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Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE
IJCA-24648; No of Pages 6 International Journal of Cardiology xxx (2017) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE Alina Achilles a,1, Annemarie Mohring a,1, Lisa Dannenberg a, Kerstin Piayda a, Bodo Levkau b, Thomas Hohlfeld c, Tobias Zeus a, Malte Kelm a, Amin Polzin a,⁎ a b c
Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany
a r t i c l e
i n f o
Article history: Received 11 December 2016 Received in revised form 19 February 2017 Accepted 24 February 2017 Available online xxxx Keywords: Aspirin Coronary artery disease Dipyrone, drug interactions Pharmacology
a b s t r a c t Background: The non-opioid analgesic dipyrone can trigger life-threatening blood formation disorders. However, it is frequently used, as many patients with coronary artery disease (CAD) rely on non-opioid analgesics to relieve pain. In this study, we investigated the incidence of death, myocardial infarction (MI) or stroke in CAD patients with aspirin and dipyrone comedication as compared to aspirin-alone. Methods: We conducted an observational pilot study in 72 CAD patients with aspirin ± dipyrone comedication in the department of cardiology of the University Hospital Düsseldorf. The primary end point was a composite of death, myocardial infarction (MI) or stroke. The secondary end points were the components of the primary end point. The median follow-up period was 3.2 years. Results: The primary end point occurred 67% of patients in the aspirin + dipyrone group as compared to 31% in the aspirin-alone group (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.7 to 12.3; P = 0.0028;). All-cause mortality was significantly higher in the aspirin + dipyrone group (44%) than the aspirin-alone group (22%; OR 2.8, 95% CI 1.01 to 7.8; P = 0.049). Ischemic events (MI and stroke) were more frequent in the aspirin + dipyrone group as compared to the aspirin alone group as well (OR 4, 95% CI 1.1 to 14; P = 0.03). Conclusion: In this hypothesis generating pilot analysis, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events. These data have to be confirmed in larger registries and trials. Clinical trial registration: http://clinicaltrials.gov/ct2/show/NCT01402804; Identifier: NCT01402804; Date of registration: July 25, 2011. © 2017 Elsevier B.V. All rights reserved.
1. Introduction In the 1950s an increased risk of life-threatening blood formation disorders (agranulocytosis) by the non-opioid pyrazolinone analgesic dipyrone was registered [1]. This led to complete withdrawal of dipyrone in some countries (e.g. United States). Nevertheless chronic pain is very frequent and analgesics are among the most frequently used medications worldwide. 40% of coronary artery disease (CAD) patients suffer from chronic pain and rely on non-opioid analgesic
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; TIA, transient ischemic attack. ⁎ Corresponding author at: Moorenstrasse 5, 40225 Düsseldorf, Klinik für Kardiologie, Pneumologie und Angiologie. E-mail address: [email protected] (A. Polzin). 1 Both authors contributed equally.
treatment [2]. However non-steroidal anti-inflammatory drugs (NSAID) are not recommended in CAD patients by the European Society of Cardiology [3,4]. Therefore, the combination of (i) superior analgesic and antipyretic effects of dipyrone, (ii) its low incidence of gastrointestinal side effects and (iii) a lack of sufficient alternatives led to increased use of dipyrone [5–9]. In central European Countries like Germany, dipyrone intake quadrupled to defined daily doses above 140 during the last 15 years [10]. It is already among the most frequently used non-opioid analgesic in regions, such as Eastern Europe and Central and South America. As it is available over the counter in Mexico, an extensive use in the United States exists despite the withdrawal by the Food and Drug Administration as well [11,12]. Besides its myelotoxic effects, dipyrone additionally inhibits laboratory response to aspirin in-vitro and ex-vivo in healthy individuals and patients with CAD [13–16]. Aspirin (acetylsalicylic acid; ASA), is a widely used cost-effective drug which is indispensable in secondary
http://dx.doi.org/10.1016/j.ijcard.2017.02.122 0167-5273/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
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A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx
prophylaxis in CAD patients. Additionally, it is the backbone of dual and triple antiplatelet therapy following coronary interventions and myocardial infarction (MI) reducing the risk of thrombotic events. However, it is known that on-treatment platelet reactivity differs interindividually [17–22]. In CAD patients, impaired pharmacodynamic response to aspirin is associated with increased incidence of mortality and stent thrombosis [23]. In patients with ischemic stroke, infarct volume and severity of stroke are associated with impaired aspirin antiplatelet effects [24]. In this study, we hypothesized, that long-term dipyrone comedication in aspirin treated CAD patients enhances the incidence of adverse events. Therefore, we investigated the incidence of death, MI and stroke in CAD patients with aspirin and dipyrone comedication.
2.3. Statistical analyses Data were analyzed using the GraphPad Prism statistical software (GraphPad Software Inc., San Diego) and the IBM SPSS©- Software (New York, USA) respectively. Odds ratios with 95% confidence interval (CI) were estimated according to Altman. Hazard ratios with 95% CI and log-rank tests were calculated for survival analyses. Normality of data distribution was tested using histograms, q-q-plots and KolmogorovSmirnov test. Non-parametric tests were used in case of non-normally distribution. t-test was used to analyze continuous variables. Chi square test and Fisher's exact test were used to analyze categorical variables. P b 0.05 was considered significant. This pilot study was explorative. No sample size calculation was conducted, as there were no data to calculate a reliable effect size.
2. Patients and methods 2.1. Study design, population and follow-up We conducted a prospective, observational, single-center all-comers pilot cohort trial between February 2011 and February 2015. Recruitment of patients was during hospitalization in the department of cardiology of the Heinrich- Heine University Medical Center Düsseldorf. Patients were in ambulatory care during follow-up. Eligibility criteria were angiographically proven CAD (both obstructive and nonobstructive), informed consent and age N 18 years. Exclusion criterion was hemorrhagic diathesis. Two groups of patients were investigated. The aspirin- alone group consisted of 36 CAD patients with permanent low-dose (100 mg/d) aspirin medication. The aspirin + dipyrone group compromised 36 patients with low-dose aspirin and permanent dipyrone comedication because of chronic pain. Dipyrone doses and dosing intervals were not controlled. Doses varied from 0.5–3 g per day and intervals from q.24 h to q.6 h. No patient matching was performed. For every patient that was included in the aspirin + dipyrone group, a patient was included in the aspirin-alone group as well. Data on baseline characteristics, clinical presentation, cardiovascular risk factors and comedication were collected during hospitalization. Follow-up was conducted by annually telephone interview of the patient's attending physician. No patient was lost for follow-up. The study conformed to the Declaration of Helsinki and was approved by the University of Düsseldorf Ethics Committee. Informed consent was obtained from all patients.
