European Heart Journal: Acute Cardiovascular Care (2023) 12, 2–11 ORIGINAL SCIENTIFIC PAPER

https://doi.org/10.1093/ehjacc/zuac154 Acute Coronary Syndromes

LidocAine Versus Opioids In MyocarDial

infarction: the AVOID-2 randomized
controlled trial
Himawan Fernando 1,2,3, Ziad Nehme4, Catherine Milne4, Jessica O’Brien1,

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Stephen Bernard3,4, Michael Stephenson3,4, Paul S. Myles3,5, Jeffrey Lefkovits3,6,
Karlheinz Peter 1,2,3, Angela Brennan3, Diem Dinh3, Emily Andrew4,
Andrew J. Taylor1, Karen Smith3,4†, and Dion Stub1,2,3,7*†, on behalf of AVOID 2
Investigators‡
1
Department of Cardiology, Alfred Hospital, 55 Commercial Rd, Melbourne, VIC 3004, Australia; 2Atherothrombosis Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road,
Melbourne, VIC 3004, Australia; 3Monash University, School of Public Health and Preventive Medicine, 553 St Kilda Road, Melbourne, VIC 3004, Australia; 4Centre for Research and
Evaluation, Ambulance Victoria, 3785 Manningham Road, Doncaster, VIC 3108, Australia; 5Department of Anaesthesiology and Perioperative Medicine, The Alfred and Monash University,
55 Commercial Road, Melbourne, VIC 3004, Australia; 6Department of Cardiology, Royal Melbourne Hospital, 300 Grattan St, Parkville VIC 3050, Australia; and 7Department of Cardiology,
Western Health, Eleanor St, Footscray, VIC 3011, Australia

Received 17 September 2022; revised 17 November 2022; accepted 6 December 2022; online publish-ahead-of-print 10 December 2022

See the editorial comment for this article ‘Efficacy and safety of lidocaine vs. opioid analgesics in acute coronary syndromes’, by M. Galli and
D. J. Angiolillo, https://doi.org/10.1093/ehjacc/zuac157.

Aims Opioid analgesia has been shown to interfere with the bioavailability of oral P2Y12 inhibitors prompting the search for safe
and effective non-opioid analgesics to treat ischaemic chest pain.
.............................................................................................................................................................................................
Methods The lidocAine Versus Opioids In MyocarDial infarction trial was a prospective, Phase II, prehospital, open-label, non-infer­
and results iority, randomized controlled trial enrolling patients with suspected STEACS with moderate to severe pain [numerical rating
scale (NRS) at least 5/10]. Intravenous lidocaine (maximum dose 300 mg) or intravenous fentanyl (up to 50 µg every 5 min)
were administered as prehospital analgesia. The co-primary end points were prehospital pain reduction and adverse events
requiring intervention. Secondary end points included peak cardiac troponin I, cardiac MRI (cMRI) assessed myocardial in­
farct size and clinical outcomes to 30 days. A total of 308 patients were enrolled. The median reduction in pain score (NRS)
was 4 vs. 3 in the fentanyl and lidocaine arms, respectively, for the primary efficacy end point [estimated median difference
−1 (95% confidence interval −1.58, −0.42, P = 0.5 for non-inferiority, P = 0.001 for inferiority of lidocaine)]. Adverse events
requiring intervention occurred in 49% vs. 36% of the fentanyl and lidocaine arms which met non-inferiority and superiority
favouring lidocaine (P = 0.016 for superiority). No significant differences in myocardial infarct size and clinical outcomes at 30
days were seen.
.............................................................................................................................................................................................
Conclusion IV Lidocaine did not meet the criteria for non-inferiority with lower prehospital pain reduction than fentanyl but was safe
and better tolerated as analgesia in ST-elevation myocardial infarction (STEMI). Future trials testing non-opioid analgesics in
STEMI and whether opioid avoidance improves clinical outcomes are needed.
.............................................................................................................................................................................................
Trial CTRN12619001521112p
Registration
---------------------------------------------------------------------------------------------------------------------------------------------------------------

