocaine for cardiac arrest, research into other an- tiarrhythmics is warranted. Literature on procainamide in cardiac arrest is limited. We evaluated procainamide for Out-of-hospital cardiac arrests from the Resuscitation Outcomes Consortium (ROC).

Methods: We included all ROC Epistry 3 OHCAs with an Initial shockable rhythm that received an antiarrhythmic. We stratified cases by antiarrhythmic: procainamide, amiodarone, or lidocaine. The outcomes were prehospital return of spontaneous circulation (ROSC), ROSC in the ED, and survival to hospital discharge. We defined propen- sity scores based on possible confounders utilizing 1:1 propensity score matching to compare procainamide to amiodarone and lidocaine. We analyzed the matched data using logistic regression. We also used multivariable logistic regression to evaluate the association between antiarrhythmic and outcomes.

Results: 3087 subjects met inclusion criteria; 51 patients received only procainamide, 1776 received amiodarone, and 1418 received lidocaine. On Propensity score analysis and compared to procainamide, amiodarone had sim- ilar prehospital ROSC (OR 0.7, 95% CI 0.3-1.8), ED ROSC (OR 0.6, 95% CI 0.3-1.3), and survival (OR 1.0, 95% CI

0.3-3.1). Lidocaine also had a similar prehospital ROSC (OR 0.9, 95% CI 0.4-2.2), ED ROSC (OR 1.2, 95% CI 0.5-2.7), and survival (OR 1.4, 95% CI 0.5-4.0). However, using Multivariable regression, amiodarone had lower prehospital ROSC than procainamide (aOR 0.3, 95% CI 0.1-0.6).

Conclusions: While associated with increased prehospital ROSC when compared with amiodarone using multi- variable regression, procainamide otherwise had similar prehospital ROSC, ED ROSC, and survival. The role of procainamide in OHCA remains unclear.

(C) 2022

1. Introduction

Out-of-hospital cardiac arrest (OHCA) remains a leading cause of death in the United States. While cardiac arrest with a shockable rhythm, such as Ventricular tachycardia or ventricular fibrillation (VF), predicts improved outcomes, less than a third of OHCA victims with a shockable rhythm survive [1].

Traditionally, amiodarone and lidocaine are considered the first line pharmacologic treatments for shockable rhythm cardiac arrest. Recent trials failed to identify a Survival benefit for lidocaine or amiodarone

* Corresponding author at: Department of Emergency Medicine, McGovern Medical School of UTHealth at Houston, 6431 Fannin Street, JJL 475, Houston, TX 77030, United States of America.

E-mail address: [email protected] (R. Huebinger).

[2,3], and evaluation of Alternative agents may be warranted. Procain- amide is another antiarrhythmic that has historically been used in OHCA but is not currently recommended [4]. While previous studies of procainamide yielded mixed results, the research is severely limited and dated [5,6]. However, the PROCAMIO trial found procainamide to be superior to amiodarone at controlling stable VT, suggesting that pro- cainamide may be more effective at controlling ventricular arrhythmias [7].

Given the favorable findings of the PROCAMIO trial in addition to the paucity of literature studying procainamide for OHCA, we sought to evaluate the use of procainamide in the Resuscitation Outcome Consor- tium (ROC). We compared procainamide to amiodarone and lidocaine, evaluating its association with return of spontaneous circulation (ROSC) and survival.

https://doi.org/10.1016/j.ajem.2022.02.031

0735-6757/(C) 2022

1. Materials and methods
   1. Data source

We performed a retrospective study of cardiac arrest victims in the ROC Cardiac Epistry Version 3 dataset. ROC was a cardiac arrest research network consisting of research centers with their affiliated hospitals and EMS agencies across North America. ROC Epistry 3 prospectively enrolled cardiac arrest victims from April 1, 2011 to June 30, 2015. The ROC Epistry 3 has been previously described [8,9].

The study was approved by the institutional review board and ROC.

• 1. Study population

We evaluated all adult, OHCA victims with an initial shockable rhythm and received an antiarrhythmic from the ROC Epistry 3 from April 2011 to June 2015.