3. Results 3.1. Study patients Patients in the aspirin- alone group had a mean age of 76 years, 39% were of male gender. The mean age in the aspirin + dipyrone group was 77 years with 50% being male. The prevalence of baseline characteristics, cardiovascular risk factors and prior diseases was similar in both groups (Table 1). Acute coronary syndrome was the reason of hospitalization in 18 patients of the aspirin- alone group (3 ST- elevation myocardial infarctions, 10 non ST- elevation myocardial infarctions, 5 unstable angina pectoris) and 12 patients in the aspirin + dipyrone group (6 non ST- elevation myocardial infarctions, 6 unstable angina pectoris). The remaining patients presented with stable coronary artery disease. Clinical presentation, symptoms and number of diseased vessels did not differ between groups (Table 2). 42% of aspirin-alone patients (15 patients) were treated with PCI as compared to 44% in the aspirin + dipyrone group (16 patients; P = 0.99). None of the patients were treated by coronary artery bypass grafting. Stent-type (bare-metal stent vs. drug eluting stent), procedural success, multi-vessel vs. singlevessel intervention, number of stents or target vessel did not differ
Table 1 Baseline patient characteristics. Aspirin-alone Group Aspirin + Dipyrone (N = 36) Group (N = 36) P valuea
2.2. Study end points The primary endpoint was a composite of death, MI or stroke. The secondary end points were the components of the primary end point. Death was defined as all-cause mortality. Cause of death was classified as death from cardiovascular cause and death from noncardiovascular cause. According to Academic Research Consortium standardized end point definitions, unless a noncardiovascular cause of death was clearly provided, unwitnessed and sudden deaths were assumed to be cardiovascular [25]. Noncardiovascular causes were subclassified in death from infection and death from cancer. MI was defined as hospitalization with typical clinical symptoms, elevation of cardiac biomarkers and new angiographically proven coronary occlusion. MI was further subclassified in ST- elevation MI and non ST- elevation MI. ST- elevation was defined as new ST elevation at the J- point in at least two contiguous leads with ≥0.2 mV in leads V1–V6 and/or ≥0.1 mV in other leads. MI without meeting the above mentioned criteria of ST elevation was classified as non ST- elevation MI. Definition of stroke was clinical presentation with new focal neurologic deficits. Stroke was subclassified in stroke with symptoms lasting N 24 h and conformation of diagnosis by computer tomographic scan or magnet resonance imaging and transient ischemic attack (TIA), defined as new focal neurologic deficits lasting b 24 h with complete remission of symptoms.
Characteristic Age - years (mean ± S.D.) Male gender – no. (%) Body mass index (mean ± S.D.)
76 ± 13 22 (61%) 27 ± 4.6
77 ± 10 18 (50%) 25 ± 3.7
0.65 0.34 0.11
Cardiovascular risk factor – no. (%) Hypertension Hypercholesterolemia Diabetes mellitus Adiposity (body mass index N 30) Smoking (current)
36 (100%) 23 (64%) 12 (33%) 8 (22%) 6 (17%)
36 (100%) 27 (75%) 11 (31%) 5 (14%) 6 (17%)
N0.99 0.31 0.8 0.36 N0.99
16 (44%) 9 (25%) 4 (11%) 16 (44%) 25 (69%)
22 (61%) 10 (28%) 4 (11%) 22 (61%) 21 (58%)
0.16 0.79 N0.99 0.16 0.33
10 (28%)
10 (28%)
N0.99
Other medical history – no. (%) Previous myocardial infarction Previous bypass surgery Previous stroke Reduced systolic LV-functionb Impaired renal function at admissionc Atrial fibrillation a
P value of chi square/Fisher's exact test analysis in categorical and t-test in continuous variables. b Reduced systolic LV- function was defined as systolic left ventricular ejection fraction b40% during index hospitalization. c Impaired renal function at admission was defined as creatinine level at admission N1.2 mg/dl in men and N0.9 mg/dl in women.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx Table 2 Clinical presentation and comedication. Aspirin-alone Group (N = 36)
Aspirin + Dipyrone Group (N = 36)
P value⁎
3 (8%) 10 (28%)
0 (0%) 6 (17%)
0.08 0.26
5 (14%) 8 (22%)
6 (17%) 8 (22%)
0.74 N0.99
Angina pectoris – no. (%) CCS IV CCS III CCS II CCS I No angina pectoris
8 (22%) 4 (11%) 6 (17%) 3 (8%) 15 (42%)
8 (22%) 7 (19%) 3 (8%) 1 (3%) 17 (47%)
N0.99 0.33 0.29 0.30 0.64
Dyspnoea– no. (%) NYHA IV NYHA III NYHA II NYHA I
6 (17%) 16 (44%) 9 (25%) 5 (14%)
4 (11%) 16 (44%) 11 (31%) 5 (14%)
0.5 N0.99 0.6 N0.99
No. of diseased vessels – no. (%) 3 vessel disease 2 vessel disease 1 vessel disease Microangiopathy
23 (64%) 4 (11%) 3 (8%) 6 (17%)
24 (67%) 4 (11%) 3 (8%) 5 (14%)
0.80 N0.99 N0.99 0.74
Medication – no. (%) Aspirin Dipyrone NSAIDs P2Y12 inhibitor ACE-/AT-II-receptor- inhibitor Beta- blocker Calcium- channel inhibitor Aldosterone antagonist Cardiac glycoside Proton-pump inhibitor Statin Oral antidiabetic Insulin Uricosuric
36 (100%) 0 (0%) 18 (50%) 27 (75%) 24 (67%) 28 (78%) 13 (36%) 7 (19%) 1 (3%) 25 (69%) 25 (69%) 5 (14%) 6 (17%) 8 (22%)
36 (100%) 36 (100%) 0 (0%) 27 (75%) 32 (89%) 32 (89%) 18 (50%) 6 (17%) 1 (3%) 22 (61%) 25 (69%) 3 (8%) 8 (22%) 6 (17%)
N0.99 b0.001 b0.001 N0.99 0.02 0.20 0.23 0.76 N0.99 0.46 N0.99 0.45 0.55 0.55
Presentation – no. (%) ST-elevation myocardial infarction Non ST-elevation myocardial infarction Unstable angina pectoris Stable coronary artery disease
⁎ P value of chi square/Fisher's exact test analysis.
between the groups as well. (not shown) Patients in the aspirin + dipyrone group were on permanent dipyrone medication because of chronic pain. Dipyrone dosing intervals and doses were chosen as clinically indicated and not controlled by the study protocol. Dosing intervals ranged from q.6 h to q.24 h with doses of 0.5 to 3 g per day.
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The musculoskeletal system was the predominant origin of pain (30 patients; 83%). Other reasons were headache (two patients), cancer (one patient), peripheral artery occlusion disease (two patients) and neuropathic pain (one patient). In the aspirin- alone group 21 patients (58%) suffered from chronic pain. Intermittent or permanent use of non-dipyrone analgesic medication was reported by 18 of these patients. Similar to the aspirin + dipyrone group pain was predominantly caused by musculoskeletal disorders (15 patients), followed by neuropathic pain (3 patients), peripheral artery occlusion disease (2 patients) and cancer related pain (1 patient). Comedication (beside analgesia) did not differ between groups (Table 2).