* Corresponding author. Tel: +61 39 076 2000, Fax: +61 39 076 2461, Email: dion.stub@monash.edu
†
Denotes equally contributing senior authors.
‡
A full list of AVOID-2 investigators is provided in the Supplementary Appendix.
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
The AVOID-2 trial
Graphical Abstract
.............................................................................................................................................................................................
Keywords STEMI • Analgesia • Ischaemic chest pain • Opioid–P2Y12 inhibitor interaction • Lidocaine
Introduction
For over half a century, opioids have remained the analgesic class of
choice for the treatment of ischaemic chest pain in myocardial infarc­
tion. The relief of pain is thought to reduce myocardial oxygen demand
through a decrease in sympathetic response, resulting in decreased sys­
temic vascular resistance and heart rate.1 Despite the widespread use
of opioids in ST-elevation myocardial infarction (STEMI), there is limited
evidence from clinical trials of benefit.
More recently, an interaction has been reported between opioids
and oral P2Y12 inhibitors such as ticagrelor which are a cornerstone
of therapy in STEMI.2 The proposed mechanism is opioid-induced gas­
troparesis which impairs the absorption of all oral P2Y12 inhibitors.
Pharmacological studies suggest this interaction delays the onset of
antiplatelet activity and reduces early plasma levels of all oral P2Y12 in­
hibitors.3–5
3
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Retrospective analysis of the CRUSADE registry suggests this inter­
action may be associated with a higher rate of myocardial infarction and
death although the overall body of evidence from observational studies
is mixed.6–8
This established drug interaction with potential clinical implications
presents for the first time an impetus for considering non-opioid an­
algesics in the treatment of ischaemic chest pain. Intravenous lidocaine
appears to be a promising non-opioid analgesic to use in this setting.
We recently demonstrated that intravenous lidocaine was well toler­
ated as procedural analgesia in patients undergoing coronary angiog­
raphy and percutaneous coronary intervention (PCI) whilst
improving early ticagrelor plasma levels and antiplatelet activity when
compared with intravenous fentanyl.5
The AVOID-2 trial seeks to determine if opioids remain the most ap­
propriate analgesic class to use in STEMI by comparing the efficacy and
safety of intravenous fentanyl to lidocaine.
4 H. Fernando et al.
Methods
Study design and patient population
The lidocAine Versus Opioids In MyocarDial Infarction (AVOID-2) study
was a prospective, Phase II, prehospital, open-label, non-inferiority, rando­
mized controlled trial conducted by Ambulance Victoria and Monash
University in metropolitan Melbourne, Victoria, Australia. The trial design
was registered prospectively (ACTRN12619001521112p) and has been re­
ported previously.9
Ambulance Victoria paramedics screened patients aged 18 years and older
with suspected ST-elevation Acute Coronary Syndromes (STEACSs) and a
verbal pain score of at least 5 of 10 [based on the numerical rating scale
(NRS)] for inclusion in the AVOID-2 trial. There was no defined time limit
from symptom onset to randomization. Study details have been previously
reported.9 The exclusion criteria included regular opioid use or administra­
tion prior to randomization, allergy to opioids or lidocaine, bradycardia (heart
rate <50 beats per minute), out-of-hospital cardiac arrest or cardiogenic
shock (systolic blood pressure <90 mmHg), past history of epilepsy, renal
or liver failure or patients dependent on others for activities of daily living.
The AVOID-2 trial was reviewed and approved by the Alfred Hospital
Human Research and Ethical Committee (HREC reference 258/19) includ­
ing the process of non-consent randomization for trials involving the emer­
gent treatment of pain in the prehospital setting, which has previously been
described in detail.9
A data and safety monitoring committee was established for the study for
the blinded adjudication and reporting of all serious adverse events as pre­
viously reported.9
Study intervention
Patients allocated to lidocaine received a dose of 50 mg IV administered
over 2 min if the patient’s weight was <70 kg or 100 mg IV over 2 min if
at least 70 kg. An additional 50–100 mg was then administered, if required,
every 15 min thereafter depending on weight as above, with a maximum
dose of 150 mg if <70kg and 300 mg if at least 70 kg. If satisfactory analgesia
was not achieved after the maximum dose of lidocaine had been adminis­
tered, the treatment protocol allowed cross-over to the fentanyl arm.
Fixed lidocaine dosing of 50–100 mg was chosen to assist in the admin­
istration of IV lidocaine in the prehospital setting in this emergency scenario
where 100 mg ampoules of IV lidocaine were available in the Ambulance.
This was deemed to be a safe dose that could be repeated every 15 min
and for most patients would approximate 0.75–2 mg/kg which has been
previously shown to provide therapeutic analgesic effects.10–12
Patients allocated to fentanyl received up to 50 µg of fentanyl IV every
5 min as required to achieve analgesia which reflects the current
Ambulance Victoria clinical practice guideline and therefore required min­
imal training or change to established practice.
As per current Ambulance Victoria guidelines, pain scores obtained utiliz­
ing a verbally reported NRS were recorded approximately every 5 min during
the prehospital transfer from initial patient contact to hospital handover. Due
to the differing characteristics of the study medication administration, para­
medics were not blinded to treatment allocation. Additionally, paramedics re­
corded clinical history and comorbidities, vital signs during care, and any
adverse reactions or complications that occurred in an electronic patient
care record based on a clinical assessment or patient reporting of symptoms.
On completion, these patient care records were uploaded to a central data
warehouse (Victorian Ambulance Clinical Information System).
The intervention ceased on arrival to hospital emergency departments.
Study end points
The co-primary efficacy end point for the study was the median reduction in
pain based on a verbal NRS at arrival to hospital. The co-primary safety end
point concerned patients with adverse drug reactions in both groups re­
quiring pharmacological management, for example, bradyarrhythmia in
the lidocaine arm requiring atropine, and respiratory depression in the fen­
tanyl arm requiring naloxone. Milder side effects such as nausea, requiring
antiemetic administration, were also considered to be adverse events.
Prehospital secondary end points included the proportion of patients re­
porting no to mild pain (NRS: 0–4) on arrival to the hospital in both groups,
the proportion of patients requiring rescue opioids in the lidocaine group,
the median pain score on arrival to the hospital in both groups, the
proportion of patients with at least 1 point reduction in pain score in
each group, the proportion of patients with significant pain reduction de­
fined by 2 or more points in each group, ventricular fibrillation (VF)/ven­
tricular tachycardia (VT) requiring intervention in both groups, and all
adverse events related to lidocaine or fentanyl administration.
Coronary angiography
In the subgroup of patients receiving primary PCI, the following end points were
also assessed; infarct size measured by peak troponin I (cTnI), pre-PCI TIMI flow
and procedural characteristics, in-hospital outcomes including survival to hos­
pital discharge, stent thrombosis, VT/VF, cardiogenic shock and stroke.
Thirty-day outcomes, including investigator-reported major adverse car­
diac events (MACEs defined as all-cause mortality, myocardial infarction,
unplanned revascularization, stroke, and heart failure), all-cause mortality,
and major adverse cardiac and cerebrovascular events (MACCEs) defined
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as all-cause mortality, myocardial infarction, stroke, and major bleeding)
were also evaluated by investigators blinded to treatment allocation.
Cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging (cMRI) investigations were performed
through a core laboratory, blinded to participant treatment allocation and
clinical data, located at The Alfred Hospital, Melbourne, Australia ∼30 days
after enrolment in the AVOID-2 study as previously described.9
Data collection
The AVOID-2 study utilized prehospital, baseline, clinical, angiographic, and
follow-up data via the Victorian Ambulance STEMI Quality Initiative, the
Ambulance Victoria Data Warehouse and Victorian Cardiac Outcomes
Registry databases which have existing collaboration agreements as previ­
ously reported.9 Identifiable data underlying this article cannot be shared
publicly due to the need to maintain the privacy of individuals that partici­
pated in the study. De-identified data will be shared on reasonable request
to the corresponding author.
Statistical analysis
Non-inferiority for the co-primary efficacy end point was established based
on a non-inferiority margin of the lower 95% confidence interval bound to
be no greater than minus one point on the NRS for a median reduction in
pain at arrival to hospital in patients receiving intravenous lidocaine vs. intra­
venous fentanyl. For the co-primary safety end point of adverse drug reac­
tion requiring pharmacological intervention, non-inferiority was met if the
upper bound of the 95% confidence interval was <5% for the absolute
risk difference between intravenous lidocaine and intravenous fentanyl (in­
feriority margin). The trial was considered positive if both co-primary end
points met the non-inferiority criteria at a significance level of <0.05.
All patients allocated to each group comprised the intention-to treat
population for all primary and secondary analyses. A pre-specified per-
protocol analysis for the co-primary end points was also performed where
patients crossing over in the lidocaine arm to fentanyl were excluded, as a
supplementary analysis. Data analyses were performed using the statistical
package STATA version 17 (StataCorp. 2021. Stata Statistical Software:
Release 17. College Station, TX: StataCorp LLC) as previously described.9
For the co-primary and secondary safety and efficacy end points, estimated
median differences between groups were calculated using quantile regres­
sion. Additionally, risk differences and risk ratios for these end points were
determined using binomial regression.
Sample size
The prior AVOID study from our group demonstrated a mean pain reduc­
tion score of 4.1+/−2.5 with opioids in STEMI.13 To calculate the sample
size for this non-inferiority trial, we estimated that a total sample size of
216 would be needed to reach a statistical power of 90% with the probabil­
ity of Type 1 error being 0.05 as previously described.9 The final sample size
was increased to 300 patients to account for patient dropout and enrol­
ment of patients who do not ultimately have STEMI.
The AVOID-2 trial 5