• 1. Study variables and outcomes

We defined our primary exposure as antiarrhythmic received; pro- cainamide, lidocaine without procainamide, and amiodarone without procainamide. We defined patient and cardiac arrest characteristics as age, sex, race, bystander witnessed arrest, public location of arrest, by- stander initiated CPR, bystander Automated external defibrillator placement, emergency medical service (EMS) response time, and duration of cardiac arrest. We defined outcomes as ROSC at ED ar- rival and survival to hospital discharge. We defined our outcomes as prehospital ROSC (reported ROSC during prehospital resuscitation or re- ported arrive for transport), ROSC at ED arrival, and survival to hospital discharge.

• 1. Statistical analysis

We first stratified patients based on antiarrhythmic given. Patients given both amiodarone and lidocaine were included in both the amio- darone and lidocaine groups as each group was compared individually to procainamide. We compared patient and cardiac arrest characteris- tics between the groups.

We then utilized a 1:1 propensity score analysis, matching subjects based on patient and cardiac arrest characteristics, comparing amioda- rone to procainamide and lidocaine to procainamide. We compared the matched groups using logistic regression.

We additionally created a multivariable logistic regression evaluat- ing the association between antiarrhythmic and outcomes. Due to sam- ple size limitations and model fit issues, we adjusted for as many variables that model fit would allow. Covariables were added incremen- tally with preference for variables that might have the largest impact on outcomes in order to obtain the most robust analysis possible while still achieving model fit. We adjusted the multivariable logistic regression for race, bystander witnessed arrest, bystander CPR, EMS response time, and duration of cardiac arrest.

Given a large number of patients that received both procainamide and lidocaine (43), we performed a two sensitivity analyses. In the

antiarrhythmic; 1776 received amiodarone, 1418 received lidocaine, 158 received lidocaine and amiodarone, and 51 received procainamide, 43 of which received lidocaine as well. Procainamide had a higher rate of white patients than lidocaine, the highest rate of public arrests, and the lowest response time. (Table 1).

Unadjusted rates of prehospital ROSC were 74.5% for procainamide, 81.4% for amiodarone, and 86.4% for lidocaine. Unadjusted ED ROSC rates were 45.1% for procainamide, 37.3% for amiodarone, and 51.9% for lidocaine. Survival rates were 15.7% for procainamide, 19.9% for ami- odarone, and 22.7% for lidocaine. (Table 2).

On propensity score analysis and compared to procainamide, amio- darone was associated with a similar rate of prehospital ROSC (65.2% v 71.8%; OR 0.7, 95% CI 0.3-1.8; 46 cases matched), ED ROSC (34.8% vs

47.8%; OR 0.6, 95% CI 0.3-1.3), and survival (15.2% vs 15.2%; OR 1.0,

95% CI 0.3-3.1). Lidocaine also had a similar rate of prehospital ROSC (65.2% v 71.8%; OR 0.9, 95% CI 0.4-2.2), ED ROSC (52.2% v 47.8%; OR

1.2, 95% CI 0.8-2.3), and survival (19.6% v 15.2%; OR 1.4, 95% CI

0.5-4.0). (Table 2).

Utilizing Multivariable logistic regression models and compared to procainamide, amiodarone was associated with decreased rate of pre- hospital ROSC (aOR 0.3, 95% CI 0.1-0.6), but not ED ROSC (OR 0.7, 95%

CI 0.3-1.6) or survival (aOR 1.2, 95% CI 0.5-2.9). Lidocaine had similar

rates of prehospital ROSC (aOR 0.4, 95% CI 0.2-1.1), ED ROSC (OR 1.3,

95% CI 0.6-2.9), and survival (aOR 1.4, 95% CI 0.5-4.0). (Table 2).

Comparing single medication regimens using univariable logistic re- gression, amiodarone had a similar rate of prehospital ROSC (OR 0.7, 95% CI 0.1-5.3) ED ROSC (OR 0.2, 95% CI 0.0-1.02) and survival (OR

0.8, 95% CI 0.2-3.8). Lidocaine also had a similar rate of prehospital ROSC (OR 1.0, 95% CI 0.1-8.0), ED ROSC (OR 0.4, 95% CI 0.1-2.0), and

survival (OR 0.9, 95% CI 0.2-4.5). Using a propensity score analysis (7 cases matched), the results were similar. (Table 3).

