- Email: [email protected]
Anxiolytics in patients suffering a suspected acute coronary syndrome: Multi-centre randomised controlled trial in Emergency Medical Service
International Journal of Cardiology 168 (2013) 3580–3587
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Anxiolytics in patients suffering a suspected acute coronary syndrome: Multi-centre randomised controlled trial in Emergency Medical Service Birgitta Wireklint Sundström a,⁎, Angela Bång a, Thomas Karlsson b, Karin Winge c, Camilla Lundberg c, Johan Herlitz a a b c
School of Health Sciences, Research Centre PreHospen, University of Borås, The Prehospital Research Centre of Western Sweden, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy and University Hospital, Göteborg, Sweden Emergency Medical Service System at Södra Älvsborg Hospital, Borås, Sweden
a r t i c l e
i n f o
Article history: Received 22 September 2012 Received in revised form 9 March 2013 Accepted 4 May 2013 Available online 31 May 2013 Keywords: Chest pain Anxiety Cardiology nursing Emergency Medical Services Benzodiazepine
a b s t r a c t Background: The prehospital treatment of pain and discomfort among patients who suffer from acute coronary syndrome (ACS) needs a treatment strategy which combines relief of pain with relief of anxiety. Aim: The aim of the present study was to evaluate the impact on pain and anxiety of the combination of an anxiolytic and an analgesic as compared with an analgesic alone in the prehospital setting of suspected ACS. Methods: A multi-centre randomised controlled trial compared the combination of Midazolam (Mi) + Morphine (Mo) and Mo alone. All measures took part: Prior to randomisation, 15 min thereafter and on admission to a hospital. Inclusion criteria were: 1) pain raising suspicion of ACS and 2) pain score ≥ 4. Primary endpoint: Pain score after 15 min. Results: In all, 890 patients were randomised to Mi + Mo and 873 to Mo alone. Pain was reduced from a median of 6 to 4 and finally to 3 in both groups. The mean dose of Mo was 5.3 mg in Mi + Mo and 6.0 mg in Mo alone (p b 0.0001). Anxiety was reported in 66% in Mi + Mo and in 64% in Mo alone at randomisation (NS); 15 min thereafter in 31% and 39% (p = 0.002) and finally in 12% and 26% respectively (p b 0.0001). On admission to a hospital nausea or vomiting was reported in 9% in Mi + Mo and in 13% in Mo alone (p = 0.003). Drowsiness differed; 15% and 14% were drowsy in Mi + Mo versus 2% and 3% in Mo alone respectively (p b 0.001). Conclusion: Despite the fact that the combination of anxiolytics and analgesics as compared with analgesics alone reduced anxiety and the requirement of Morphine in the prehospital setting of acute coronary syndrome, this strategy did not reduce patients' estimation of pain (primary endpoint). More effective pain relief among these patients is warranted. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients and the Emergency Medical Service (EMS) staff could benefit from more data on the prehospital treatment of pain and discomfort in patients' experience suffering from acute coronary syndrome (ACS). The background idea is to combine nursing and medical science when meeting the suffering patient. Symptoms of ACS have been reported to be more intense in the prehospital setting than after admission to a hospital [1]. One gets the impression that the estimated intensity of pain is higher prior to the arrival of the Emergency Medical Service (EMS) than after their arrival [1–3]. Furthermore, since anxiety is most likely a strong component in the experience of pain or discomfort in acute chest pain [4–6], a treatment strategy
⁎ Corresponding author at: School of Health Sciences, University of Borås, SE-501 90 Borås, Sweden. Tel.: +46 33 435 47 77; fax: +46 33 435 44 46. E-mail address: [email protected] (B.W. Sundström). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.05.067
which combines relief of pain with relief of anxiety appears to be reasonable [7]. Whereas opioids and nitrates are the most widely used treatment alternatives today, randomised clinical trials (RCT) have in principal only been performed with beta-blockers in order to assess the drug effect on pain in this particular clinical situation [2,3]. The use of beta-blockers, despite probably the best documentation of the 4 alternatives, has been less popular due to the risk of hypotension [8]. Knowledge about the effect and the safety of benzodiazepines in the prehospital setting of a presumed ACS is limited. In the guidelines given by the European Society of Cardiology [9], it is reported that a tranquilliser could be an appropriate treatment if the patient becomes excessively disturbed by anxiety, but opioids are required in many cases. In the American Heart Association guidelines [10] no such recommendations are given. Consequently, effects of combining anxiolytics with analgesics are still unclear. Randomised studies comparing an anxiolytic and an analgesic are few. Thus, it seems reasonable to attempt an evaluation of such combinations in controlled trials with
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
an emphasis on pain as well as anxiety relief. There are reasons to believe that benzodiazepines in addition to opioids would potentiate pain and anxiety relief. Based on the above assumption the aim of the present study was to evaluate the combination of an anxiolytic and an analgesic as compared with an analgesic alone on pain and anxiety in the prehospital setting of a suspected ACS. At the same time safety data were assessed. Our hypothesis was that such a combination will reduce these symptoms. 2. Methods
3581
to be 2 mg if both the following conditions were fulfilled: younger than 70 years old and body weight 70 kg or more. 2.4. Inclusion and exclusion criteria Patients who were seen by the PEN and complained of pain or discomfort that aroused suspicion of ACS and reported pain ≥4 on a visual analogue scale VAS were included in the study [12]. The exclusion criteria were: 1) systolic blood pressure b100 mm Hg, 2) age b18 years, 3) under the influence of alcohol, 4) under the influence of drugs, 5) benzodiazepine abuse, 6) dementia or disorientation, 7) communication problems, 8) the symptoms that were judged as caused by trauma and 9) secondary transports (i.e. treatment already started).
2.1. Study design
2.5. Randomisation
This multi-centre RCT was designed to evaluate pain [11] and anxiety relief among patients with pain or discomfort raising suspicion of ACS, with two different types of intervention: A) an educational intervention for prehospital emergency nurses (PENs) and B) a medical intervention. The study has a 4-factor design (Fig. 1), where patients randomised in the trial were divided in two groups, i.e. those who were treated by a PEN with qualifications from a prehospital emergency cardiac care course of 7.5 credits (Educational Intervention) and those who were treated by PENs without this special training (Standard EMS Education), i.e. RN or RN in prehospital emergency care. In this study the medical intervention is reported. The study took place in Western Sweden (1.5 million inhabitants) with five EMS organisations involving 500 PENs, 60 ambulances and one boat in the Region of Västra Götaland, and in the city of Halmstad. All EMS organisations participating in the study were staffed with at least one PEN. Ethics approval was provided by the Research Ethics Committee in Gothenburg (registration number 022-08). Pharmaceutical approval was provided by the Medical Products Agency (Läkemedelsverket) in Stockholm (registration number 151:2008/4564). The study is registered in ClinicalTrials.gov Protocol Registration System (registration number 151:2008/4564). Informed consent was obtained from each patient. On 1 May 2008 the RCT started. During the first year of the study various EMS organisations successively joined the study group. The last patient was recruited on December 31, 2010.
Allocation to care given by the emergency cardiac trained nurse (Educational Intervention) or a nurse without this special training (Standard EMS Education) was decided at the dispatch before randomisation. The randomisation was conducted as an envelope method with the patient's written consent. In the envelope, a note stated whether Mi was to be administered to the patient or not. However, all patients received the standard treatment with Mo. This means that all patients in the study were placed in one of the four groups demonstrated in Fig. 1: 1) treated by PEN trained in prehospital emergency cardiac care and Mi + Mo, 2) treated by PEN trained in prehospital emergency cardiac care + Mo only, 3) treated by standard educated PEN and Mi + Mo and 4) standard educated PEN and Mo only (control group).
2.2. Educational intervention The educational intervention is a course both in caring science and in medical science and is focused on caring relationship together with knowledge in cardiology. It is expected to deepen the knowledge in the caregivers' possibilities of relieving and treating chest pain and anxiety. By an inclusive approach allowing caring and medicine to be applied in a natural way at the same time a vicious circle of stress is supposed to be broken for patients.
2.3. Medical intervention The medical intervention included the combination of the anxiolytic Midazolam (Mi) and the analgesic Morphine (Mo) (Fig. 1). The control group received Morphine alone (Mo alone). The initial dose of Mo had to be given according to clinical routine (mostly 5 mg). The dose of Mi had to be titrated at 0.5 mg at a time with a 2 minute interval between doses. The maximum dose was to be 1 mg if any of the following conditions pertained: age 70 or more, body weight less than 70 kg, known renal failure, known heart failure, known respiratory depression, and known liver dysfunction. The maximum dose was
2.6. Measures of pain intensity and clinical status The power calculation of the trial was based on the estimated intensity of pain according to VAS as perceived and judged by the patients. The patients' clinical status was further assessed by the PEN following the trial protocol using these parameters: 1) anxiety, 2) paleness or cold sweat, 3) pain or discomfort in chest, arms, back, neck or jaw and stomach, and 4) other symptoms including dyspnea, nausea and vomiting. There was no written information besides basic EMS training on how to assess these 4 items. Other observations included the heart rate, systolic blood pressure, pulse-oximetry and rate of breathing. Finally the patients' reaction level was assessed as follows: 1) awake, 2) slow, confused, 3) very dozy, confused and 4) unconscious. Presence of respiratory depression (yes, no), treated heart failure, hypotension, supraventricular or ventricular arrhythmias and AV-block was also evaluated. All above measures took part at three points in time: prior to randomisation, 15 min thereafter and on admission to a hospital. Evaluation of signs of heart failure and heart rhythm was carried out once, prior to randomisation. Pain and anxiety treated after hospital admission were reported. Survival (30 days and 1 year) and the proportion of patients with a final diagnosis of acute myocardial infarction (AMI) were reported. Finally, treated heart failure, hypotension, supraventricular or ventricular arrhythmia and AV block after hospital admission were reported. 2.7. Outcome measures The primary endpoint (the same for the medical and educational intervention) was the estimated intensity of pain or discomfort according to VAS as perceived and assessed by the patients 15 min after randomisation. The nurses assisted the patients in handling VAS. Secondary endpoints (the same for the medical and educational intervention) were 1. Estimated intensity of pain or discomfort according to VAS as perceived and
Fig. 1. Research plan with a 4 factor design; educational and medical intervention. Medical intervention included the combination of the anxiolytic Midazolam (Mi) and the analgesic Morphine (Mo).