AVOID-2 lidocAine Versus Opioids In

myocarDial infarction

Enrolment Assessed for eligibility

(n=2,464)

Not meeting inclusion criteria (n=2156)

o Chest pain not ≥ 5/10 (n=1305)
o ECG criteria not consistent for STEMI (n=310)

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o Not transported to metropolitan PCI hospital
(n=44)
o No IV access (n=32)
o Bradycardia <50 bpm (n=57)
o Cardiac arrest/Cardiogenic shock (n=118)
o Opioids given prior to randomisation (n=160)
o Regular opioid use (n=39)
o Allergy to opioids/lignocaine (n=14)
o History of epilepsy, renal or liver failure
(n=29)
o Dependent on others for ADLs (n=48)

Randomized (n=308)
[300 required]

Allocation
Fentanyl (n=154) Lidocaine (n=154)

STEMI confirmation
o Primary PCI performed (n=128) o Primary PCI performed (n=129)
o Not STEMI (n=26) o Not STEMI (n=25)

Eligible (n=253)
MRI substudy Consented (n=125)
Completed (n=114)
[102 required]

Figure 1 The lidocAine Versus Opioids In MyocarDial infarction trial enrolment flow chart. Summary of patient enrolment, treatment allocation,
patients treated with primary PCI and inclusion in the MRI sub-study are presented. ECG = electrocardiogram; STEMI = ST-elevation myocardial in­
farction; PCI = percutaneous coronary intervention; IV = intravenous; bpm = beats per minute; ADL = activities of daily living; MRI = magnetic reson­
ance imaging.