3.2. End points During a median follow-up duration of 3.2 years, the primary end point (death, MI or stroke) occurred in 24 of 36 patients (67%) in the aspirin + dipyrone group as compared to 11 of 36 patients (31%) in the aspirin- alone group (odds ratio, 4.5; 95% CI, 1.7 to 12.3; P = 0.0028; hazard ratio, 2.81; 95% CI, 1.42 to 5.53; P = 0.0029) (Table 3 and Fig. 1A). Mortality was higher in the aspirin + dipyrone group (16 patients [44%]) than in the aspirin- alone group (8 patients [22%]; (odds ratio, 2.8; 95% CI, 1.01 to 7.8; P = 0.049; hazard ratio, 2.29; 95% CI, 1.03 to 5.14; P = 0.042) (Table 3 and Fig. 1B) Deaths were predominantly due to cardiovascular causes (14 of 16 deaths [88%] in the aspirin + dipyrone group and 7 of 8 deaths (88%) in the aspirin alone group. Non-cardiovascular causes of deaths were cancer (1 patient per group) and infection (1 patient died of pneumonia in the aspirin + dipyrone group) (Table 3). There was no significant effect of dipyrone comedication on the incidence of MI although it was numerically more frequent in dipyrone-treated patients (6 patients [17%] in the aspirin + dipyrone group vs. 3 patients [8%] in the aspirin- alone group; odds ratio, 2.2; 95% CI, 0.5 to 9.58; P = 0.29; hazard ratio, 1.85; 95% CI, 0.5 to 6.85; P = 0.36) (Table 3 and Fig. 1C). There was also a trend towards increased incidence of stroke in the aspirin + dipyrone group (6 patients [17%] vs. 1 patient [3%]; odds ratio, 7; 95% CI, 0.8 to 61.5; P = 0.079; hazard ratio, 3.9; 95% CI, 0.88 to 17.25; P = 0.073). (Table 3 and Fig. 1D) Ischemic events (MI and stroke) were more frequent in the aspirin + dipyrone group as compared to the aspirin alone group (12 patients [33%] vs. 4 patients [11%]; odds ratio, 3.5; 95% CI, 1 to 12.4; P = 0.03). (Table 3) Treatment with NSAIDs was more frequent in the aspirin- alone group (18 patients [50%] vs. 0 patients [0%]; P b 0.001). Analysis of variance showed a significant association of dipyrone comedication in aspirin treated patients with the primary end point after controlling for the effect of NSAID treatment (F[1, 69] = 6.1; P = 0.016).
Table 3 Study end points.
Primary end point – no. (%) Composite of death, MI, or stroke/TIA Secondary end point – no. (%) Death From cardiovascular causes From noncardiovascular causes Infection Cancer MI ST- elevation MI Non-ST-elevation MI Stroke Stroke TIA Ischemic events (MI + stroke)
Aspirin-alone Group (N = 36)
Aspirin + Dipyrone Group (N = 36)
Odds ratio (95% CI)
P value⁎
11 (31%)
24 (67%)
4.5 (1.7–12.3)
0.0028
8 (22%) 7 (19%) 1 (3%) 0 (0%) 1 (3%) 3 (8%) 0 (0%) 3 (8%) 1 (3%) 1 (3%) 0 (0%) 4 (11%)
16 (44%) 14 (39%) 2 (6%) 1 (3%) 1 (3%) 6 (17%) 0 (0%) 6 (14%) 6 (17%) 4 (11%) 2 (6%) 12 (33%)
2.8 (1.01–7.8) 2.64 (0.91–7.63) 2.06 (0.18–23.7)
0.049 0.074 0.563
2.2 (0.5–9.58)
0.29
7 (0.8–61.5)
0.079
4 (1.1–14)
0.03
⁎ Odds ratio and P value are calculated according to Altman.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
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A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx 20
A
C Myocardial infarction [%]
Death, MI, Stroke [%]
100
Hazard ratio, 2.81 (95% CI, 1.42-5.53) P= 0.0029 Aspirin + dipyrone
80 60 40
Aspirin - alone
20 0
0
1
2
3
Aspirin + dipyrone
15
4
100
10
80
Aspirin - alone
5 0
60
0
1
2
3
4
40 Hazard ratio, 1.95 (95% CI, 0.5-6.85) P= 0.36
20 0
0
1
2
Years
3
4
Years
No. at Risk
No. at Risk
Aspirin- alone
36
29
27
14
3
Aspirin- alone
36
34
33
14
2
Aspirin+ diyprone
36
21
18
15
1
Aspirin+ diyprone
36
33
32
22
1
B
D
25
Aspirin + dipyrone
20
100
Hazard ratio, 2.29 (95% CI, 1.03-5.14) P= 0.042
80
10
60 Aspirin + dipyrone
40 20 0 1
Aspirin+ diyprone
3
36 36
31 25
30 25
0
17
1
2
3
4
Hazard ratio, 3.9 (95% CI, 0.88-17.3) P= 0.07
0
1
2
3
4
Years
No. at Risk 17
Aspirin - alone 0
40
0
4
Years
No. at Risk Aspirin- alone
2
5
60
20
Aspirin - alone
0
15
80
Stroke
Total mortality [%]
100
2
Aspirin- alone
36
35
35
16
2
1
Aspirin+ diyprone
36
33
33
24
1
Fig. 1. Kaplan-Meier Curve for the (A) Primary End Point of Death, Myocardial Infarction, or Stroke, (B) Secondary End Point of All-Cause Mortality, (C) Secondary End Point of Myocardial Infarction and (D) Secondary End Point of Stroke (the insets of panel C and D show the same data on an enlarged y axis).