Comparing combination of amiodarone and lidocaine to procain- amide and lidocaine using multivariable logistic regression, there was a similar rate of prehospital ROSC (OR 0.4, 95% CI 0.1-1.1), ED ROSC (1.1, 95% 0.4-3.2), and survival (OR 1.3, 95% CI 0.4-4.5). (Table 4).

4. Discussion

In our study evaluating the association of procainamide with out- comes in the ROC Epistry 3, procainamide was linked to a better prehos- pital ROSC when compared to amiodarone when using a multivariable logistic regression model. However, procainamide had a similar rate of ROSC to lidocaine. Prehospital ROSC, ED ROSC, and survival were all sim- ilar on propensity score analysis. Comparing individual medications and combination medication regimens, there were no significant associa- tions with outcomes, but procainamide and procainamide combination regimens had higher rates of ED ROSC.

Previous studies evaluating procainamide for OHCA yielded mixed results with an early study linking procainamide with the highest sur- vival of studied antiarrhythmic [5]. The most recent study evaluating

Table 1

Characteristics of cardiac arrest victims, stratified by antiarrhythmic

first sensitivity analysis, we compared patients that were given only procainamide to those given only amiodarone and those given only li-

Characteristic Procainamide

N = 51

Amiodarone

N = 1776

Lidocaine

N = 1418

docaine using both a univariable logistic regression and the propensity score matched analysis from above. For the second sensitivity analysis, we compared patients given procainamide and lidocaine to those given amiodarone and lidocaine using the above multivariable logistic regression model.

Age^a 58 (48-65) 55 (55-65) 64 (54-74)

Male^b 44 (86.3%) 1488 (85.8%) 1109 (78.2%)

White^b 32 (62.8%) 352/461 (76.4%) 462 (32.6%)

Bystander witnessed^b 34/50 (68.0%) 1258/1738 (72.4%) 1017/1387 (73.3%)

Bystander CPR^b 34 (66.7%) 1030 (58.0%) 880 (62.1%)

Bystander AED^b 6 (11.8%) 114 (6.4%) 124 (8.7%)

Public Location^b 22 (43.1%) 568 (32.1%) 432 (30.6%)

3. Results

EMS response time in seconds^a

287 (214-345) 346 (270-428) 319 (246-409)

Of 120,306 adult cardiac arrests, 67,204 were treated by EMS, 14,005 of which had an initial shockable rhythm and 3087 an received an

^a Reported as median (IQR).

^b Reported as n(%).

Table 2

Outcomes of cardiac arrest victims, stratified by antiarrhythmic given

Table 4

Outcomes of cardiac arrest victims, comparison of patients given more than one antiar- rhythmic

Prehospital ROSC ED ROSC Survival

OHCA outcomes for full cohorta Procainamide	38 (74.5%)	23 (45.1%)	8 (15.7%)	Prehospital ROSC	ED ROSC	Survival
Amiodarone	1445 (81.4%)	661 (37.3%)	353 (19.9%)	OHCA Outcomes for patients give 2 medicationsa
Lidocaine	1225 (86.4%)	736 (51.9%)	322 (22.7%)	Procainamide & lidocaine 31/43 (72.0%)	17 (39.5%)	6 (14.0%)

Adjusted odds of outcomes for full cohort^b

Amiodarone vs Procainamide 0.3 (0.1-0.6) 0.7 (0.3-1.6) 1.2 (0.5-2.9)

Lidocaine & amiodarone 118/158 (74.7%) 46 (29.10%) 26 (16.5%)

Adjusted odds of outcomes^b

Lidocaine vs Procainamide 0.4 (0.2-1.1) 1.3 (0.6-2.9) 1.4 (0.6-3.3)

OHCA outcomes for propensity-matched cohort^c

Amiodarone & procainamide vs Amiodarone & lidocaine

^a Reported as N (%).