Results with suspected STEACS were screened with 308 patients enrolled
and randomized in the study (see Figure 1). The predominant reason
The AVOID-2 study commenced recruitment in October 2020 with for exclusion was an initial pain score <5/10. One hundred fifty-four
target recruitment achieved in July 2021. A total of 2464 patients patients were allocated to each treatment arm (total 308) with a total
6 H. Fernando et al.

of 257 patients (83%) receiving primary PCI. Of the patients that did
not undergo primary PCI, the final diagnoses at hospital discharge in­ Table 1 Baseline characteristics
cluded non-ST-elevation myocardial infarction (n = 23), pericarditis/ Characteristic Fentanyl Lidocaine
myopericarditis (n = 15), non-cardiac chest pain (n = 7), takotsubo n = 154 n = 154
cardiomyopathy (n = 3) and decompensated heart failure (n = 3). .....................................................................................
Thirty-day follow-up data were available for all patients. There Age in years, mean (SD) 60 (12) 62 (12)
were no protocol violations and 16 (5.2%) protocol deviations re­
Male, n (%) 124 (81) 126 (82)
ported during the recruitment period (see Supplementary material
online, Table S6). BMI (kg/m2), median (IQR) 26.6 (24.5,30.2) 27.7 (25.4, 30.2)
The baseline characteristics of all patients enrolled in the trial are Diabetes on medication, n (%) 26 (17) 25 (16)
presented in Table 1. The proportion of patients receiving primary Hypertension, n (%) 74 (48) 78 (51)
PCI was similar between the two arms (fentanyl 83% vs. lidocaine
Dyslipidaemia, n (%) 69 (45) 68 (44)
84%, P = 0.88). Median door-to-balloon time was 51 min in the fentanyl
arm compared with 47 min in the lidocaine arm. Median symptom to Current or ex-smoker, n (%) 47 (31) 38 (25)
intervention time was 141 min in the fentanyl compared with Family history of premature CAD, 26 (17) 33 (21)