4. Discussion In this study, dipyrone comedication was associated with an enhanced incidence of the composite end point (death, MI or stroke) in aspirin treated CAD patients. Additionally, all-cause mortality was increased in dipyrone treated patients and there was a trend for higher incidence of MI and stroke. The primary end point of this study was driven by the high rate of mortality in the aspirin + dipyrone group. The predominant cause of death was cardiovascular (88% of patients). All patients had CAD and received secondary prophylaxis with aspirin to reduce the risk of death, MI and stroke [26]. However, we recently demonstrated that dipyrone impairs pharmacodynamic response to aspirin in-vitro and ex-vivo [13,14]. During the last decade it was discussed controversially, if impaired pharmacodynamic response to aspirin is an artificial phenomenon or truly affects clinical outcome. By now, different metanalyses and large registry analyses showed an association between impaired aspirin antiplatelet effects ex-vivo and adverse events [23,27]. Therefore it was not surprising, that beside cardiovascular death both MI and stroke showed a trend towards increased incidence in the aspirin + dipyrone group as compared with the aspirin- alone group. Additionally, the composite of ischemic events (MI + stroke) was more frequent in aspirin + dipyrone treated patients. The reason for the impaired pharmacodynamic response to aspirin may be reversible binding of dipyrone at a position in the substrate channel of cyclooxygenasis-1 (COX-1) which overlaps with the docking of aspirin. This sterically hinders the access of aspirin to the active site and prevents the permanent
acetylation of serine 530 in the active channel of COX-1 by aspirin. Hence aspirin may fail to exhibit its irreversible inhibition of platelet activation for the remaining life span of the affected platelet [28–31]. Furthermore dipyrone can cause blood formation disorders (agranulocytosis) with concomitant risk of severe life-threatening infections [1]. In this study, one patient in the aspirin + dipyrone group died from infection (pneumonia). According to the attending physician no signs of agranulocytosis existed. As mentioned in the introduction, dipyrone was banned in some countries like the United States due to the risk of agranulocytosis, whereas it is widely used in the rest of the world. In this study, we report a higher incidence of MACCE in aspirin + dipyrone comedicated patients. This finding has important implications especially regarding patient enrollment in large international cardiovascular clinical studies. The enhanced incidence of adverse events in dipyrone comedicated patients may confound the cardiovascular outcomes observed. Therefore, analgesic comedication with dipyrone should be documented and controlled carefully in international clinical trials. In patients with prior MI, NSAIDs have been shown to increase the risk of death and recurrent MI [32]. The study protocol did not exclude non-dipyrone analgesic medication in the aspirin- alone group. 18 patients (50%) of the aspirin- alone group reported intermittent or permanent use of NSAIDs. Nevertheless the incidence of the primary end point and mortality was increased in the aspirin + dipyrone group as compared with the aspirin- alone group. A reason for this may be that NSAIDs in the aspirin- alone group were mostly taken as required and not permanently. This hypothesis is supported by findings from Kurth
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx
et al., who described that only regular and not intermittent use of NSAIDs increases the risk of MI in aspirin treated participants [33]. However a nationwide study in Denmark including over 83,000 patients revealed that also short term usage of NSAIDs increases the incidence of death and recurrent MI [34]. The present study was not designed to compare the risk of adverse events between dipyrone and NSAIDs. Therefore the question if dipyrone is more or less harmful than NSAIDs has to be addressed in future trials. Recently, Kötter et al. conducted a meta-analysis including almost 4000 patients, investigating the safety of short-term dipyrone usage in acute pain. Studies comparing dipyrone to placebo, acetaminophen, aspirin, NSAIDs and opioids were included in this meta-analysis. They concluded that dipyrone is safe in short-term treatment of renal colic or postoperative pain in hospital setting [35]. At first sight, the results of the meta-analysis seem to be conflictive with the findings of this study. However, in the meta-analysis aspirin and dipyrone comedication was a criterion of exclusion. Additionally, patients were young (mean age 45 years) and only short term usage and follow-up was conducted. Therefore the results of the meta-analysis and the present study are not comparable, as we investigated elderly, aspirin treated CAD patients with permanent dipyrone comedication because of chronic pain. The incidence of MACCE was high in this study. However, as we investigated a cohort of elderly, comorbid patients with CAD, this was not surprising. Therefore the generalizability of the present study is limited. However, this finding may be of particular interest in these patients, as dipyrone is already the most frequently used analgesic in European nursing homes [36]. In this observational study, comedication like statins and P2Y12 inhibition was not controlled by the study reflecting a real world population. 75% of patients in both groups had P2Y12 inhibition and 69% of patients in both groups had statin therapy. Clinical follow-up was conducted by phone and not by regular visits. Adjudication of outcomes was done by the investigators based on the medical record. Additionally, patients were in ambulatory care during follow-up. Therefore drug intake was not controlled and noncompliance might have confounded the results. The number of participants in this pilot study was limited. Therefore the results are preliminary and have to be interpreted with caution. The small sample size did not allow proper stratification of the patient population in each group. Additionally, no time varying covariate analysis was conducted. This observational study was not a randomized controlled trial. Neither patients, nor investigators were blinded. Therefore bias of the investigators might have affected the results. Analgesic medication with NSAIDs was more frequent in the aspirin- alone group. Besides this, no significant differences between characteristics of both groups existed. The association between dipyrone comedication in aspirin treated patients and the primary end point was robust after controlling for the effect of NSAID treatment. However, given the small sample size of the investigated cohort, even non-significant differences between the groups may have biased the results of the study. Additionally, intermittent use of dipyrone in the aspirin-only group cannot be ruled out. However it seems unlikely, as dipyrone is available on prescription only in Germany. Furthermore the confidence intervals of the clinical end points were fairly wide due to this small sample size. Due to the study limitations, the results of this study have to be considered as hypothesis generating. However, they are in line with pharmacodynamical analyses, that dipyrone comedication in aspirin treated patients impairs aspirin antiplatelet effects [14–16]. Nevertheless, the findings of this pilot study have to be reconfirmed in large scale patient populations.
5. Conclusion In summary, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events.
5
This was a hypothesis generating pilot analysis and these data have to be confirmed in larger registries and trials. Funding source Part of this work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 16-2014) (to A.P.). Ethics committee approval The study conformed to the Declaration of Helsinki and was accepted by the University of Düsseldorf Ethics Committee. Authors' contributions A.P. and T.Z. designed the study, analyzed and interpreted data and wrote the manuscript. A.A., A.M., K.P. and L.D. collected data and revised the manuscript. T.H., B.L. and M.K. supervised the study and revised the manuscript. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments None. References [1] C.M. Huguley Jr., Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic, JAMA 189 (1964) 938–941. [2] G.H. Gislason, S. Jacobsen, J.N. Rasmussen, et al., Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction, Circulation 113 (2006) 2906–2913. [3] J.J. McMurray, S. Adamopoulos, S.D. Anker, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur. Heart J. 33 (2012) 1787–1847. [4] G. Montalescot, U. Sechtem, S. Achenbach, et al., 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology, Eur. Heart J. 34 (2013) 2949–3003. [5] J.R. Laporte, L. Ibanez, X. Vidal, L. Vendrell, R. Leone, Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents, Drug Saf. 27 (2004) 411–420. [6] J.R. Laporte, X. Carne, X. Vidal, V. Moreno, J. Juan, Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan countries study on upper gastrointestinal bleeding, Lancet 337 (1991) 85–89. [7] U. Grundmann, C. Wornle, A. Biedler, S. Kreuer, M. Wrobel, W. Wilhelm, The efficacy of the non-opioid analgesics parecoxib, paracetamol and metamizol for postoperative pain relief after lumbar microdiscectomy, Anesth. Analg. 103 (2006) 217–222 (table of contents). [8] A. Saray, U. Buyukkocak, I. Cinel, A.T. Tellioglu, U. Oral, Diclofenac and metamizol in postoperative analgesia in plastic surgery, Acta Chir. Plast. 43 (2001) 71–76. [9] L. Hearn, S. Derry, R.A. Moore, Single dose dipyrone (metamizole) for acute postoperative pain in adults, Cochrane Database Syst. Rev. 4 (2016), CD011421. [10] U.P. Schwabe, D. Arzneiverordnungs-Report 2014: Aktuelle Daten, Kosten, Trends Und Kommentare, Springer Verlag, Germany, 2014. [11] S. Garcia, M. Canoniero, G. Lopes, A.O. Soriano, Metamizole use among Hispanics in Miami: report of a survey conducted in a primary care setting, South. Med. J. 99 (2006) 924–926. [12] J.L. Bonkowsky, J.K. Frazer, K.F. Buchi, C.L. Byington, Metamizole use by Latino immigrants: a common and potentially harmful home remedy, Pediatrics 109 (2002), e98. [13] T. Hohlfeld, N. Zimmermann, A.A. Weber, et al., Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis, J. Thromb. Haemost. 6 (2008) 166–173. [14] A. Polzin, T. Zeus, K. Schror, M. Kelm, T. Hohlfeld, Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease, J. Am. Coll. Cardiol. 62 (2013) 1725–1726.