0.4 (0.1-1.1) 1.1 (0.4-3.2) 1.3 (CI 0.4-4.5)

^b Reported as adjusted odds ratios (95% CI); adjusted the multivariable logistic regres- sion for race, bystander witnessed arrest, bystander CPR, EMS response time, and duration of cardiac arrest.

Procainamide	33 (71.8%)	22 (47.8%)	7 (15.2%)
Amiodarone	30 (65.2%)	16 (34.8%)	7 (15.2%)
Lidocaine	32 (69.6%)	24 (52.2%)	9 (19.6%)
Propensity-matched odds of outcomesd
Amiodarone vs Procainamide 0.7 (0.3-1.8)		0.6 (0.3-1.3)	1.0 (0.3-3.1)
Lidocaine vs Procainamide 0.9 (0.4-2.2)		1.2 (0.5-2.7)	1.4 (0.5-4.0)

^a Reported as N (%).

^b Reported as adjusted odds ratios (95% CI); adjusted the multivariable logistic regres- sion for race, bystander witnessed arrest, bystander CPR, EMS response time, and duration of cardiac arrest.

^c Reported as N (%); propensity matched for age, sex, race, public location of arrest, bystander witnessed, bystander CPR, bystander AED application, EMS response time, and duration of cardiac arrest; 46 cases were matched that had arrest time available.

^d Reported as odds ratio (95% CI).

procainamide found that procainamide use was associated with de- creased survival (aOR, 0.51, 95% CI 0.32-0.79). However, procainamide was given as a second line agent in the study, so their results are subject to immortality bias with only prolonged cardiac arrest victims receiving procainamide [10]. As prolonged cardiac arrest is associated with worse survival [11], this could explain the decreased survival.

The PROCAMIO trial compared procainamide to amiodarone for sta- ble monomorphic VT, and found procainamide to be more effective at terminating VT (67% v 38%, OR 3.3, 95% CI 1.2-9.3) and had a lower

MACE (9% v 41% OR 0.1, 95% CI 0.03-0.6). Additionally, studies have found procainamide to be superior to lidocaine at terminating mono- morphic ventricular tachycardia [12,13]. While another retrospective study failed to demonstrate a benefit of procainamide for termination of monomorphic VT [14], these recent positive findings beg the question if procainamide might be a superior at treating ventricular arrhythmias

Table 3

Outcomes of cardiac arrest victims, comparison of single medication regimens; excluding cardiac arrests with more than one antiarrhythmic given

Prehospital ROSC ED ROSC Survival

during cardiac arrest as well. Procainamide’s role in OHCA is felt to be limited due to slow infusion rate though; however, there are no studies to support this recommendation [4], and its superiority as an antiar- rhythmic may outweigh this limitation. Particularly as recent trials sug- gest that lidocaine and amiodarone may not improve survival after shockable rhythm cardiac arrest [2,3], investigation into alternative agents is warranted.

In animal studies, procainamide has been found to have different physiological effects on the heart than amiodarone or lidocaine. In a ca- nine model, lidocaine administration during ventricular fibrillation led to increased defibrillation threshold as well as decreased cardiac output when compared to placebo, while procainamide had no effect of defi- brillation potential or cardiac output [15]. Mackin et al. also found pro- cainamide to have no effect cardiac contractility, while amiodarone administration decreased cardiac contractility [16]. Results on the effect of amiodarone on defibrillation threshold however remain mixed [17]. These physiological differences may translate into real world advan- tages in treating cardiac arrest.

The crux of studying procainamide in OHCA is the lack of patient data. With the AHA no longer recommending procainamide, any retro- spective analyses of procainamide will likely include a limited number of patients and will be subject to significant bias related to the reason agencies choose to give procainamide. In fact, while preparing this analysis, we also evaluated the NEMSIS and ESO prehospital databases, neither of which possessed an adequate number of procainamide ad- ministrations to be studied. The solution to this problem would be a prospective trial, but without retrospective data supporting procain- amide in OHCA, there is currently not equipoise for a prospective study of procainamide. Despite promising animal and non-cardiac ar- rest data, the path to appropriately studying procainamide in cardiac ar-

OHCA Outcomes for patients given a single medicaiton Procainamide 7/8 (87.5%) Amiodarone 1287/1618 (82.0%)		a 6 (75.0%) 615 (38.1%)	2 (25.0%) 327 (20.2%)	rest appears challenging. So, while studies such as this are imperfect in many ways, this analysis of ROC data may be the only remaining oppor-
Lidocaine	1124/1.303 (87.3%)	707 (54.3%)	302 (23.2%)	tunity to study procainamide in US OHCA using a modern dataset.