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142 min in the lidocaine arm. Baseline medications are presented in n (%)
Supplementary material online, Table S1 with no significant differences Peripheral vascular disease, n (%) 1 (0.6) 2 (1.3)
seen between the two arms. The median prehospital IV dose of fentanyl
was 110 µg and lidocaine 200 mg (see Supplementary material online, Stroke, n (%) 3 (1.9) 4 (2.6)
Table S2). There was a significantly higher proportion of patients in IHD, n (%) 29 (19) 21 (14)
the fentanyl arm administered antiemetics compared to lidocaine CKD, n (%) 1 (0.6) 4 (2.6)
(44% vs. 28%, P = 0.003). At hospital arrival, vital signs were similar in Killip Class I, n (%) 115 (75) 112 (73)
both groups (see Supplementary material online, Table S2).
Hemoglobin g/L, median (IQR) 143 (130,152) 138 (128,153)
In the primary intention-to-treat analysis, the co-primary end point
of median prehospital pain reduction was an NRS score of 4 compared Platelet count (109/L), median 237 (200,270) 231 (201,264)
with 3 in the fentanyl and lidocaine arms, respectively, which did not (IQR)
meet non-inferiority and showed that lidocaine was inferior to fentanyl Creatinine µmol/L, median (IQR) 79 (71,90) 83 (69,96)
for pain reduction [P = 0.5 for non-inferiority; P = 0.001 for inferiority; Heart failure, n (%) 1 (0.6) 0
estimated median difference −1.0 (95% confidence interval −1.58,
−0.42)]. For the co-primary safety end point, 49% of patients in the fen­ Anxiety/depression, n (%) 16 (10) 13 (8.4)
tanyl arm and 36% in the lidocaine arm experienced adverse events re­ Atrial fibrillation, n (%) 2 (1.3) 4 (2.6)
quiring intervention which met non-inferiority (P < 0.001) and Primary PCI STEMI, n (%) 128 (83) 129 (84)
superiority favouring lidocaine [P = 0.016 for superiority; absolute risk Culprit vessel in
difference −14% (95% confidence interval −25%, −2.7%)]. Overall, IV
lidocaine did not meet the criterion set for non-inferiority in this trial Primary PCI,
which required both co-primary end points to meet the pre-specified n = 257
non-inferiority margins (see Figure 2). LAD, n (%) 66 (52) 67 (52)
The pre-specified secondary efficacy end points are presented in LCx, n (%) 15 (12) 11 (8.5)
Table 2 and Figure 3. A total of 13 patients (8.4%) in the lidocaine group
RCA, n (%) 46 (36) 51 (40)
required rescue opioid administration.
A significantly higher rate of nausea and or vomiting requiring inter­ Other, n (%) 1 (0.8) 0
vention was seen in the fentanyl vs. lidocaine arms (44% vs. 28%, P = Door-to-balloon time in minutes, 51 (36,64) 47 (37,60)
0.003, see Table 3 and Figure 4). median (IQR)
The interventional characteristics in both groups are presented in
Symptom to intervention time in 141 (122,187) 142 (114,190)
Supplementary material online, Table S3 with no significant differences
minutes, median (IQR)
between the groups.
In-hospital peak cTnI levels were similar in both arms (fentanyl 26 SD = standard deviation; BMI = body mass index; IQR = interquartile range; CAD =
638 ng/mL vs. lidocaine 27 000 ng/mL, P = 0.5, see Table 4). coronary artery disease; IHD = ischaemic heart disease; CKD = chronic kidney
In-hospital clinical outcomes were similar between the two arms. disease; LAD = left anterior descending artery; LCx = left circumflex artery; RCA =
Discharge medications were also similar between the two arms (see right coronary artery
Supplementary material online, Table S4). At 30 days, there were no sig­
nificant differences in MACE between the two groups (fentanyl 10% vs.
lidocaine 13%, P = 0.45).
A total of 125 patients consented to cardiac MRI with the main
reason for patients declining cMRI due to the need to travel to a ter­
Discussion
tiary healthcare facility during the COVID-19 pandemic (see Intravenous lidocaine did not meet non-inferiority criteria and was not
Figure 1). There were no significant differences seen between the as effective at reducing ischaemic chest pain in STEMI compared with
two arms in terms of left ventricular ejection fraction or infarct fentanyl. However, compared with IV fentanyl, lidocaine was associated
size (see Table 5). There was a trend towards reduced microvascular with a significantly lower adverse event rate which met the superiority
obstruction in the lidocaine arm (fentanyl 9.1% vs. lidocaine 2%, P = criteria. It may present an analgesic alternative where the trade-off for
0.08). improved tolerability is mildly lower efficacy in pain reduction. We be­
We also performed a per-protocol analysis for the co-primary end lieve that despite the lower pain reduction seen in our study, the
points of prehospital pain reduction and adverse events requiring inter­ improved tolerability coupled with the avoidance of a potential
vention with similar results to the intention-to-treat analysis seen (see drug interaction with oral P2Y12 inhibitors, supports the further consid­
Supplementary material online, Table S5). eration of IV lidocaine as a viable alternative analgesic agent either as a
The AVOID-2 trial 7

Pre-hospital pain reduction Adverse events requiring intervention

*‡ *‡

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-2 -1 0 1 2 -60 -40 -20 0 20 40
Fentanyl better Lidocaine better Lidocaine better Fentanyl better
Dotted line represents non-inferiority margin Dotted line represents non-inferiority margin
*p=0.5 for non-inferiority *p<0.001 for non-inferiority
‡p=0.001 for inferiority ‡ p=0.016 for superiority

Figure 2 Prehospital pain reduction and adverse events requiring intervention. The left panel presents estimated median difference in prehospital
pain reduction and 95% confidence interval between intravenous lidocaine and fentanyl using the NRS. The dotted line represents the pre-specified
non-inferiority margin of −1 point on the NRS. P = 0.5 for non-inferiority, P = 0.001 for inferiority of lidocaine. The right panel presents estimated
risk difference in prehospital adverse events requiring intervention and 95% confidence interval between intravenous lidocaine and fentanyl expressed
as a percentage. The dotted line represents the pre-specified non-inferiority margin of +5%. * Denotes P < 0.001 for non-inferiority; ‡ P = 0.016 for su­
periority between groups.