3582
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
assessed by the patients on admission to a hospital. 2. Anxiety, 3. Hypotension, 4. Respiratory depression, 5. Drowsiness, 6. Nausea or vomiting, 7. Further requirement of pain relieving treatment, 8. Heart rate, 9. Systolic blood pressure, 10. Oxygen saturation, 11. Survival to 30 days, and 12. A final diagnosis of AMI and ACS. Acute myocardial infarction was defined according to the diagnosis given in the hospital records. Acute coronary syndrome was defined as a final hospital diagnosis of either AMI or unstable angina pectoris.
2.8. Statistical methods Sample size calculation was based on a difference of 20% in pain intensity between treatment groups (Mi + Mo or Mo only), 15 min after randomisation. To show this with 80% power and a significance level of 0.05 (two-sided test) the required number of patients in each group was 255. However, in order to include a reasonable number of patients in the prehospital emergency cardiac care trained group of PEN (Educational Intervention), under the assumption of a tenfold larger part of PEN not trained in prehospital emergency cardiac care (Standard EMS Education), it was decided to include at least 1650 patients in total (150 + 1500). All analyses were performed on an intention-to-treat basis, i.e. irrespective of whether a patient actually received the treatment to which he/she was randomised. There were 33 patients deviating from the randomised treatment: 28 in the Mi + Mo group did not receive the treatment and 5 in the Mo only group did receive Mi. Fisher's exact test was used to test for differences in dichotomous variables and the Mann–Whitney U test was used for ordered/continuous variables. For survival analysis Kaplan–Meier estimates were used and groups were compared using the log rank test. Interaction between the different interventions was analysed using the adjusted rank transform test (ART) [13]. All tests are two-sided and a p-value of b0.05 for the primary endpoint and b0.01 for other comparisons were considered statistically significant. All analyses were performed using SAS for Windows version 9.2.
3. Results A total of 3666 patients were included, and of these 1830 were not admitted to the RCT due to not fulfilling the inclusion criteria or had any exclusion criteria (Fig. 2). Of 1836 randomised patients, 73 were not included in analyses, 62 (32 + 30) did not agree to participate and 11 had incomplete randomised registration. The remaining 1763 patients with suspected ACS were included in analyses. Of these, 69
patients were randomised and therefore kept in the analyses despite not fulfilling the inclusion criteria or having exclusion criteria. Among these 1763 patients 890 were randomised to the combination Mi + Mo and 873 to Mo alone. In the following, results will be presented according to intention to treat for all randomised patients and separately for the patients who finally fulfilled the criteria for ACS (subgroup analyses) as shown in the following tables. There was no statistically significant difference between the two treatment arms in terms of age, sex, previous history or treatment by a PEN trained in prehospital emergency cardiac care (Table 1). Heart rate, systolic blood pressure and oxygen saturation were significantly lower on admission to a hospital among patients randomised to combination therapy when all patients were analysed (Table 2). There was no statistically significant difference between groups in terms of treatment with oxygen, aspirin, clopidogrel, nitrates or beta-blockers prior to hospital admission. The proportion of patients who received Mo did not differ but the mean dose of Mo given was lower among those who received Mi + Mo (5.3 mg versus 6.0 mg; p b 0.0001) (Table 3). In the ACS patient subgroup nitrates was less frequently given to those who received combination therapy. There was no statistically significant difference between groups in terms of proportion of patients who had ECG-recorded, ECG sent or various ECG findings (Table 4). There was no statistically significant difference between the two groups regarding the primary endpoint of the estimated intensity of pain 15 min after randomisation (p = 0.78) and the interaction between the effects of the different interventions (Mi + Mo vs Mo only and treated PEN trained vs not trained in prehospital emergency cardiac care) was nonsignificant (p = 0.85) nor was there any significant difference between the groups prior to randomisation or on admission to a hospital. There was no significant difference between the two groups regarding presence of pain in any localisation at any time (Table 5).
Fig. 2. CONSORT flow diagram on patients with suspected ACS.
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
3583
Table 1 Age, sex and previous history. Randomised treatment (ACS)a
Randomised treatment (all)
Age; years mean ± SD Median (25th,75th percentile) Women (%) Previous history (%) Myocardial infarction (31/32/2/3)c Angina pectoris (37/39/4/5) Hypertension (35/29/3/1) Diabetes mellitus (28/26/1/1) Heart failure (44/38/7/7) Stroke (29/26/0/2) Peripheral artery disease (33/30/4/2) Chronic obstructive pulmonary disease (30/27/2/1) Renal disease (29/28/1/3) Cancer (29/26/2/2) Smoking (%) (218/202/58/60) Treated by PEN trained in prehospital emergency cardiac care (%) (11/15/6/2) a b c
Midazolam + Morphine
Morphine only
n = 890 69.8 ± 13.5 72 (61, 81) 44 38 29 44 21 14 8 3 9 6 10 21 18
pb
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
69.8 ± 13.4 71 (61, 80) 46
72.5 ± 12.4 74 (64, 82) 36
72.5 ± 12.1 73 (64, 82) 35
35 29 40 19 15 11 3 9 7 11 18 20
49 41 46 23 15 9 4 8 7 9 22 19
40 38 44 23 13 12 4 6 7 11 18 21
0.08
0.03
pb
0.03
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
In terms of other symptoms there was no difference between groups regarding paleness or cold sweat. However, anxiety was less frequent among the patients randomised to Mi + Mo both 15 min after randomisation (31% versus 39%; p = 0.002) and on admission to a hospital (12% versus 26%; p b 0.0001). Furthermore nausea and vomiting were less frequent among patients randomised to Mi + Mo on admission to a hospital (9% versus 13%; p = 0.003) (Table 5). In the subset of patients with ACS both anxiety and nausea/vomiting were less frequent on admission to a hospital in the group that received combination therapy. The distribution of patients according to drowsiness differed significantly both 15 min after randomisation and on admission to a hospital. Thus, patients who were randomised to Mi + Mo were drowsier (Table 5).
There was no difference between groups in terms of respiratory depression and aggressiveness (Table 5). There was no difference between groups either with regard to complications prior to hospital admission or complications after hospital admission. Survival to 30 days did not differ and the proportion of patients who had a final diagnosis of AMI and ACS were similar in the two groups (Table 6).
4. Discussion To the best of our knowledge this is the first large scale intervention study with the aim to evaluate symptom relief prior to hospital admission in suspected ACS.
Table 2 Cardiopulmonary findings prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Heart rate; beats/min mean ± SD Prior to randomisation (19/17/9/3) c 15 min after randomisation (60/50/15/10) On admission to a hospital (65/75/18/21) Systolic blood pressure; mm Hg mean ± SD Prior to randomisation (18/22/9/5) 15 min after randomisation (82/88/28/18) On admission to a hospital (85/114/28/33) Oxygen saturation; % mean ± SD Prior to randomisation (30/36/13/11) 15 min after randomisation (55/62/19/14) On admission to a hospital (62/82/20/25) Rate of breathing; breath/min mean ± SD Prior to randomisation (100/81/47/23) 15 min after randomisation (154/131/62/40) On admission to a hospital (162/149/64/48) Signs of heart failure (auscultatory rates) (%) (418/422/156/133) Sinus rhythm (%) (44/50/22/12) a b c
Midazolam + Morphine
Morphine only
n = 890
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
86.1 ± 24.2 81.5 ± 21.7 78.8 ± 20.6
87.1 ± 25.2 84.0 ± 23.3 81.5 ± 22.6
0.02
82.3 ± 20.3 78.5 ± 18.5 76.1 ± 17.3
83.8 ± 24.8 80.8 ± 22.8 78.4 ± 21.9
151.6. ± 27.1 134.8 ± 23.9 131.7 ± 22.5
152.0 ± 27.7 139.3 ± 25.1 135.5 ± 23.2
0.0003 0.003
152.4. ± 29.3 135.5. ± 25.8 132.9. ± 22.8
151.7 ± 28.0 141.1 ± 24.7 136.2 ± 23.6
95.7. ± 3.8 96.8 ± 2.7 97.1 ± 2.4
96.0 ± 3.4 97.2 ± 2.3 97.5 ± 2.1
0.01 0.006
95.6. ± 3.5 96.9. ± 2.5 97.2. ± 2.3
95.5 ± 3.9 96.9 ± 2.6 97.5 ± 2.2
18.3. ± 5.1 17.0 ± 4.2 16.4 ± 3.8 4 81
18.4 ± 5.2 17.2 ± 4.3 16.6 ± 3.8 5 79
18.0. ± 5.1 16.7. ± 4.1 16.1. ± 3.8 7 83
18.2 ± 5.2 17.1 ± 4.3 16.4 ± 3.5 6 80
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
p
b
pb
0.01
3584
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
Table 3 Treatment prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Oxygen (%) (12/14/6/2)c Mean (median) dosed; l/min Aspirin (%) (12/16/6/2) Mean (median) dosed; mg Clopidogrel (%) (14/14/6/2) Mean (median) dosed; mg Nitrates (%) (12/15/6/3) Mean (median) dosed; mg Beta-blockers (%) (15/15/6/2) Mean (median) dosed; mg Midazolam (%) (10/15/5/2) Mean (median) dosed; mg Morphine (%) (15/13/7/1) Mean (median) dosed; mg a b c d e f
Midazolam + Morphine
Morphine only
n = 890 81 3.8 (3) 65 294 (320) 9 575 (600) 83 0.78 (0.8) 4 11.2 (10) 97e 1.12 (1.00) 83 5.3 (5.0)
pb
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
81 3.7 (3) 66 295 (320) 9 564 (600) 86 0.77 (0.8) 5 10.5 (10) b1f 1.60 (2.00) 81 6.0 (5.0)
86 4.3 (3) 72 294 (320) 20 569 (600) 80 0.79 (0.8) 5 11.4 (12.5) 97e 1.13 (1.00) 85 6.1 (5.0)
89 4.1 (3) 75 301 (320) 21 570 (600) 88 0.83 (0.8) 6 10.4 (15) b1f 2.25 (2.25) 86 6.7 (6.0)
b0.0001
b0.0001
pb
0.009
b0.0001 0.004 0.04
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Of those receiving treatment. 28/9 of patients did not receive Midazolam. 5/2 of patients received Midazolam.