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[15] A. Polzin, S. Richter, K. Schror, et al., Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects, Thromb. Haemost. 114 (2015) 87–95. [16] L. Dannenberg, V. Erschoff, F. Bonner, et al., Dipyrone comedication in aspirin treated stroke patients impairs outcome, Vasc. Pharmacol. (2016). [17] A. Polzin, M. Schleicher, H. Seidel, et al., High on-treatment platelet reactivity in transcatheter aortic valve implantation patients, Eur. J. Pharmacol. 751 (2015) 24–27. [18] A. Polzin, M. Kelm, T. Zeus, Impaired clopidogrel antiplatelet effects and age: young patients at risk, Int. J. Cardiol. 187 (2015) 216–218. [19] A. Polzin, T. Hohlfeld, M. Kelm, T. Zeus, Impairment of aspirin antiplatelet effects by non-opioid analgesic medication, World J. Cardiol. 7 (2015) 383–391. [20] A. Polzin, S. Afzal, J. Balzer, T. Rassaf, M. Kelm, T. Zeus, Platelet reactivity in MitraClip patients, Vasc. Pharmacol. 77 (2016) 54–59. [21] A. Polzin, L. Dannenberg, V. Sophia Popp, M. Kelm, T. Zeus, Antiplatelet effects of clopidogrel and aspirin after interventional patent foramen ovale/atrium septum defect closure, Platelets 27 (2016) 317–321. [22] A. Polzin, L. Dannenberg, R. Sansone, et al., Antiplatelet effects of aspirin in chronic kidney disease patients, J. Thromb. Haemost. 14 (2016) 375–380. [23] K. Mayer, I. Bernlochner, S. Braun, et al., Aspirin treatment and outcomes after percutaneous coronary intervention: results of the ISAR-ASPI registry, J. Am. Coll. Cardiol. 64 (2014) 863–871. [24] A.S. Zheng, L. Churilov, R.E. Colley, C. Goh, S.M. Davis, B. Yan, Association of aspirin resistance with increased stroke severity and infarct size, JAMA Neurol. 70 (2013) 208–213. [25] D.E. Cutlip, S. Windecker, R. Mehran, et al., Clinical end points in coronary stent trials: a case for standardized definitions, Circulation 115 (2007) 2344–2351. [26] J.S. Berger, D.L. Brown, R.C. Becker, Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis, Am. J. Med. 121 (2008) 43–49.
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Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE Alina Achilles a,1, Annemarie Mohring a,1, Lisa Dannenberg a, Kerstin Piayda a, Bodo Levkau b, Thomas Hohlfeld c, Tobias Zeus a, Malte Kelm a, Amin Polzin a,⁎ a b c
Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich Heine University Medical Center Dusseldorf, Dusseldorf, Germany Institute of Pathophysiology, West German Heart and Vascular Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Institute for Pharmacology and Clinical Pharmacology, Heinrich Heine University, Dusseldorf, Germany
a r t i c l e
i n f o
Article history: Received 11 December 2016 Received in revised form 19 February 2017 Accepted 24 February 2017 Available online xxxx Keywords: Aspirin Coronary artery disease Dipyrone, drug interactions Pharmacology
a b s t r a c t Background: The non-opioid analgesic dipyrone can trigger life-threatening blood formation disorders. However, it is frequently used, as many patients with coronary artery disease (CAD) rely on non-opioid analgesics to relieve pain. In this study, we investigated the incidence of death, myocardial infarction (MI) or stroke in CAD patients with aspirin and dipyrone comedication as compared to aspirin-alone. Methods: We conducted an observational pilot study in 72 CAD patients with aspirin ± dipyrone comedication in the department of cardiology of the University Hospital Düsseldorf. The primary end point was a composite of death, myocardial infarction (MI) or stroke. The secondary end points were the components of the primary end point. The median follow-up period was 3.2 years. Results: The primary end point occurred 67% of patients in the aspirin + dipyrone group as compared to 31% in the aspirin-alone group (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.7 to 12.3; P = 0.0028;). All-cause mortality was significantly higher in the aspirin + dipyrone group (44%) than the aspirin-alone group (22%; OR 2.8, 95% CI 1.01 to 7.8; P = 0.049). Ischemic events (MI and stroke) were more frequent in the aspirin + dipyrone group as compared to the aspirin alone group as well (OR 4, 95% CI 1.1 to 14; P = 0.03). Conclusion: In this hypothesis generating pilot analysis, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events. These data have to be confirmed in larger registries and trials. Clinical trial registration: http://clinicaltrials.gov/ct2/show/NCT01402804; Identifier: NCT01402804; Date of registration: July 25, 2011. © 2017 Elsevier B.V. All rights reserved.
1. Introduction In the 1950s an increased risk of life-threatening blood formation disorders (agranulocytosis) by the non-opioid pyrazolinone analgesic dipyrone was registered [1]. This led to complete withdrawal of dipyrone in some countries (e.g. United States). Nevertheless chronic pain is very frequent and analgesics are among the most frequently used medications worldwide. 40% of coronary artery disease (CAD) patients suffer from chronic pain and rely on non-opioid analgesic
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; MI, myocardial infarction; NSAID, non-steroidal anti-inflammatory drug; TIA, transient ischemic attack. ⁎ Corresponding author at: Moorenstrasse 5, 40225 Düsseldorf, Klinik für Kardiologie, Pneumologie und Angiologie. E-mail address: [email protected] (A. Polzin). 1 Both authors contributed equally.
treatment [2]. However non-steroidal anti-inflammatory drugs (NSAID) are not recommended in CAD patients by the European Society of Cardiology [3,4]. Therefore, the combination of (i) superior analgesic and antipyretic effects of dipyrone, (ii) its low incidence of gastrointestinal side effects and (iii) a lack of sufficient alternatives led to increased use of dipyrone [5–9]. In central European Countries like Germany, dipyrone intake quadrupled to defined daily doses above 140 during the last 15 years [10]. It is already among the most frequently used non-opioid analgesic in regions, such as Eastern Europe and Central and South America. As it is available over the counter in Mexico, an extensive use in the United States exists despite the withdrawal by the Food and Drug Administration as well [11,12]. Besides its myelotoxic effects, dipyrone additionally inhibits laboratory response to aspirin in-vitro and ex-vivo in healthy individuals and patients with CAD [13–16]. Aspirin (acetylsalicylic acid; ASA), is a widely used cost-effective drug which is indispensable in secondary
http://dx.doi.org/10.1016/j.ijcard.2017.02.122 0167-5273/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
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A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx
prophylaxis in CAD patients. Additionally, it is the backbone of dual and triple antiplatelet therapy following coronary interventions and myocardial infarction (MI) reducing the risk of thrombotic events. However, it is known that on-treatment platelet reactivity differs interindividually [17–22]. In CAD patients, impaired pharmacodynamic response to aspirin is associated with increased incidence of mortality and stent thrombosis [23]. In patients with ischemic stroke, infarct volume and severity of stroke are associated with impaired aspirin antiplatelet effects [24]. In this study, we hypothesized, that long-term dipyrone comedication in aspirin treated CAD patients enhances the incidence of adverse events. Therefore, we investigated the incidence of death, MI and stroke in CAD patients with aspirin and dipyrone comedication.