standalone or in combination with other non-opioid agents such as IV

acetaminophen to use in patients with acute STEMI in the prehospital Table 2 Prehospital pain characteristics
setting. Prehospital pain Fentanyl Lidocaine P-value
With respect to prehospital pain reduction, lidocaine resulted in a characteristics—Numerical n = 154 n = 154
median 3-point reduction in NRS pain scores compared to a 4-point Rating Scale
reduction with fentanyl. The subjective and complex nature of chest ....................................................................................
pain severity has been well established and we recently found no asso­ Initial pain score on paramedic 8 (7,9) 8 (6,9) 0.24
ciation between prehospital chest pain severity in STEMI and biomar­
arrival, median (IQR)
kers of myocardial injury or clinical outcomes.14–16 We also found no
association between achieving complete pain resolution in the prehos­ Final pain score on hospital 3 (1,5) 4 (2,6) 0.001
pital setting and improved clinical outcomes.14 Furthermore, the rela­ arrival, median (IQR)
tionship between the extent of ischaemic injury in myocardial NRS 0–4 on arrival to hospital, 105 (68) 83 (54) 0.01
infarction and chest pain severity is weak with factors such as age and n (%)
comorbidities influencing reported pain severity.17,18 Additionally, pre­
Patients requiring rescue opioids — 13 (8.4) NA
hospital pain relief with analgesia is very much a temporary measure un­
in lidocaine group, n (%)
til definitive revascularization is performed which frequently leads to
durable alleviation of pain. Therefore, perhaps a change in prehospital Proportion of patients with at 143 (93) 122 (79) 0.001
focus to achieving patient comfort rather than aggressive numerical least 1 point reduction in pain
pain reduction with opioids is needed. If greater analgesia is required, score, n (%)
the addition of IV acetaminophen to IV lidocaine may provide a viable Proportion of patients with 2 or 133 (86) 111 (72) 0.002
alternative to fentanyl.19
more-point pain reduction,
We found a significantly higher rate of adverse events requiring
intervention in patients prescribed prehospital IV fentanyl compared n (%)
with IV lidocaine in our trial. This was predominately driven by a sig­
AV = Ambulance Victoria; IQR = interquartile range; NRS = Numerical Rating Scale
nificantly higher rate of nausea and vomiting requiring intervention in
the fentanyl arm. This is consistent with prior studies and has been
commonly reported as a problematic side effect of opioid analgesia,
particularly in the prehospital setting.20,21 Whilst it is not standard
paramedic practice in Victoria to co-administer an antiemetic and opioids and demonstrated that this improved ticagrelor plasma levels
prokinetic such as metoclopramide with opioid therapy, this presents and antiplatelet effects, mitigating the opioid–P2Y12 inhibitor inter­
a potentially useful strategy. The Mon-AMI trial tested the utility of action.22 This also pre-emptively treated nausea and vomiting which
routine IV metoclopramide administration in patients receiving is a known and common side effect of opioid administration.
8 H. Fernando et al.

10
Fentanyl
Lidocaine
*

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0
e

e
or

or
sc

sc
in
n
ai

pa
lp

al
tia

n
i

Fi
In

100 *
* Fentanyl
80 Lidocaine
*
60
%

40

20

0
4

n
0-

io

tio
ct
S

c
R

du

du
N

re

re
in

n
ai
pa

tp
t
in

in
po

po
≥1

≥2

Figure 3 Prehospital pain scores in the lidocaine and fentanyl arm based on NRS. The top panel depicts median initial and final (on hospital arrival)
pain scores in the lidocaine (square) and fentanyl (circle) arms with error bars representing interquartile range. The bottom panel displays the percent­
age of patients in the lidocaine (right bar) and fentanyl (left bar) arms meeting key secondary end points including final NRS pain scores 0–4 on hospital
arrival, at least 1 point and at least 2-point prehospital pain reduction in the two arms. * Denotes P < 0.05 between groups.
The AVOID-2 trial 9

Table 3 Prehospital adverse events

50
* Fentanyl
Adverse events Fentanyl Lidocaine P-value
Adverse reaction %

Lidocaine n = 154 n = 154

.....................................................................................
Hypotension requiring 7 (4.6) 7 (4.6) 1
25 intervention, n (%)
Nausea and/or vomiting 68 (44) 43 (28) 0.004
requiring intervention, n (%)
Ondansetron/ 68 (44) 43 (28) 0.003
0 metoclopramide use, n (%)
Prehospital death, n (%) 0 0
ia
on