unlikely that the choice of another primary endpoint would have changed the results and the interpretation of this study.
4.1. The primary and secondary endpoints The trial found that treatment of patients suspected of ACS in the prehospital setting with a combination of an anxiolytic and an analgesic did not reduce the estimated intensity of pain as compared with an analgesic alone. This was the primary endpoint of the study. However, the combination therapy resulted in less anxiety and less nausea and vomiting, and a reduced use of Mo. There was increased drowsiness but no sign of respiratory depression or increased aggressiveness. The primary hypothesis was that the combination of an anxiolytic and an analgesic reduced pain. This was not confirmed. Thus, it does not appear as though reduced anxiety is reflected in a lower estimation of pain on VAS. The effect of an anxiolytic should be reflected in reduced anxiety rather than in reduced pain, and the present study underlined this.
4.3. Comparison with other trials A few previous studies have addressed pain relief in suspected myocardial ischemia and the use of benzodiazepines. In the first study, 38 patients admitted for AMI were randomised to intravenous followed by oral Diazepam for 3 days or control. The Diazepam group had a lower requirement of Morphine [14]. In the second study 40 patients with cocaine associated ACS were randomised to either Diazepam or nitroglycerin with a similar effect on chest pain [15]. In a third study 13 patients with a known coronary artery disease had undergone an exercise test on two separate days, one with pretreatment with Diazepam and one with placebo. Treatment with Diazepam was associated with prolonged time to ST-depression and improved exercise duration [16]. Overall, our results highlight the activity of the PEN in provision of a more effective pain-relieving strategy in the prehospital setting of a suspected ACS. Thus, only about half of the patients had a pain score of b 3 on admission to a hospital. This could not be considered as a sufficient EMS care. One might argue that the dose of Mo given was too low [14]. However, there is a risk that higher levels of Mo would have resulted in more symptoms of nausea and vomiting.
4.2. Choice of endpoint One might argue whether an alternative primary endpoint had been more appropriate when evaluating the effect of an anxiolytic added to a narcotic analgesic. The overall aim of the intervention was to improve well-being in a life threatening situation. Regardless of the instrument being used this task will be associated with difficulties. We therefore studied a large number of secondary endpoints in order to give a clinical picture as complete as ever possible. It is Table 4 ECG findings prior to hospital admission.
Randomised treatment (ACS)a
Randomised treatment (all) Midazolam + Morphine
ECG recorded (%) (12/14/6/2)c ECG sent (%) (16/24/8/5) ECG findings (%) ST-elevation (93/94/44/28) ST-depression (109/128/52/44) T-wave inversion (242/235/102/90) Pathologic Q-wave (340/323/137/122) Left bundle branch block (232/225/99/83) a b c
Morphine only
pb
Midazolam + Morphine
Morphine only
n = 890
n = 873
n = 308
n = 291
>99 75
>99 78
100 84
>99 91
19 28 16 7 7
19 30 13 8 9
38 38 21 9 11
37 45 19 12 11
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
pb
0.01
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
3585
Table 5 Symptom prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Morphine only
n = 873
n = 308
n = 291
6 (5,7.2)
6 (5,7.5)
6 (5,7.5)
6.3 (5,8)
4 (3,5.5)
4 (3,5.4)
4 (2.5,5.8)
4 (3,6)
3 (1,4)
3 (1,4)
2.5 (1,4.4)
3 (1,4.4)
97 45 23 23 10
97 46 25 25 12
97 51 20 21 7
96 54 19 26 7
81 28 18 18 7
84 31 19 18 9
81 33 16 15 5
85 39 15 18 4
63 20 13 13 6
67 22 14 14 8
66 25 10 12 5
69 27 12 12 3
45 26 66 39
44 27 64 36
54 26 63 38
54 30 60 34
30 15 31 18
28 16 39 19
38 13 31 16
36 19 38 16
18 9 12 9
21 13 26 12
24 8 11 10
25 18 23 8
85 13 2 b1
98 2 b1 b1
84 15 b1 b1
98 1 b1 b1
86 12 2 b1
97 3 b1 0
85 13 2 b1
97 2 b1 0
Respiratory depression (%) 15 min after randomisation (41/275/16/84) On admission to a hospital (39/285/16/88)
b1 b1
b1 b1
1 1
1 b1
Aggressiveness (%) 15 min after randomisation (45/275/17/84) On admission to a hospital (40/286/15/88)
b1 b1
b1 b1
b1 b1
b1 0
Localisation of pain or discomfort (%) Prior to randomisation Chest (14/17/7/2) Arm(s) (26/33/10/9) Back (30/40/13/11) Neck (36/41/14/8) Stomach (28/45/11/11) 15 min after randomisation Chest (54/57/15/11) Arm(s) (69/66/20/14) Back (76/78/24/19) Neck (79/76/24/17) Stomach (70/83/20/20) On admission to a hospital Chest (102/89/29/25) Arm(s) (108/97/33/28) Back (109/97/34/28) Neck (112/100/33/26) Stomach (102/102/33/26) Other symptoms (%) Prior to randomisation Pale, cold sweat (15/18/7/2) Nausea, vomiting (32/33/13/12) Anxiety (30/32/16/10) Dyspnea (28/34/13/13) 15 min after randomisation Pale, cold sweat (59/51/16/12) Nausea, vomiting (68/67/21/18) Anxiety (76/68/28/17) Dyspnea (73/66/23/20) On admission to a hospital Pale, cold sweat (95/81/30/22) Nausea, vomiting (106/90/31/26) Anxiety (115/105/37/29) Dyspnea (109/100/34/30) Alertness (%) 15 min after randomisation (46/277/18/85) Awake Dozy, confused Very dozy, confused Unconscious On admission to a hospital (39/286/15/89) Awake Dozy, confused Very dozy, confused Unconscious
a b c d
Morphine only
n = 890
pb
Midazolam + Morphine
Estimated severity of pain or discomfort Prior to randomisation Pain score (54/68/21/26)c median (25th, 75th percentile) 15 min after randomisation Pain score (78/99/31/36) median (25th,75th percentile) On admission to a hospital Pain score (92/112/32/39) median (25th,75th percentile)
Midazolam + Morphine
0.08
0.002
0.003 b0.0001
b0.0001d
0.08
0.0007 0.0005
b0.0001d
b0.0001d
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Ordered degree of alertness used in p-value calculation.
pb
b0.0001d
3586
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
Table 6 Complications and final diagnosis. Randomised treatment (ACS)a
Randomised treatment (all)
Prior to hospital admission (%) Treated heart failure (13/15/3/1)c Treated hypotension (14/15/4/1) Treated supraventricular arrhythmia (14/17/3/2) Treated ventricular arrhythmia (13/18/3/3) Treated AV block (13/15/3/1) After hospital admission (%) Treated anxiety (40/33/11/5) Treated heart failure (30/32/4/5) Treated hypotension (31/31/4/5) Treated supraventricular arrhythmia (30/30/4/5) Treated ventricular arrhythmia (33/31/4/5) Treated AV block (30/32/4/6) Treated chest pain (39/39/12/10) Survival to 30 daysd,e (%) Survival to 1 yeard,e (%) Final diagnosis (%) (62/48) Acute myocardial infarction Acute coronary syndrome a b c d e
Morphine only
Midazolam + Morphine
n = 890
n = 873
1.4 2.2 0.9 0.0 0.5
1.5 0.9 0.8 0.5 0.5
11.8 11.6 4.7 5.6 1.8 2.0 35.8 97.2 89.4 25.5 37.2
pb
Midazolam + Morphine
Morphine only
n = 308
n = 291
2.3 3.0 0.0 0.0 0.3
2.8 0.7 0.0 1.0 0.3
9.8 12.6 3.8 6.0 1.2 2.1 39.8 97.2 90.0
14.8 15.1 7.6 6.2 3.9 2.6 48.6 95.5 87.8
11.9 19.2 6.6 7.0 2.8 3.2 53.7 96.4 88.7
26.4 35.3
68.5
74.9
0.06
pb
0.06
0.09
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Only the first occasion (n = 817 and 800, respectively) included for those with multiple inclusions. Kaplan–Meier estimate (not all patients are followed for 1 year, end of follow-up = 2011-04-01).