2.3. Statistical analyses Data were analyzed using the GraphPad Prism statistical software (GraphPad Software Inc., San Diego) and the IBM SPSS©- Software (New York, USA) respectively. Odds ratios with 95% confidence interval (CI) were estimated according to Altman. Hazard ratios with 95% CI and log-rank tests were calculated for survival analyses. Normality of data distribution was tested using histograms, q-q-plots and KolmogorovSmirnov test. Non-parametric tests were used in case of non-normally distribution. t-test was used to analyze continuous variables. Chi square test and Fisher's exact test were used to analyze categorical variables. P b 0.05 was considered significant. This pilot study was explorative. No sample size calculation was conducted, as there were no data to calculate a reliable effect size.
2. Patients and methods 2.1. Study design, population and follow-up We conducted a prospective, observational, single-center all-comers pilot cohort trial between February 2011 and February 2015. Recruitment of patients was during hospitalization in the department of cardiology of the Heinrich- Heine University Medical Center Düsseldorf. Patients were in ambulatory care during follow-up. Eligibility criteria were angiographically proven CAD (both obstructive and nonobstructive), informed consent and age N 18 years. Exclusion criterion was hemorrhagic diathesis. Two groups of patients were investigated. The aspirin- alone group consisted of 36 CAD patients with permanent low-dose (100 mg/d) aspirin medication. The aspirin + dipyrone group compromised 36 patients with low-dose aspirin and permanent dipyrone comedication because of chronic pain. Dipyrone doses and dosing intervals were not controlled. Doses varied from 0.5–3 g per day and intervals from q.24 h to q.6 h. No patient matching was performed. For every patient that was included in the aspirin + dipyrone group, a patient was included in the aspirin-alone group as well. Data on baseline characteristics, clinical presentation, cardiovascular risk factors and comedication were collected during hospitalization. Follow-up was conducted by annually telephone interview of the patient's attending physician. No patient was lost for follow-up. The study conformed to the Declaration of Helsinki and was approved by the University of Düsseldorf Ethics Committee. Informed consent was obtained from all patients.
3. Results 3.1. Study patients Patients in the aspirin- alone group had a mean age of 76 years, 39% were of male gender. The mean age in the aspirin + dipyrone group was 77 years with 50% being male. The prevalence of baseline characteristics, cardiovascular risk factors and prior diseases was similar in both groups (Table 1). Acute coronary syndrome was the reason of hospitalization in 18 patients of the aspirin- alone group (3 ST- elevation myocardial infarctions, 10 non ST- elevation myocardial infarctions, 5 unstable angina pectoris) and 12 patients in the aspirin + dipyrone group (6 non ST- elevation myocardial infarctions, 6 unstable angina pectoris). The remaining patients presented with stable coronary artery disease. Clinical presentation, symptoms and number of diseased vessels did not differ between groups (Table 2). 42% of aspirin-alone patients (15 patients) were treated with PCI as compared to 44% in the aspirin + dipyrone group (16 patients; P = 0.99). None of the patients were treated by coronary artery bypass grafting. Stent-type (bare-metal stent vs. drug eluting stent), procedural success, multi-vessel vs. singlevessel intervention, number of stents or target vessel did not differ
Table 1 Baseline patient characteristics. Aspirin-alone Group Aspirin + Dipyrone (N = 36) Group (N = 36) P valuea
2.2. Study end points The primary endpoint was a composite of death, MI or stroke. The secondary end points were the components of the primary end point. Death was defined as all-cause mortality. Cause of death was classified as death from cardiovascular cause and death from noncardiovascular cause. According to Academic Research Consortium standardized end point definitions, unless a noncardiovascular cause of death was clearly provided, unwitnessed and sudden deaths were assumed to be cardiovascular [25]. Noncardiovascular causes were subclassified in death from infection and death from cancer. MI was defined as hospitalization with typical clinical symptoms, elevation of cardiac biomarkers and new angiographically proven coronary occlusion. MI was further subclassified in ST- elevation MI and non ST- elevation MI. ST- elevation was defined as new ST elevation at the J- point in at least two contiguous leads with ≥0.2 mV in leads V1–V6 and/or ≥0.1 mV in other leads. MI without meeting the above mentioned criteria of ST elevation was classified as non ST- elevation MI. Definition of stroke was clinical presentation with new focal neurologic deficits. Stroke was subclassified in stroke with symptoms lasting N 24 h and conformation of diagnosis by computer tomographic scan or magnet resonance imaging and transient ischemic attack (TIA), defined as new focal neurologic deficits lasting b 24 h with complete remission of symptoms.
Characteristic Age - years (mean ± S.D.) Male gender – no. (%) Body mass index (mean ± S.D.)
76 ± 13 22 (61%) 27 ± 4.6
77 ± 10 18 (50%) 25 ± 3.7
0.65 0.34 0.11
Cardiovascular risk factor – no. (%) Hypertension Hypercholesterolemia Diabetes mellitus Adiposity (body mass index N 30) Smoking (current)
36 (100%) 23 (64%) 12 (33%) 8 (22%) 6 (17%)
36 (100%) 27 (75%) 11 (31%) 5 (14%) 6 (17%)
N0.99 0.31 0.8 0.36 N0.99
16 (44%) 9 (25%) 4 (11%) 16 (44%) 25 (69%)
22 (61%) 10 (28%) 4 (11%) 22 (61%) 21 (58%)
0.16 0.79 N0.99 0.16 0.33
10 (28%)
10 (28%)
N0.99
Other medical history – no. (%) Previous myocardial infarction Previous bypass surgery Previous stroke Reduced systolic LV-functionb Impaired renal function at admissionc Atrial fibrillation a
P value of chi square/Fisher's exact test analysis in categorical and t-test in continuous variables. b Reduced systolic LV- function was defined as systolic left ventricular ejection fraction b40% during index hospitalization. c Impaired renal function at admission was defined as creatinine level at admission N1.2 mg/dl in men and N0.9 mg/dl in women.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx Table 2 Clinical presentation and comedication. Aspirin-alone Group (N = 36)
Aspirin + Dipyrone Group (N = 36)
P value⁎
3 (8%) 10 (28%)
0 (0%) 6 (17%)
0.08 0.26
5 (14%) 8 (22%)
6 (17%) 8 (22%)
0.74 N0.99
Angina pectoris – no. (%) CCS IV CCS III CCS II CCS I No angina pectoris
8 (22%) 4 (11%) 6 (17%) 3 (8%) 15 (42%)
8 (22%) 7 (19%) 3 (8%) 1 (3%) 17 (47%)
N0.99 0.33 0.29 0.30 0.64
Dyspnoea– no. (%) NYHA IV NYHA III NYHA II NYHA I
6 (17%) 16 (44%) 9 (25%) 5 (14%)
4 (11%) 16 (44%) 11 (31%) 5 (14%)
0.5 N0.99 0.6 N0.99
No. of diseased vessels – no. (%) 3 vessel disease 2 vessel disease 1 vessel disease Microangiopathy
23 (64%) 4 (11%) 3 (8%) 6 (17%)
24 (67%) 4 (11%) 3 (8%) 5 (14%)
0.80 N0.99 N0.99 0.74
Medication – no. (%) Aspirin Dipyrone NSAIDs P2Y12 inhibitor ACE-/AT-II-receptor- inhibitor Beta- blocker Calcium- channel inhibitor Aldosterone antagonist Cardiac glycoside Proton-pump inhibitor Statin Oral antidiabetic Insulin Uricosuric
36 (100%) 0 (0%) 18 (50%) 27 (75%) 24 (67%) 28 (78%) 13 (36%) 7 (19%) 1 (3%) 25 (69%) 25 (69%) 5 (14%) 6 (17%) 8 (22%)
36 (100%) 36 (100%) 0 (0%) 27 (75%) 32 (89%) 32 (89%) 18 (50%) 6 (17%) 1 (3%) 22 (61%) 25 (69%) 3 (8%) 8 (22%) 6 (17%)
N0.99 b0.001 b0.001 N0.99 0.02 0.20 0.23 0.76 N0.99 0.46 N0.99 0.45 0.55 0.55
Presentation – no. (%) ST-elevation myocardial infarction Non ST-elevation myocardial infarction Unstable angina pectoris Stable coronary artery disease
⁎ P value of chi square/Fisher's exact test analysis.