es u s
ed V

rh x i a
Ti S

ia
VF
u c N+

es
C

hm
it
i

o
ns

/
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Pa nn

VT
th

yp

yt Reduced GCS (>2) requiring 2 (1.3) 1 (0.7) 1

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ot

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ra
yp

intervention, n (%)
ar
ed
H

dy
R

ue

ra

Tinnitus, n (%) 0 4 (2.6) 0.12

B
ng
To

Tongue paresthaesia, n (%) 0 2 (1.3) 0.5

Figure 4 Prehospital adverse events in the lidocaine and fentanyl
arms. The percentage of patients experiencing the adverse reactions
listed on the × axis are displayed in the lidocaine (right bar) and fen­
tanyl (left bar) arms. N + V = nausea and vomiting; GCS = Glasgow
Coma Scale; VT/VF = ventricular tachycardia/ventricular fibrillation *
Denotes P < 0.05 between groups.
Reassuringly, we did not see any safety concerns with the use of IV
lidocaine for this indication, despite the narrow therapeutic window
and concerns relating to neurological and cardiac toxicity including
hypotension and bradyarrhythmias.10 Despite these previous con­
cerns, studies in man have not identified significant prolongation
of AV nodal or intraventricular conduction time after IV doses of
1–2 mg/kg.23 A Cochrane review of trials of lidocaine as VT prophy­
laxis in ACS did not identify an increased risk of harm or benefit.24 In
further detail, the Cochrane review included RCTs evaluating the ef­
fect of prophylactic lidocaine in myocardial infarction. The pooled
analysis included 37 randomized controlled studies with almost 12
000 patients. There was a slightly higher absolute risk of asystole (4
per 1000 in placebo vs. 9 per 1000 in lidocaine arm, relative risk
(RR) 2.32); however the grade of evidence was very low. There was
no difference in sinus bradycardia in this pooled analysis.
Additionally, the review did not identify an increased risk of heart fail­
ure or cardiogenic shock when lidocaine was used in patients with
AMI. There was no difference in reported pulmonary oedema
(9.56% lidocaine vs. 9.32% placebo, RR: 1.08), cardiogenic shock
(9.58% vs. 8.87%, RR: 1.04), hypotension (10.69% vs. 9.94%, RR:
1.07) or heart failure (15.74% vs. 21.25%, RR: 0.91). In awake patients
with heart disease and those post-AMI, doses of 1–2 mg/kg and bo­
luses up to 100 mg did not cause significant reductions in cardiac out­
put.24,25 We note, however, that our study may be underpowered to
assess these adverse events. Additionally, we excluded patients with
cardiogenic shock and pre-existing bradycardia or second-degree or
greater AV block and therefore our results are not generalizable to
this population. Paramedics were also able to follow this protocol suc­
cessfully and feasibly in the prehospital setting.
Additionally, we included peak cTnI, cardiac MRI evaluation of infarct
size and clinical and interventional characteristics as secondary end
points to determine if avoiding opioids in the prehospital setting may
have improved the efficacy of oral P2Y12 inhibitors. However, no differ­
ences between the two arms were seen. Given the delay in the thera­
peutic effect of oral P2Y12 inhibition in STEMI irrespective of opioid
administration, in-hospital ticagrelor administration immediately before
PCI in our study may have been too short a timeframe to identify a
VT/VF arrest, n (%) 7 (4.6) 7 (4.6) 1
Respiratory depression, n (%) 0 0
Naloxone use, n (%) 0 0 1
Hypoxia, n (%) 5 (3.3) 1 (0.7) 0.21
Seizure activity, n (%) 0 0
Bradyarrhythmia requiring 1 (0.7) 0 1
intervention, n (%)
Atropine use, n (%) 1 (0.6) 0 0.32
GCS = Glasgow Coma Scale; VT = ventricular tachycardia; VF = ventricular fibrillation
difference in myocardial infarct size, cardiac biomarker or pre-PCI
TIMI flow between the groups. We did identify a trend towards re­
duced microvascular obstruction in patients receiving lidocaine, how­
ever, further research is required to confirm these findings. Finally,
we did not see a significant difference in 30-day outcomes between
the groups however event rates were low in both arms and the present
study was not powered to identify a difference in these end points.
Limitations
This study has several limitations. Paramedics were not blinded to treat­
ment allocation and were responsible for ascertainment of pain scores
and reporting of adverse events. Given the differences in drug adminis­
tration and dosing, blinding posed an unacceptable safety risk to parti­
cipants. In terms of objectively evaluating pain severity, NRS pain scores
were favoured over visual analogue scale measurement given parame­
dics are trained and have extensive experience using the former meth­
od as this is current standard practice. In addition to the present trial
which had a very high rate of protocol compliance, Ambulance
Victoria has undertaken several similar unblinded trials previously
with a very high rate of protocol compliance. We note that the fre­
quency of administration differed between the two comparator agents
where fentanyl could be administered more frequently which may have
influenced patient pain assessment by creating the impression that it
was more effective. For safety reasons, however, related to the half-life
of lidocaine and the potential for toxicity with cumulative dosing, a min­
imum administration interval of 15 min with bolus dosing was deemed
to be the most suitable approach. We note that this does limit real
world application for patients with ongoing chest pain despite the first
bolus of IV lidocaine and this suggests it may be desirable to pair this
non-opioid analgesic with another agent such as IV acetaminophen.
This may enable further non-opioid analgesic dosing for patients with
10 H. Fernando et al.

Table 4 In-hospital and 30-day outcomes for patients receiving primary PCI
Outcomes – patients receiving primary PCI Fentanyl (n = 128) Lidocaine (n = 129) P-value
......................................................................................................................................................................................
In-hospital
Peak cardiac troponin I ng/mL, median (IQR) 26 638 (10000, 50 000) 27 000 (8290, 50000) 0.5
Mortality, n (%) 0 1 (0.8) 0.32
Cardiac mortality, n (%) 0 1 (0.8) 0.32
Stroke/TIA, n (%) 1 (0.7) 0 0.31
Heart failure, n (%) 11 (8.5) 13 (10) 0.62
Major bleeding, n (%) 4 (3.1) 3 (2.3) 0.7
In-hospital cardiogenic shock, n (%) 2 (1.5) 6 (4.6) 0.15
VT/VF, n (%) 7 (5.4) 7 (5.4) 1