4.4. Anxiety and nausea or vomiting A secondary objective of this study was to assess the impact of the combination of an anxiolytic and an analgesic on the presence of anxiety as assessed by an EMS nurse. Out of consideration for the patients' status we did not use a self-rating anxiety scale. Although our finding of a lower anxiety level, particularly on admission to a hospital, might be regarded as an expected finding, since this has not previously been reported in the prehospital setting, these data are new. Treatment of patients in a life threatening situation should, as always in medical practice, be based on facts rather than expectations. However, two previous studies have evaluated the association between treatments with Diazepam and anxiety in AMI in a hospital. One showed reduced anxiety [14] and the other did not [16]. Symptoms of nausea and vomiting on admission to a hospital were reduced among patients who received the combination of Mi and Mo. This might at least to some extent be explained by a lower dose of Mo given to this treatment group. 4.5. Safety and side effects The combination therapy was associated with increased drowsiness. We do not know whether patients had a positive or a negative reaction to this type of side effect. The reaction was characterised by decreased alertness but not unconsciousness. Previous experience of this combination therapy indicates that adverse events are infrequent even when the medications were given intravenously [14,17–21]. These studies were performed on humans as well as animals. There was no indication that the combination therapy resulted in respiratory depression or change in mood. Heart rate, blood pressure and oxygen saturation were significantly lower after combination therapy on admission to a hospital. However, differences in absolute numbers were small and the clinical relevance might be argued. 4.6. Final diagnosis Slightly more than one third had a final diagnosis of ACS. There were no ECG criteria and only a suspicion of ACS was required for
inclusion. Thus our results might be extrapolated to a patient population with pain or discomfort raising either a vague or a strong suspicion of ACS. 4.7. Limitation Although it was recommended that all patients in the participating EMS organisations should be considered for inclusion, we know that this was not always the case. However, there is no information on the numbers of the total population of patients with chest pain and discomfort admitted to EMS units in the study areas that were available. Since verbal acceptance was required for inclusion, we assume that the PENs had a tendency not to include patients suffering from severe insufficiency in vital functions and those with a very severe pain, due to communication problems. We have no information about the characteristics of the baseline population from which the study cohort was recruited. The doses of Mo and Mi given were low. We do not know whether tolerability would be the same if doses were increased. Further, since a great number of the patients admitted to EMS were not randomised, the study has a selection bias due to unspecific symptoms of a suspected ACS and the demand for reported pain ≥4 on a VAS. Since the patients sometimes and the healthcare provider always were aware of which treatment alternative the patient was allocated to we cannot exclude the risk of bias. Thus, the combination of an open label design and some not very objective endpoints may lead to considerable bias in reporting. There were no written information on how to assess anxiety, paleness, cold sweat, nausea, vomiting and dyspnea. In terms of anxiety one cannot exclude the risk that patients who were drowsier might only seem to be less anxious in the eyes of the external observer. There is also a risk that the increased drowsiness in the intervention group might have affected the reliability of the main outcome measure (pain) in this group. The difference in missing rate between the two groups in the reporting of alertness, respiratory depression and aggressiveness is explained by the fact that in the initial phase of the study this was only reported among patients allocated to Mi.
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
5. Conclusion Despite the fact that the combination of anxiolytics and analgesics as compared with analgesics alone reduced anxiety and the requirement of morphine in the prehospital setting of acute coronary syndrome, this strategy did not reduce patients' estimation of pain (primary endpoint). More effective pain relief among these patients is warranted.
5.1. Clinical implications The clinical implications of this trial are dependent on how to balance the results regarding the primary endpoint with the results regarding the secondary endpoints. A conservative approach would be to ignore the results on the secondary endpoints and regard them as hypotheses generating. However, much of the results on the secondary endpoints are, from a pharmacological point of view, expected and therefore most likely of clinical relevance. Among patients with pain or discomfort in the chest raising some suspicion of an ACS and showing signs of anxiety, the combination of an analgesic and an anxiolytic does not appear to relieve pain but anxiety. The combination also seems to relieve nausea or vomiting and reduce the requirement of Mo. However, the combination will result in an increased prevalence of drowsiness in some patients but no respiratory depression. Drowsiness may impair their ability to engage in meaningful conversation by ED/treating physician. Furthermore history may be difficult to obtain and consent can be an issue if the patient is going for a procedure. Whether similar problems may appear if the patient suffers from severe anxiety remains speculative. From a hemodynamic and respiratory perspective, the combination appears to be safe to use among patients with acute chest pain and anxiety in the prehospital setting. More effective pain relieving drugs than the addition of anxiolytics to narcotic analgesics are warranted.
Funding This study was funded by the University of Borås, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland and Sparbanksstiftelsen Sjuhärad, Sweden.
Acknowledgements The authors would like to thank the EMS organisations and their personnel in the Region of Västra Götaland and in the city of Halmstad, Sweden. Special thanks to the contact persons in each organisation and last but not least to all patients agreeing to take part in the trial.
3587
References [1] Herlitz J, Richter A, Hjalmarson Å, et al. Chest pain in acute myocardial infarction. A descriptive study according to subjective assessment and morphine requirement. Clin Cardiol 1986;9:423–8. [2] Gardtman M, Dellborg M, Brunnhage Ch, et al. Effect of intravenous metoprolol before hospital admission on chest pain in suspected acute myocardial infarction. Am Heart J 1999;137:821–9. [3] Zedigh C, Alho A, Hammar E, et al. Aspects on the intensity and the relief of pain in the pre-hospital phase of acute coronary syndrome: experiences from a randomised clinical trial. Coron Artery Dis 2010;21:113–20. [4] De Jong MJ, Chung ML, Roser LP, et al. A five-country comparison of anxiety early after acute myocardial infarction. Eur J Cardiovasc Nurs 2004;3:129–34. [5] Khan MA, Karamat M, Hafizullah M, Nazar Z, Fahim M, Gul AM. Frequency of anxiety and psychosocial stressful events in patients with acute myocardial infraction. J Ayub Med Coll Abbottabad 2010;22:32–5. [6] Guanghui L, Xianzheng W, Wenlin M, et al. Epidemiology and preventive medicine: epidemiology of cardiovascular disease: e0282 effect of comprehensive intervention on anxiety and depressive symptoms in patients after ACS. Heart 2010;96(Suppl. 3): A89–90. [7] Herlitz J, Bång A, Omerovic E, et al. Is pre-hospital treatment of chest pain optimal? Both relief of pain and anxiety are needed. Int J Cardiol 2011;149:147–51. [8] COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45.852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1622–32. [9] European Society of Cardiology. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur Heart J 2008;29:2909–45. [10] American College of Cardiology/American Heart Association. A report of the American College of Cardiology/American Heart Association Task Force on Practise Guidelines. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 2004;110:e82-293. [11] McGrath P, Seifert C, Speechley K, et al. A new analogue scale for assessing children's pain: an initial validation study. Pain 1996;64:435–43. [12] McLean SA, Domeier RM, DeVore HK, Hill EM, Maio RF, Fredriksen SM. The feasibility of pain assessment in the pre-hospital setting. Prehosp Emerg Care 2004;8: 155–61. [13] Leys C, Schumann S. A nonparametric method to analyze interactions: the adjusted rank transform test. J Exp Soc Psychol 2010;46:684–8. [14] Melsom M, Andreassen H, Melsom T, et al. Diazepam in acute myocardial infarction: clinical effects and effects on catecholamines, free fatty acids, and cortisol. Br Heart J 1976;38:804–10. [15] Baumann BM, Perrone J, Hornig SE, et al. Randomised double-blind, placebocontrolled trial of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndromes. Acad Emerg Med 2000;7:878–85. [16] Rossetti E, Fragasso G, Xuereb RG, et al. Antiischemic effects of intravenous diazepam in patients with coronary artery disease. J Cardiovasc Pharmacol 1994;24: 55–8. [17] Dixon RA, Edwards IR, Pilcher J. Diazepam in immediate post-myocardial infarct period. A double blind trial. Br Heart J 1980;43:535–40. [18] Vrana M, Hess L, Vranova Z, et al. An experimental contribution to the treatment of acute myocardial infarction. Czech Med 1987;10:142–55. [19] Hess L, Vrana M, Vranova Z, et al. The electrostabilizing effect of a combination of midazolam and fentanyl: an experimental study in the dog. Cor Vasa 1989;31: 411–8. [20] Vrana M, Fejfar Z, Hess L, et al. Analgosedation-enhanced baroreflex sensitivity in acute local myocardial infarction. Cor Vasa 1991;33:428–34. [21] Baris S, Karakaya D, Aykent T, et al. Comparison of midazolam with or without fentanyl for conscious sedation and hemodynamics in coronary angiography. Can J Cardiol 2001;173:277–81.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Anxiolytics in patients suffering a suspected acute coronary syndrome: Multi-centre randomised controlled trial in Emergency Medical Service Birgitta Wireklint Sundström a,⁎, Angela Bång a, Thomas Karlsson b, Karin Winge c, Camilla Lundberg c, Johan Herlitz a a b c
School of Health Sciences, Research Centre PreHospen, University of Borås, The Prehospital Research Centre of Western Sweden, Sweden Department of Molecular and Clinical Medicine, Sahlgrenska Academy and University Hospital, Göteborg, Sweden Emergency Medical Service System at Södra Älvsborg Hospital, Borås, Sweden
a r t i c l e
i n f o
Article history: Received 22 September 2012 Received in revised form 9 March 2013 Accepted 4 May 2013 Available online 31 May 2013 Keywords: Chest pain Anxiety Cardiology nursing Emergency Medical Services Benzodiazepine