Unadjusted odds of outcomes^b

Amiodarone vs Procainamide

0.7 (0.1-5.3) 0.2

(0.0-1.02)

0.8 (0.2-3.8)

Our sample size was limited, but we found it surprising that procain- amide was associated with improved ROSC when compared to amioda- rone in our main analysis. Also, while not significant, both primary

Lidocaine vs Procainamide 1.0 (0.1-8.0) 0.4 (0.1-2.0) 0.9 (0.2-4.5)

Propensity matched comparison of single medications^a

Procainamide	6 (85.7%)	5 (71.4%)	1 (14.2%)
Amiodarone	5 (71.4%)	4 (57.1%)	1 (14.2%)
Lidocaine	6 (85.7%)	6 (85.7%)	1 (14.2%)

Propensity-matched odds of outcomes for single medications^c

analyses favored procainamide over amiodarone for prehospital ROSC and ED ROSC as well as over lidocaine for prehospital ROSC. While both models had trends toward favoring amiodarone and lidocaine over procainamide for survival, this trend of better ROSC but worse sur- vival might be expected from superior antiarrhythmic that is given late in cardiac arrest. Additionally while not significant, rates of ED ROSC

Amiodarone vs Procainamide

0.4 (0.0-6.1) 0.5 (0.1-4.9) 1.0 (CI

0.1-20.0)

were higher comparing single medication and combination medication

regimens with procainamide. Prospective randomize trials are not likely

Lidocaine vs Procainamide 1.0 (0.1-20.0) 2.4 (0.0-6.1) 1.0 (0.1-20.0)

^a Reported as N (%).

^b Reported as odds ratio (95% CI).

^c Reported as N (%); propensity matched for age, sex, race, public location of arrest, bystander witnessed, bystander CPR, bystander AED application, EMS response time, and duration of cardiac arrest; 7 cases were matched that had arrest time available.

indicated based on these preliminary results, but further evaluation of procainamide may be warranted. Datasets from other practice settings or countries where procainamide is used more frequently may allow for further investigation of the utility of procainamide in shockable rhythm cardiac arrest.

4.1. Limitations

Our study is limited due to small sample size and retrospective na- ture. Additionally, it is likely that procainamide is used by a subset of agencies participating in ROC, which could bias our results if these were better preforming agencies. Adjusting for clustering due to agency was not possible due to our small sample size though. There may be other factors influencing the choice to give procainamide, but by using multiple models, we attempted to minimize bias. We could not adjust for time to antiarrhythmic administration or order of antiarrhythmic administration, two important factors that likely impact outcomes. However, if procainamide was given as a second line agent in most cases, one would expect recipients of procainamide to have experienced worse outcomes. Procainamide did have a trend toward worse survival, and a better powered study may have identified an association with lower survival. Additionally, many of the patients given procainamide were also given lidocaine, so this could confound the results.

5. Conclusion

While associated with increased prehospital ROSC when compared with amiodarone in one of our models, no other analysis identified an association between procainamide and improved outcomes. The role of procainamide in OHCA remains unclear, but further study is war- ranted.

Prior presentations

None.

Funding sources/Disclosures

None.

CRediT authorship contribution statement Ryan Huebinger: Conceptualization, Data curation, Formal analysis,

Investigation, Methodology, Supervision, Writing - original draft, Writ- ing - review & editing. John A. Harvin: Data curation, Methodology, Writing - original draft. Hei Kit Chan: Writing - review & editing, Data curation, Conceptualization. Ahamed Idris: Conceptualization, Writing - review & editing. Benjamin Cooper: Writing - review & editing, Conceptualization. Jonathan Giordano: Conceptualization, Writing - review & editing. Henry E. Wang: Writing - review & editing, Writing - original draft, Conceptualization.

Acknowledgments

None.

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