between the groups as well. (not shown) Patients in the aspirin + dipyrone group were on permanent dipyrone medication because of chronic pain. Dipyrone dosing intervals and doses were chosen as clinically indicated and not controlled by the study protocol. Dosing intervals ranged from q.6 h to q.24 h with doses of 0.5 to 3 g per day.
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The musculoskeletal system was the predominant origin of pain (30 patients; 83%). Other reasons were headache (two patients), cancer (one patient), peripheral artery occlusion disease (two patients) and neuropathic pain (one patient). In the aspirin- alone group 21 patients (58%) suffered from chronic pain. Intermittent or permanent use of non-dipyrone analgesic medication was reported by 18 of these patients. Similar to the aspirin + dipyrone group pain was predominantly caused by musculoskeletal disorders (15 patients), followed by neuropathic pain (3 patients), peripheral artery occlusion disease (2 patients) and cancer related pain (1 patient). Comedication (beside analgesia) did not differ between groups (Table 2).
3.2. End points During a median follow-up duration of 3.2 years, the primary end point (death, MI or stroke) occurred in 24 of 36 patients (67%) in the aspirin + dipyrone group as compared to 11 of 36 patients (31%) in the aspirin- alone group (odds ratio, 4.5; 95% CI, 1.7 to 12.3; P = 0.0028; hazard ratio, 2.81; 95% CI, 1.42 to 5.53; P = 0.0029) (Table 3 and Fig. 1A). Mortality was higher in the aspirin + dipyrone group (16 patients [44%]) than in the aspirin- alone group (8 patients [22%]; (odds ratio, 2.8; 95% CI, 1.01 to 7.8; P = 0.049; hazard ratio, 2.29; 95% CI, 1.03 to 5.14; P = 0.042) (Table 3 and Fig. 1B) Deaths were predominantly due to cardiovascular causes (14 of 16 deaths [88%] in the aspirin + dipyrone group and 7 of 8 deaths (88%) in the aspirin alone group. Non-cardiovascular causes of deaths were cancer (1 patient per group) and infection (1 patient died of pneumonia in the aspirin + dipyrone group) (Table 3). There was no significant effect of dipyrone comedication on the incidence of MI although it was numerically more frequent in dipyrone-treated patients (6 patients [17%] in the aspirin + dipyrone group vs. 3 patients [8%] in the aspirin- alone group; odds ratio, 2.2; 95% CI, 0.5 to 9.58; P = 0.29; hazard ratio, 1.85; 95% CI, 0.5 to 6.85; P = 0.36) (Table 3 and Fig. 1C). There was also a trend towards increased incidence of stroke in the aspirin + dipyrone group (6 patients [17%] vs. 1 patient [3%]; odds ratio, 7; 95% CI, 0.8 to 61.5; P = 0.079; hazard ratio, 3.9; 95% CI, 0.88 to 17.25; P = 0.073). (Table 3 and Fig. 1D) Ischemic events (MI and stroke) were more frequent in the aspirin + dipyrone group as compared to the aspirin alone group (12 patients [33%] vs. 4 patients [11%]; odds ratio, 3.5; 95% CI, 1 to 12.4; P = 0.03). (Table 3) Treatment with NSAIDs was more frequent in the aspirin- alone group (18 patients [50%] vs. 0 patients [0%]; P b 0.001). Analysis of variance showed a significant association of dipyrone comedication in aspirin treated patients with the primary end point after controlling for the effect of NSAID treatment (F[1, 69] = 6.1; P = 0.016).
Table 3 Study end points.
Primary end point – no. (%) Composite of death, MI, or stroke/TIA Secondary end point – no. (%) Death From cardiovascular causes From noncardiovascular causes Infection Cancer MI ST- elevation MI Non-ST-elevation MI Stroke Stroke TIA Ischemic events (MI + stroke)
Aspirin-alone Group (N = 36)
Aspirin + Dipyrone Group (N = 36)
Odds ratio (95% CI)
P value⁎
11 (31%)
24 (67%)
4.5 (1.7–12.3)
0.0028
8 (22%) 7 (19%) 1 (3%) 0 (0%) 1 (3%) 3 (8%) 0 (0%) 3 (8%) 1 (3%) 1 (3%) 0 (0%) 4 (11%)
16 (44%) 14 (39%) 2 (6%) 1 (3%) 1 (3%) 6 (17%) 0 (0%) 6 (14%) 6 (17%) 4 (11%) 2 (6%) 12 (33%)
2.8 (1.01–7.8) 2.64 (0.91–7.63) 2.06 (0.18–23.7)
0.049 0.074 0.563
2.2 (0.5–9.58)
0.29
7 (0.8–61.5)
0.079
4 (1.1–14)
0.03
⁎ Odds ratio and P value are calculated according to Altman.