a b s t r a c t Background: The prehospital treatment of pain and discomfort among patients who suffer from acute coronary syndrome (ACS) needs a treatment strategy which combines relief of pain with relief of anxiety. Aim: The aim of the present study was to evaluate the impact on pain and anxiety of the combination of an anxiolytic and an analgesic as compared with an analgesic alone in the prehospital setting of suspected ACS. Methods: A multi-centre randomised controlled trial compared the combination of Midazolam (Mi) + Morphine (Mo) and Mo alone. All measures took part: Prior to randomisation, 15 min thereafter and on admission to a hospital. Inclusion criteria were: 1) pain raising suspicion of ACS and 2) pain score ≥ 4. Primary endpoint: Pain score after 15 min. Results: In all, 890 patients were randomised to Mi + Mo and 873 to Mo alone. Pain was reduced from a median of 6 to 4 and finally to 3 in both groups. The mean dose of Mo was 5.3 mg in Mi + Mo and 6.0 mg in Mo alone (p b 0.0001). Anxiety was reported in 66% in Mi + Mo and in 64% in Mo alone at randomisation (NS); 15 min thereafter in 31% and 39% (p = 0.002) and finally in 12% and 26% respectively (p b 0.0001). On admission to a hospital nausea or vomiting was reported in 9% in Mi + Mo and in 13% in Mo alone (p = 0.003). Drowsiness differed; 15% and 14% were drowsy in Mi + Mo versus 2% and 3% in Mo alone respectively (p b 0.001). Conclusion: Despite the fact that the combination of anxiolytics and analgesics as compared with analgesics alone reduced anxiety and the requirement of Morphine in the prehospital setting of acute coronary syndrome, this strategy did not reduce patients' estimation of pain (primary endpoint). More effective pain relief among these patients is warranted. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patients and the Emergency Medical Service (EMS) staff could benefit from more data on the prehospital treatment of pain and discomfort in patients' experience suffering from acute coronary syndrome (ACS). The background idea is to combine nursing and medical science when meeting the suffering patient. Symptoms of ACS have been reported to be more intense in the prehospital setting than after admission to a hospital [1]. One gets the impression that the estimated intensity of pain is higher prior to the arrival of the Emergency Medical Service (EMS) than after their arrival [1–3]. Furthermore, since anxiety is most likely a strong component in the experience of pain or discomfort in acute chest pain [4–6], a treatment strategy
⁎ Corresponding author at: School of Health Sciences, University of Borås, SE-501 90 Borås, Sweden. Tel.: +46 33 435 47 77; fax: +46 33 435 44 46. E-mail address: [email protected] (B.W. Sundström). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.05.067
which combines relief of pain with relief of anxiety appears to be reasonable [7]. Whereas opioids and nitrates are the most widely used treatment alternatives today, randomised clinical trials (RCT) have in principal only been performed with beta-blockers in order to assess the drug effect on pain in this particular clinical situation [2,3]. The use of beta-blockers, despite probably the best documentation of the 4 alternatives, has been less popular due to the risk of hypotension [8]. Knowledge about the effect and the safety of benzodiazepines in the prehospital setting of a presumed ACS is limited. In the guidelines given by the European Society of Cardiology [9], it is reported that a tranquilliser could be an appropriate treatment if the patient becomes excessively disturbed by anxiety, but opioids are required in many cases. In the American Heart Association guidelines [10] no such recommendations are given. Consequently, effects of combining anxiolytics with analgesics are still unclear. Randomised studies comparing an anxiolytic and an analgesic are few. Thus, it seems reasonable to attempt an evaluation of such combinations in controlled trials with
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
an emphasis on pain as well as anxiety relief. There are reasons to believe that benzodiazepines in addition to opioids would potentiate pain and anxiety relief. Based on the above assumption the aim of the present study was to evaluate the combination of an anxiolytic and an analgesic as compared with an analgesic alone on pain and anxiety in the prehospital setting of a suspected ACS. At the same time safety data were assessed. Our hypothesis was that such a combination will reduce these symptoms. 2. Methods
3581
to be 2 mg if both the following conditions were fulfilled: younger than 70 years old and body weight 70 kg or more. 2.4. Inclusion and exclusion criteria Patients who were seen by the PEN and complained of pain or discomfort that aroused suspicion of ACS and reported pain ≥4 on a visual analogue scale VAS were included in the study [12]. The exclusion criteria were: 1) systolic blood pressure b100 mm Hg, 2) age b18 years, 3) under the influence of alcohol, 4) under the influence of drugs, 5) benzodiazepine abuse, 6) dementia or disorientation, 7) communication problems, 8) the symptoms that were judged as caused by trauma and 9) secondary transports (i.e. treatment already started).
2.1. Study design
2.5. Randomisation
This multi-centre RCT was designed to evaluate pain [11] and anxiety relief among patients with pain or discomfort raising suspicion of ACS, with two different types of intervention: A) an educational intervention for prehospital emergency nurses (PENs) and B) a medical intervention. The study has a 4-factor design (Fig. 1), where patients randomised in the trial were divided in two groups, i.e. those who were treated by a PEN with qualifications from a prehospital emergency cardiac care course of 7.5 credits (Educational Intervention) and those who were treated by PENs without this special training (Standard EMS Education), i.e. RN or RN in prehospital emergency care. In this study the medical intervention is reported. The study took place in Western Sweden (1.5 million inhabitants) with five EMS organisations involving 500 PENs, 60 ambulances and one boat in the Region of Västra Götaland, and in the city of Halmstad. All EMS organisations participating in the study were staffed with at least one PEN. Ethics approval was provided by the Research Ethics Committee in Gothenburg (registration number 022-08). Pharmaceutical approval was provided by the Medical Products Agency (Läkemedelsverket) in Stockholm (registration number 151:2008/4564). The study is registered in ClinicalTrials.gov Protocol Registration System (registration number 151:2008/4564). Informed consent was obtained from each patient. On 1 May 2008 the RCT started. During the first year of the study various EMS organisations successively joined the study group. The last patient was recruited on December 31, 2010.
Allocation to care given by the emergency cardiac trained nurse (Educational Intervention) or a nurse without this special training (Standard EMS Education) was decided at the dispatch before randomisation. The randomisation was conducted as an envelope method with the patient's written consent. In the envelope, a note stated whether Mi was to be administered to the patient or not. However, all patients received the standard treatment with Mo. This means that all patients in the study were placed in one of the four groups demonstrated in Fig. 1: 1) treated by PEN trained in prehospital emergency cardiac care and Mi + Mo, 2) treated by PEN trained in prehospital emergency cardiac care + Mo only, 3) treated by standard educated PEN and Mi + Mo and 4) standard educated PEN and Mo only (control group).
2.2. Educational intervention The educational intervention is a course both in caring science and in medical science and is focused on caring relationship together with knowledge in cardiology. It is expected to deepen the knowledge in the caregivers' possibilities of relieving and treating chest pain and anxiety. By an inclusive approach allowing caring and medicine to be applied in a natural way at the same time a vicious circle of stress is supposed to be broken for patients.
2.3. Medical intervention The medical intervention included the combination of the anxiolytic Midazolam (Mi) and the analgesic Morphine (Mo) (Fig. 1). The control group received Morphine alone (Mo alone). The initial dose of Mo had to be given according to clinical routine (mostly 5 mg). The dose of Mi had to be titrated at 0.5 mg at a time with a 2 minute interval between doses. The maximum dose was to be 1 mg if any of the following conditions pertained: age 70 or more, body weight less than 70 kg, known renal failure, known heart failure, known respiratory depression, and known liver dysfunction. The maximum dose was
2.6. Measures of pain intensity and clinical status The power calculation of the trial was based on the estimated intensity of pain according to VAS as perceived and judged by the patients. The patients' clinical status was further assessed by the PEN following the trial protocol using these parameters: 1) anxiety, 2) paleness or cold sweat, 3) pain or discomfort in chest, arms, back, neck or jaw and stomach, and 4) other symptoms including dyspnea, nausea and vomiting. There was no written information besides basic EMS training on how to assess these 4 items. Other observations included the heart rate, systolic blood pressure, pulse-oximetry and rate of breathing. Finally the patients' reaction level was assessed as follows: 1) awake, 2) slow, confused, 3) very dozy, confused and 4) unconscious. Presence of respiratory depression (yes, no), treated heart failure, hypotension, supraventricular or ventricular arrhythmias and AV-block was also evaluated. All above measures took part at three points in time: prior to randomisation, 15 min thereafter and on admission to a hospital. Evaluation of signs of heart failure and heart rhythm was carried out once, prior to randomisation. Pain and anxiety treated after hospital admission were reported. Survival (30 days and 1 year) and the proportion of patients with a final diagnosis of acute myocardial infarction (AMI) were reported. Finally, treated heart failure, hypotension, supraventricular or ventricular arrhythmia and AV block after hospital admission were reported. 2.7. Outcome measures The primary endpoint (the same for the medical and educational intervention) was the estimated intensity of pain or discomfort according to VAS as perceived and assessed by the patients 15 min after randomisation. The nurses assisted the patients in handling VAS. Secondary endpoints (the same for the medical and educational intervention) were 1. Estimated intensity of pain or discomfort according to VAS as perceived and
Fig. 1. Research plan with a 4 factor design; educational and medical intervention. Medical intervention included the combination of the anxiolytic Midazolam (Mi) and the analgesic Morphine (Mo).