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AFib/Flutter, n (%) 5 (3.9) 7 (5.4) 0.56
Complete heart block, n (%) 1 (0.7) 1 (0.7) 1
Length of stay in days, median (IQR) 3.7 (2.8,4.6) 3.5 (2.9,4.3) 0.54
In-hospital stent thrombosis, n (%) 0 0 null
MACE, n (%) 12 (9.4) 14 (11) 0.85
MACCE, n (%) 5 (3.9) 4 (3.1) 0.73
30-day outcomes
Mortality, n (%) 0 2 (2.3) 0.16
Cardiac mortality, n (%) 0 2 (2.3) 0.16
MACE, n (%) 13 (10) 17 (13) 0.45
MACCE, n (%) 8 (6.3) 6 (4.7) 0.57

IQR = interquartile range; TIA = transient ischaemic attack; VT = ventricular tachycardia; VF = ventricular fibrillation; Afib = atrial fibrillation; MACE = major adverse cardiac events;
MACCE = major adverse cardiac and cerebrovascular events

weight-adjusted however, we note that higher doses per kilogram,

Table 5 Cardiac MRI secondary end points for example, may be administered to individual patients which may in­
Variable Fentanyl Lidocaine P-value
crease the risk of adverse events such as nausea. Additionally, to pre­
(n = 55) (n = 59) vent selection bias, randomization was performed in the prehospital
..................................................................................... setting prior to confirmation of STEMI by coronary angiography leading
LVEDV ml, median (IQR) 166 (122,207) 175 (152,212) 0.068 to the enrolment of a small proportion of patients without STEMI. To
address this, the sample size was increased by 30% to ensure the trial
LVESV ml, median (IQR) 75 (55,103) 85 (66,111) 0.3
was adequately powered and a higher-than-expected rate of patients
SV ml, mean (95% CI) 82 (77,87) 91 (86,95) 0.3 receiving primary PCI for STEMI was seen in our study (>80%).
LVEF %, mean (95% CI) 51 (49,53) 51 (49,53) 0.99 Furthermore, given that the intervention in our study stopped on ar­
LV Mass in g, mean (95% CI) 92 (86,98) 102 (95,110) 0.4 rival to hospital, it is possible that patients in the lidocaine arm received
opioids in hospital. In-hospital opioid dosing data were not available;
Infarct size in g, median (IQR) 16 (6.9,27) 19 (6.8,29) 0.7
however, we believe patients in the lidocaine arm are likely to receive
Infarct size as percentage of 17 (14,19) 17 (14,20) 0.1 much lower doses in total compared with patients in the fentanyl arm
mass, mean (95% CI) prior to successful PCI, given the short door-to-balloon times in our
MVO, n (%) 5 (9.1) 1 (2) 0.08 study. Finally, our trial did not include a platelet reactivity component
or prehospital ticagrelor administration, however, this study was de­
LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic signed to complement the LOCAL study which demonstrated a clear
volume; IQR = interquartile range; SV = stroke volume; CI = confidence interval; drug interaction between IV fentanyl and ticagrelor which was not
LVEF = left ventricular ejection fraction; LV = left ventricle; MVO = microvascular seen in the IV lidocaine group.5
obstruction.

ongoing pain where transfer times to a PCI centre are shorter than
15 min. Furthermore, we note that weight-based bolus dosing of IV fen­
tanyl was not used but rather the current clinical practice guideline of
up to 50mcg every 5 min was adopted. This was deemed to simplify ad­
ministration and reduce the risk of error as paramedics are trained and
familiar with administering these doses of fentanyl. Given this was not
Conclusions
IV lidocaine was not as effective in reducing ischaemic chest pain in the
prehospital setting compared with IV fentanyl and did not meet criteria
for non-inferiority; however, it was safe and better tolerated with fewer
adverse effects. We await future studies that investigate whether the
use of non-opioid analgesics leads to improved clinical outcomes by
avoiding a drug interaction with oral P2Y12 inhibitors.
The AVOID-2 trial
Supplementary material
Supplementary material is available at European Heart Journal: Acute
Cardiovascular Care online.
Acknowledgements
We are grateful to the paramedics and Ambulance Victoria staff that
contributed to the AVOID-2 study for their commitment and support
during a very challenging period of time. Graphical Abstract created using
Servier Medical Art Images available at smart.servier.com.
Funding
Z.N. is supported by a NHMRC Early Career Fellowship (No.
1146809). P.M. is supported by an NHMRC Practitioner Fellowship
grant (No. 1135937). K.P. is supported by a NHMRC L3 Investigator
Fellowship (No. 1174098). D.S. is supported by a National Heart
Foundation of Australia Future Leader Fellowship (No. 101908). H.F.
is supported by an Australian Government RTP scholarship and
Monash Graduate Excellence Scholarship.
Conflict of interest: None declared
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