3582
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
assessed by the patients on admission to a hospital. 2. Anxiety, 3. Hypotension, 4. Respiratory depression, 5. Drowsiness, 6. Nausea or vomiting, 7. Further requirement of pain relieving treatment, 8. Heart rate, 9. Systolic blood pressure, 10. Oxygen saturation, 11. Survival to 30 days, and 12. A final diagnosis of AMI and ACS. Acute myocardial infarction was defined according to the diagnosis given in the hospital records. Acute coronary syndrome was defined as a final hospital diagnosis of either AMI or unstable angina pectoris.
2.8. Statistical methods Sample size calculation was based on a difference of 20% in pain intensity between treatment groups (Mi + Mo or Mo only), 15 min after randomisation. To show this with 80% power and a significance level of 0.05 (two-sided test) the required number of patients in each group was 255. However, in order to include a reasonable number of patients in the prehospital emergency cardiac care trained group of PEN (Educational Intervention), under the assumption of a tenfold larger part of PEN not trained in prehospital emergency cardiac care (Standard EMS Education), it was decided to include at least 1650 patients in total (150 + 1500). All analyses were performed on an intention-to-treat basis, i.e. irrespective of whether a patient actually received the treatment to which he/she was randomised. There were 33 patients deviating from the randomised treatment: 28 in the Mi + Mo group did not receive the treatment and 5 in the Mo only group did receive Mi. Fisher's exact test was used to test for differences in dichotomous variables and the Mann–Whitney U test was used for ordered/continuous variables. For survival analysis Kaplan–Meier estimates were used and groups were compared using the log rank test. Interaction between the different interventions was analysed using the adjusted rank transform test (ART) [13]. All tests are two-sided and a p-value of b0.05 for the primary endpoint and b0.01 for other comparisons were considered statistically significant. All analyses were performed using SAS for Windows version 9.2.
3. Results A total of 3666 patients were included, and of these 1830 were not admitted to the RCT due to not fulfilling the inclusion criteria or had any exclusion criteria (Fig. 2). Of 1836 randomised patients, 73 were not included in analyses, 62 (32 + 30) did not agree to participate and 11 had incomplete randomised registration. The remaining 1763 patients with suspected ACS were included in analyses. Of these, 69
patients were randomised and therefore kept in the analyses despite not fulfilling the inclusion criteria or having exclusion criteria. Among these 1763 patients 890 were randomised to the combination Mi + Mo and 873 to Mo alone. In the following, results will be presented according to intention to treat for all randomised patients and separately for the patients who finally fulfilled the criteria for ACS (subgroup analyses) as shown in the following tables. There was no statistically significant difference between the two treatment arms in terms of age, sex, previous history or treatment by a PEN trained in prehospital emergency cardiac care (Table 1). Heart rate, systolic blood pressure and oxygen saturation were significantly lower on admission to a hospital among patients randomised to combination therapy when all patients were analysed (Table 2). There was no statistically significant difference between groups in terms of treatment with oxygen, aspirin, clopidogrel, nitrates or beta-blockers prior to hospital admission. The proportion of patients who received Mo did not differ but the mean dose of Mo given was lower among those who received Mi + Mo (5.3 mg versus 6.0 mg; p b 0.0001) (Table 3). In the ACS patient subgroup nitrates was less frequently given to those who received combination therapy. There was no statistically significant difference between groups in terms of proportion of patients who had ECG-recorded, ECG sent or various ECG findings (Table 4). There was no statistically significant difference between the two groups regarding the primary endpoint of the estimated intensity of pain 15 min after randomisation (p = 0.78) and the interaction between the effects of the different interventions (Mi + Mo vs Mo only and treated PEN trained vs not trained in prehospital emergency cardiac care) was nonsignificant (p = 0.85) nor was there any significant difference between the groups prior to randomisation or on admission to a hospital. There was no significant difference between the two groups regarding presence of pain in any localisation at any time (Table 5).
Fig. 2. CONSORT flow diagram on patients with suspected ACS.
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
3583
Table 1 Age, sex and previous history. Randomised treatment (ACS)a
Randomised treatment (all)
Age; years mean ± SD Median (25th,75th percentile) Women (%) Previous history (%) Myocardial infarction (31/32/2/3)c Angina pectoris (37/39/4/5) Hypertension (35/29/3/1) Diabetes mellitus (28/26/1/1) Heart failure (44/38/7/7) Stroke (29/26/0/2) Peripheral artery disease (33/30/4/2) Chronic obstructive pulmonary disease (30/27/2/1) Renal disease (29/28/1/3) Cancer (29/26/2/2) Smoking (%) (218/202/58/60) Treated by PEN trained in prehospital emergency cardiac care (%) (11/15/6/2) a b c
Midazolam + Morphine
Morphine only
n = 890 69.8 ± 13.5 72 (61, 81) 44 38 29 44 21 14 8 3 9 6 10 21 18
pb
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
69.8 ± 13.4 71 (61, 80) 46
72.5 ± 12.4 74 (64, 82) 36
72.5 ± 12.1 73 (64, 82) 35
35 29 40 19 15 11 3 9 7 11 18 20
49 41 46 23 15 9 4 8 7 9 22 19
40 38 44 23 13 12 4 6 7 11 18 21
0.08
0.03
pb
0.03
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
In terms of other symptoms there was no difference between groups regarding paleness or cold sweat. However, anxiety was less frequent among the patients randomised to Mi + Mo both 15 min after randomisation (31% versus 39%; p = 0.002) and on admission to a hospital (12% versus 26%; p b 0.0001). Furthermore nausea and vomiting were less frequent among patients randomised to Mi + Mo on admission to a hospital (9% versus 13%; p = 0.003) (Table 5). In the subset of patients with ACS both anxiety and nausea/vomiting were less frequent on admission to a hospital in the group that received combination therapy. The distribution of patients according to drowsiness differed significantly both 15 min after randomisation and on admission to a hospital. Thus, patients who were randomised to Mi + Mo were drowsier (Table 5).
There was no difference between groups in terms of respiratory depression and aggressiveness (Table 5). There was no difference between groups either with regard to complications prior to hospital admission or complications after hospital admission. Survival to 30 days did not differ and the proportion of patients who had a final diagnosis of AMI and ACS were similar in the two groups (Table 6).
4. Discussion To the best of our knowledge this is the first large scale intervention study with the aim to evaluate symptom relief prior to hospital admission in suspected ACS.
Table 2 Cardiopulmonary findings prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Heart rate; beats/min mean ± SD Prior to randomisation (19/17/9/3) c 15 min after randomisation (60/50/15/10) On admission to a hospital (65/75/18/21) Systolic blood pressure; mm Hg mean ± SD Prior to randomisation (18/22/9/5) 15 min after randomisation (82/88/28/18) On admission to a hospital (85/114/28/33) Oxygen saturation; % mean ± SD Prior to randomisation (30/36/13/11) 15 min after randomisation (55/62/19/14) On admission to a hospital (62/82/20/25) Rate of breathing; breath/min mean ± SD Prior to randomisation (100/81/47/23) 15 min after randomisation (154/131/62/40) On admission to a hospital (162/149/64/48) Signs of heart failure (auscultatory rates) (%) (418/422/156/133) Sinus rhythm (%) (44/50/22/12) a b c
Midazolam + Morphine
Morphine only
n = 890
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
86.1 ± 24.2 81.5 ± 21.7 78.8 ± 20.6
87.1 ± 25.2 84.0 ± 23.3 81.5 ± 22.6
0.02
82.3 ± 20.3 78.5 ± 18.5 76.1 ± 17.3
83.8 ± 24.8 80.8 ± 22.8 78.4 ± 21.9
151.6. ± 27.1 134.8 ± 23.9 131.7 ± 22.5
152.0 ± 27.7 139.3 ± 25.1 135.5 ± 23.2
0.0003 0.003
152.4. ± 29.3 135.5. ± 25.8 132.9. ± 22.8
151.7 ± 28.0 141.1 ± 24.7 136.2 ± 23.6
95.7. ± 3.8 96.8 ± 2.7 97.1 ± 2.4
96.0 ± 3.4 97.2 ± 2.3 97.5 ± 2.1
0.01 0.006
95.6. ± 3.5 96.9. ± 2.5 97.2. ± 2.3
95.5 ± 3.9 96.9 ± 2.6 97.5 ± 2.2
18.3. ± 5.1 17.0 ± 4.2 16.4 ± 3.8 4 81
18.4 ± 5.2 17.2 ± 4.3 16.6 ± 3.8 5 79
18.0. ± 5.1 16.7. ± 4.1 16.1. ± 3.8 7 83
18.2 ± 5.2 17.1 ± 4.3 16.4 ± 3.5 6 80
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
p
b
pb
0.01
3584
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
Table 3 Treatment prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Oxygen (%) (12/14/6/2)c Mean (median) dosed; l/min Aspirin (%) (12/16/6/2) Mean (median) dosed; mg Clopidogrel (%) (14/14/6/2) Mean (median) dosed; mg Nitrates (%) (12/15/6/3) Mean (median) dosed; mg Beta-blockers (%) (15/15/6/2) Mean (median) dosed; mg Midazolam (%) (10/15/5/2) Mean (median) dosed; mg Morphine (%) (15/13/7/1) Mean (median) dosed; mg a b c d e f
Midazolam + Morphine
Morphine only
n = 890 81 3.8 (3) 65 294 (320) 9 575 (600) 83 0.78 (0.8) 4 11.2 (10) 97e 1.12 (1.00) 83 5.3 (5.0)
pb
Midazolam + Morphine
Morphine only
n = 873
n = 308
n = 291
81 3.7 (3) 66 295 (320) 9 564 (600) 86 0.77 (0.8) 5 10.5 (10) b1f 1.60 (2.00) 81 6.0 (5.0)
86 4.3 (3) 72 294 (320) 20 569 (600) 80 0.79 (0.8) 5 11.4 (12.5) 97e 1.13 (1.00) 85 6.1 (5.0)
89 4.1 (3) 75 301 (320) 21 570 (600) 88 0.83 (0.8) 6 10.4 (15) b1f 2.25 (2.25) 86 6.7 (6.0)
b0.0001
b0.0001
pb
0.009
b0.0001 0.004 0.04
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Of those receiving treatment. 28/9 of patients did not receive Midazolam. 5/2 of patients received Midazolam.
unlikely that the choice of another primary endpoint would have changed the results and the interpretation of this study.
4.1. The primary and secondary endpoints The trial found that treatment of patients suspected of ACS in the prehospital setting with a combination of an anxiolytic and an analgesic did not reduce the estimated intensity of pain as compared with an analgesic alone. This was the primary endpoint of the study. However, the combination therapy resulted in less anxiety and less nausea and vomiting, and a reduced use of Mo. There was increased drowsiness but no sign of respiratory depression or increased aggressiveness. The primary hypothesis was that the combination of an anxiolytic and an analgesic reduced pain. This was not confirmed. Thus, it does not appear as though reduced anxiety is reflected in a lower estimation of pain on VAS. The effect of an anxiolytic should be reflected in reduced anxiety rather than in reduced pain, and the present study underlined this.
4.3. Comparison with other trials A few previous studies have addressed pain relief in suspected myocardial ischemia and the use of benzodiazepines. In the first study, 38 patients admitted for AMI were randomised to intravenous followed by oral Diazepam for 3 days or control. The Diazepam group had a lower requirement of Morphine [14]. In the second study 40 patients with cocaine associated ACS were randomised to either Diazepam or nitroglycerin with a similar effect on chest pain [15]. In a third study 13 patients with a known coronary artery disease had undergone an exercise test on two separate days, one with pretreatment with Diazepam and one with placebo. Treatment with Diazepam was associated with prolonged time to ST-depression and improved exercise duration [16]. Overall, our results highlight the activity of the PEN in provision of a more effective pain-relieving strategy in the prehospital setting of a suspected ACS. Thus, only about half of the patients had a pain score of b 3 on admission to a hospital. This could not be considered as a sufficient EMS care. One might argue that the dose of Mo given was too low [14]. However, there is a risk that higher levels of Mo would have resulted in more symptoms of nausea and vomiting.
4.2. Choice of endpoint One might argue whether an alternative primary endpoint had been more appropriate when evaluating the effect of an anxiolytic added to a narcotic analgesic. The overall aim of the intervention was to improve well-being in a life threatening situation. Regardless of the instrument being used this task will be associated with difficulties. We therefore studied a large number of secondary endpoints in order to give a clinical picture as complete as ever possible. It is Table 4 ECG findings prior to hospital admission.
Randomised treatment (ACS)a
Randomised treatment (all) Midazolam + Morphine
ECG recorded (%) (12/14/6/2)c ECG sent (%) (16/24/8/5) ECG findings (%) ST-elevation (93/94/44/28) ST-depression (109/128/52/44) T-wave inversion (242/235/102/90) Pathologic Q-wave (340/323/137/122) Left bundle branch block (232/225/99/83) a b c
Morphine only
pb
Midazolam + Morphine
Morphine only
n = 890
n = 873
n = 308
n = 291
>99 75
>99 78
100 84
>99 91
19 28 16 7 7
19 30 13 8 9
38 38 21 9 11
37 45 19 12 11
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively.
pb
0.01
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
3585
Table 5 Symptom prior to hospital admission. Randomised treatment (ACS)a
Randomised treatment (all)
Morphine only
n = 873
n = 308
n = 291
6 (5,7.2)
6 (5,7.5)
6 (5,7.5)
6.3 (5,8)
4 (3,5.5)
4 (3,5.4)
4 (2.5,5.8)
4 (3,6)
3 (1,4)
3 (1,4)
2.5 (1,4.4)
3 (1,4.4)
97 45 23 23 10
97 46 25 25 12
97 51 20 21 7
96 54 19 26 7
81 28 18 18 7
84 31 19 18 9
81 33 16 15 5
85 39 15 18 4
63 20 13 13 6
67 22 14 14 8
66 25 10 12 5
69 27 12 12 3
45 26 66 39
44 27 64 36
54 26 63 38
54 30 60 34
30 15 31 18
28 16 39 19
38 13 31 16
36 19 38 16
18 9 12 9
21 13 26 12
24 8 11 10
25 18 23 8
85 13 2 b1
98 2 b1 b1
84 15 b1 b1
98 1 b1 b1
86 12 2 b1
97 3 b1 0
85 13 2 b1
97 2 b1 0
Respiratory depression (%) 15 min after randomisation (41/275/16/84) On admission to a hospital (39/285/16/88)
b1 b1
b1 b1
1 1
1 b1
Aggressiveness (%) 15 min after randomisation (45/275/17/84) On admission to a hospital (40/286/15/88)
b1 b1
b1 b1
b1 b1
b1 0
Localisation of pain or discomfort (%) Prior to randomisation Chest (14/17/7/2) Arm(s) (26/33/10/9) Back (30/40/13/11) Neck (36/41/14/8) Stomach (28/45/11/11) 15 min after randomisation Chest (54/57/15/11) Arm(s) (69/66/20/14) Back (76/78/24/19) Neck (79/76/24/17) Stomach (70/83/20/20) On admission to a hospital Chest (102/89/29/25) Arm(s) (108/97/33/28) Back (109/97/34/28) Neck (112/100/33/26) Stomach (102/102/33/26) Other symptoms (%) Prior to randomisation Pale, cold sweat (15/18/7/2) Nausea, vomiting (32/33/13/12) Anxiety (30/32/16/10) Dyspnea (28/34/13/13) 15 min after randomisation Pale, cold sweat (59/51/16/12) Nausea, vomiting (68/67/21/18) Anxiety (76/68/28/17) Dyspnea (73/66/23/20) On admission to a hospital Pale, cold sweat (95/81/30/22) Nausea, vomiting (106/90/31/26) Anxiety (115/105/37/29) Dyspnea (109/100/34/30) Alertness (%) 15 min after randomisation (46/277/18/85) Awake Dozy, confused Very dozy, confused Unconscious On admission to a hospital (39/286/15/89) Awake Dozy, confused Very dozy, confused Unconscious
a b c d
Morphine only
n = 890
pb
Midazolam + Morphine
Estimated severity of pain or discomfort Prior to randomisation Pain score (54/68/21/26)c median (25th, 75th percentile) 15 min after randomisation Pain score (78/99/31/36) median (25th,75th percentile) On admission to a hospital Pain score (92/112/32/39) median (25th,75th percentile)
Midazolam + Morphine
0.08
0.002
0.003 b0.0001
b0.0001d
0.08
0.0007 0.0005
b0.0001d
b0.0001d
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Ordered degree of alertness used in p-value calculation.
pb
b0.0001d
3586
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
Table 6 Complications and final diagnosis. Randomised treatment (ACS)a
Randomised treatment (all)
Prior to hospital admission (%) Treated heart failure (13/15/3/1)c Treated hypotension (14/15/4/1) Treated supraventricular arrhythmia (14/17/3/2) Treated ventricular arrhythmia (13/18/3/3) Treated AV block (13/15/3/1) After hospital admission (%) Treated anxiety (40/33/11/5) Treated heart failure (30/32/4/5) Treated hypotension (31/31/4/5) Treated supraventricular arrhythmia (30/30/4/5) Treated ventricular arrhythmia (33/31/4/5) Treated AV block (30/32/4/6) Treated chest pain (39/39/12/10) Survival to 30 daysd,e (%) Survival to 1 yeard,e (%) Final diagnosis (%) (62/48) Acute myocardial infarction Acute coronary syndrome a b c d e
Morphine only
Midazolam + Morphine
n = 890
n = 873
1.4 2.2 0.9 0.0 0.5
1.5 0.9 0.8 0.5 0.5
11.8 11.6 4.7 5.6 1.8 2.0 35.8 97.2 89.4 25.5 37.2
pb
Midazolam + Morphine
Morphine only
n = 308
n = 291
2.3 3.0 0.0 0.0 0.3
2.8 0.7 0.0 1.0 0.3
9.8 12.6 3.8 6.0 1.2 2.1 39.8 97.2 90.0
14.8 15.1 7.6 6.2 3.9 2.6 48.6 95.5 87.8
11.9 19.2 6.6 7.0 2.8 3.2 53.7 96.4 88.7
26.4 35.3
68.5
74.9
0.06
pb
0.06
0.09
Only patients with confirmed ACS. p-Values given if below 0.10. Number of patients with missing information in the two groups, respectively. Only the first occasion (n = 817 and 800, respectively) included for those with multiple inclusions. Kaplan–Meier estimate (not all patients are followed for 1 year, end of follow-up = 2011-04-01).
4.4. Anxiety and nausea or vomiting A secondary objective of this study was to assess the impact of the combination of an anxiolytic and an analgesic on the presence of anxiety as assessed by an EMS nurse. Out of consideration for the patients' status we did not use a self-rating anxiety scale. Although our finding of a lower anxiety level, particularly on admission to a hospital, might be regarded as an expected finding, since this has not previously been reported in the prehospital setting, these data are new. Treatment of patients in a life threatening situation should, as always in medical practice, be based on facts rather than expectations. However, two previous studies have evaluated the association between treatments with Diazepam and anxiety in AMI in a hospital. One showed reduced anxiety [14] and the other did not [16]. Symptoms of nausea and vomiting on admission to a hospital were reduced among patients who received the combination of Mi and Mo. This might at least to some extent be explained by a lower dose of Mo given to this treatment group. 4.5. Safety and side effects The combination therapy was associated with increased drowsiness. We do not know whether patients had a positive or a negative reaction to this type of side effect. The reaction was characterised by decreased alertness but not unconsciousness. Previous experience of this combination therapy indicates that adverse events are infrequent even when the medications were given intravenously [14,17–21]. These studies were performed on humans as well as animals. There was no indication that the combination therapy resulted in respiratory depression or change in mood. Heart rate, blood pressure and oxygen saturation were significantly lower after combination therapy on admission to a hospital. However, differences in absolute numbers were small and the clinical relevance might be argued. 4.6. Final diagnosis Slightly more than one third had a final diagnosis of ACS. There were no ECG criteria and only a suspicion of ACS was required for
inclusion. Thus our results might be extrapolated to a patient population with pain or discomfort raising either a vague or a strong suspicion of ACS. 4.7. Limitation Although it was recommended that all patients in the participating EMS organisations should be considered for inclusion, we know that this was not always the case. However, there is no information on the numbers of the total population of patients with chest pain and discomfort admitted to EMS units in the study areas that were available. Since verbal acceptance was required for inclusion, we assume that the PENs had a tendency not to include patients suffering from severe insufficiency in vital functions and those with a very severe pain, due to communication problems. We have no information about the characteristics of the baseline population from which the study cohort was recruited. The doses of Mo and Mi given were low. We do not know whether tolerability would be the same if doses were increased. Further, since a great number of the patients admitted to EMS were not randomised, the study has a selection bias due to unspecific symptoms of a suspected ACS and the demand for reported pain ≥4 on a VAS. Since the patients sometimes and the healthcare provider always were aware of which treatment alternative the patient was allocated to we cannot exclude the risk of bias. Thus, the combination of an open label design and some not very objective endpoints may lead to considerable bias in reporting. There were no written information on how to assess anxiety, paleness, cold sweat, nausea, vomiting and dyspnea. In terms of anxiety one cannot exclude the risk that patients who were drowsier might only seem to be less anxious in the eyes of the external observer. There is also a risk that the increased drowsiness in the intervention group might have affected the reliability of the main outcome measure (pain) in this group. The difference in missing rate between the two groups in the reporting of alertness, respiratory depression and aggressiveness is explained by the fact that in the initial phase of the study this was only reported among patients allocated to Mi.
B.W. Sundström et al. / International Journal of Cardiology 168 (2013) 3580–3587
5. Conclusion Despite the fact that the combination of anxiolytics and analgesics as compared with analgesics alone reduced anxiety and the requirement of morphine in the prehospital setting of acute coronary syndrome, this strategy did not reduce patients' estimation of pain (primary endpoint). More effective pain relief among these patients is warranted.
5.1. Clinical implications The clinical implications of this trial are dependent on how to balance the results regarding the primary endpoint with the results regarding the secondary endpoints. A conservative approach would be to ignore the results on the secondary endpoints and regard them as hypotheses generating. However, much of the results on the secondary endpoints are, from a pharmacological point of view, expected and therefore most likely of clinical relevance. Among patients with pain or discomfort in the chest raising some suspicion of an ACS and showing signs of anxiety, the combination of an analgesic and an anxiolytic does not appear to relieve pain but anxiety. The combination also seems to relieve nausea or vomiting and reduce the requirement of Mo. However, the combination will result in an increased prevalence of drowsiness in some patients but no respiratory depression. Drowsiness may impair their ability to engage in meaningful conversation by ED/treating physician. Furthermore history may be difficult to obtain and consent can be an issue if the patient is going for a procedure. Whether similar problems may appear if the patient suffers from severe anxiety remains speculative. From a hemodynamic and respiratory perspective, the combination appears to be safe to use among patients with acute chest pain and anxiety in the prehospital setting. More effective pain relieving drugs than the addition of anxiolytics to narcotic analgesics are warranted.
Funding This study was funded by the University of Borås, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland and Sparbanksstiftelsen Sjuhärad, Sweden.
Acknowledgements The authors would like to thank the EMS organisations and their personnel in the Region of Västra Götaland and in the city of Halmstad, Sweden. Special thanks to the contact persons in each organisation and last but not least to all patients agreeing to take part in the trial.
3587
References [1] Herlitz J, Richter A, Hjalmarson Å, et al. Chest pain in acute myocardial infarction. A descriptive study according to subjective assessment and morphine requirement. Clin Cardiol 1986;9:423–8. [2] Gardtman M, Dellborg M, Brunnhage Ch, et al. Effect of intravenous metoprolol before hospital admission on chest pain in suspected acute myocardial infarction. Am Heart J 1999;137:821–9. [3] Zedigh C, Alho A, Hammar E, et al. Aspects on the intensity and the relief of pain in the pre-hospital phase of acute coronary syndrome: experiences from a randomised clinical trial. Coron Artery Dis 2010;21:113–20. [4] De Jong MJ, Chung ML, Roser LP, et al. A five-country comparison of anxiety early after acute myocardial infarction. Eur J Cardiovasc Nurs 2004;3:129–34. [5] Khan MA, Karamat M, Hafizullah M, Nazar Z, Fahim M, Gul AM. Frequency of anxiety and psychosocial stressful events in patients with acute myocardial infraction. J Ayub Med Coll Abbottabad 2010;22:32–5. [6] Guanghui L, Xianzheng W, Wenlin M, et al. Epidemiology and preventive medicine: epidemiology of cardiovascular disease: e0282 effect of comprehensive intervention on anxiety and depressive symptoms in patients after ACS. Heart 2010;96(Suppl. 3): A89–90. [7] Herlitz J, Bång A, Omerovic E, et al. Is pre-hospital treatment of chest pain optimal? Both relief of pain and anxiety are needed. Int J Cardiol 2011;149:147–51. [8] COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45.852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1622–32. [9] European Society of Cardiology. The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation. Eur Heart J 2008;29:2909–45. [10] American College of Cardiology/American Heart Association. A report of the American College of Cardiology/American Heart Association Task Force on Practise Guidelines. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 2004;110:e82-293. [11] McGrath P, Seifert C, Speechley K, et al. A new analogue scale for assessing children's pain: an initial validation study. Pain 1996;64:435–43. [12] McLean SA, Domeier RM, DeVore HK, Hill EM, Maio RF, Fredriksen SM. The feasibility of pain assessment in the pre-hospital setting. Prehosp Emerg Care 2004;8: 155–61. [13] Leys C, Schumann S. A nonparametric method to analyze interactions: the adjusted rank transform test. J Exp Soc Psychol 2010;46:684–8. [14] Melsom M, Andreassen H, Melsom T, et al. Diazepam in acute myocardial infarction: clinical effects and effects on catecholamines, free fatty acids, and cortisol. Br Heart J 1976;38:804–10. [15] Baumann BM, Perrone J, Hornig SE, et al. Randomised double-blind, placebocontrolled trial of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndromes. Acad Emerg Med 2000;7:878–85. [16] Rossetti E, Fragasso G, Xuereb RG, et al. Antiischemic effects of intravenous diazepam in patients with coronary artery disease. J Cardiovasc Pharmacol 1994;24: 55–8. [17] Dixon RA, Edwards IR, Pilcher J. Diazepam in immediate post-myocardial infarct period. A double blind trial. Br Heart J 1980;43:535–40. [18] Vrana M, Hess L, Vranova Z, et al. An experimental contribution to the treatment of acute myocardial infarction. Czech Med 1987;10:142–55. [19] Hess L, Vrana M, Vranova Z, et al. The electrostabilizing effect of a combination of midazolam and fentanyl: an experimental study in the dog. Cor Vasa 1989;31: 411–8. [20] Vrana M, Fejfar Z, Hess L, et al. Analgosedation-enhanced baroreflex sensitivity in acute local myocardial infarction. Cor Vasa 1991;33:428–34. [21] Baris S, Karakaya D, Aykent T, et al. Comparison of midazolam with or without fentanyl for conscious sedation and hemodynamics in coronary angiography. Can J Cardiol 2001;173:277–81.