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
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A. Achilles et al. / International Journal of Cardiology xxx (2017) xxx–xxx 20
A
C Myocardial infarction [%]
Death, MI, Stroke [%]
100
Hazard ratio, 2.81 (95% CI, 1.42-5.53) P= 0.0029 Aspirin + dipyrone
80 60 40
Aspirin - alone
20 0
0
1
2
3
Aspirin + dipyrone
15
4
100
10
80
Aspirin - alone
5 0
60
0
1
2
3
4
40 Hazard ratio, 1.95 (95% CI, 0.5-6.85) P= 0.36
20 0
0
1
2
Years
3
4
Years
No. at Risk
No. at Risk
Aspirin- alone
36
29
27
14
3
Aspirin- alone
36
34
33
14
2
Aspirin+ diyprone
36
21
18
15
1
Aspirin+ diyprone
36
33
32
22
1
B
D
25
Aspirin + dipyrone
20
100
Hazard ratio, 2.29 (95% CI, 1.03-5.14) P= 0.042
80
10
60 Aspirin + dipyrone
40 20 0 1
Aspirin+ diyprone
3
36 36
31 25
30 25
0
17
1
2
3
4
Hazard ratio, 3.9 (95% CI, 0.88-17.3) P= 0.07
0
1
2
3
4
Years
No. at Risk 17
Aspirin - alone 0
40
0
4
Years
No. at Risk Aspirin- alone
2
5
60
20
Aspirin - alone
0
15
80
Stroke
Total mortality [%]
100
2
Aspirin- alone
36
35
35
16
2
1
Aspirin+ diyprone
36
33
33
24
1
Fig. 1. Kaplan-Meier Curve for the (A) Primary End Point of Death, Myocardial Infarction, or Stroke, (B) Secondary End Point of All-Cause Mortality, (C) Secondary End Point of Myocardial Infarction and (D) Secondary End Point of Stroke (the insets of panel C and D show the same data on an enlarged y axis).
4. Discussion In this study, dipyrone comedication was associated with an enhanced incidence of the composite end point (death, MI or stroke) in aspirin treated CAD patients. Additionally, all-cause mortality was increased in dipyrone treated patients and there was a trend for higher incidence of MI and stroke. The primary end point of this study was driven by the high rate of mortality in the aspirin + dipyrone group. The predominant cause of death was cardiovascular (88% of patients). All patients had CAD and received secondary prophylaxis with aspirin to reduce the risk of death, MI and stroke [26]. However, we recently demonstrated that dipyrone impairs pharmacodynamic response to aspirin in-vitro and ex-vivo [13,14]. During the last decade it was discussed controversially, if impaired pharmacodynamic response to aspirin is an artificial phenomenon or truly affects clinical outcome. By now, different metanalyses and large registry analyses showed an association between impaired aspirin antiplatelet effects ex-vivo and adverse events [23,27]. Therefore it was not surprising, that beside cardiovascular death both MI and stroke showed a trend towards increased incidence in the aspirin + dipyrone group as compared with the aspirin- alone group. Additionally, the composite of ischemic events (MI + stroke) was more frequent in aspirin + dipyrone treated patients. The reason for the impaired pharmacodynamic response to aspirin may be reversible binding of dipyrone at a position in the substrate channel of cyclooxygenasis-1 (COX-1) which overlaps with the docking of aspirin. This sterically hinders the access of aspirin to the active site and prevents the permanent
acetylation of serine 530 in the active channel of COX-1 by aspirin. Hence aspirin may fail to exhibit its irreversible inhibition of platelet activation for the remaining life span of the affected platelet [28–31]. Furthermore dipyrone can cause blood formation disorders (agranulocytosis) with concomitant risk of severe life-threatening infections [1]. In this study, one patient in the aspirin + dipyrone group died from infection (pneumonia). According to the attending physician no signs of agranulocytosis existed. As mentioned in the introduction, dipyrone was banned in some countries like the United States due to the risk of agranulocytosis, whereas it is widely used in the rest of the world. In this study, we report a higher incidence of MACCE in aspirin + dipyrone comedicated patients. This finding has important implications especially regarding patient enrollment in large international cardiovascular clinical studies. The enhanced incidence of adverse events in dipyrone comedicated patients may confound the cardiovascular outcomes observed. Therefore, analgesic comedication with dipyrone should be documented and controlled carefully in international clinical trials. In patients with prior MI, NSAIDs have been shown to increase the risk of death and recurrent MI [32]. The study protocol did not exclude non-dipyrone analgesic medication in the aspirin- alone group. 18 patients (50%) of the aspirin- alone group reported intermittent or permanent use of NSAIDs. Nevertheless the incidence of the primary end point and mortality was increased in the aspirin + dipyrone group as compared with the aspirin- alone group. A reason for this may be that NSAIDs in the aspirin- alone group were mostly taken as required and not permanently. This hypothesis is supported by findings from Kurth
Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122
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et al., who described that only regular and not intermittent use of NSAIDs increases the risk of MI in aspirin treated participants [33]. However a nationwide study in Denmark including over 83,000 patients revealed that also short term usage of NSAIDs increases the incidence of death and recurrent MI [34]. The present study was not designed to compare the risk of adverse events between dipyrone and NSAIDs. Therefore the question if dipyrone is more or less harmful than NSAIDs has to be addressed in future trials. Recently, Kötter et al. conducted a meta-analysis including almost 4000 patients, investigating the safety of short-term dipyrone usage in acute pain. Studies comparing dipyrone to placebo, acetaminophen, aspirin, NSAIDs and opioids were included in this meta-analysis. They concluded that dipyrone is safe in short-term treatment of renal colic or postoperative pain in hospital setting [35]. At first sight, the results of the meta-analysis seem to be conflictive with the findings of this study. However, in the meta-analysis aspirin and dipyrone comedication was a criterion of exclusion. Additionally, patients were young (mean age 45 years) and only short term usage and follow-up was conducted. Therefore the results of the meta-analysis and the present study are not comparable, as we investigated elderly, aspirin treated CAD patients with permanent dipyrone comedication because of chronic pain. The incidence of MACCE was high in this study. However, as we investigated a cohort of elderly, comorbid patients with CAD, this was not surprising. Therefore the generalizability of the present study is limited. However, this finding may be of particular interest in these patients, as dipyrone is already the most frequently used analgesic in European nursing homes [36]. In this observational study, comedication like statins and P2Y12 inhibition was not controlled by the study reflecting a real world population. 75% of patients in both groups had P2Y12 inhibition and 69% of patients in both groups had statin therapy. Clinical follow-up was conducted by phone and not by regular visits. Adjudication of outcomes was done by the investigators based on the medical record. Additionally, patients were in ambulatory care during follow-up. Therefore drug intake was not controlled and noncompliance might have confounded the results. The number of participants in this pilot study was limited. Therefore the results are preliminary and have to be interpreted with caution. The small sample size did not allow proper stratification of the patient population in each group. Additionally, no time varying covariate analysis was conducted. This observational study was not a randomized controlled trial. Neither patients, nor investigators were blinded. Therefore bias of the investigators might have affected the results. Analgesic medication with NSAIDs was more frequent in the aspirin- alone group. Besides this, no significant differences between characteristics of both groups existed. The association between dipyrone comedication in aspirin treated patients and the primary end point was robust after controlling for the effect of NSAID treatment. However, given the small sample size of the investigated cohort, even non-significant differences between the groups may have biased the results of the study. Additionally, intermittent use of dipyrone in the aspirin-only group cannot be ruled out. However it seems unlikely, as dipyrone is available on prescription only in Germany. Furthermore the confidence intervals of the clinical end points were fairly wide due to this small sample size. Due to the study limitations, the results of this study have to be considered as hypothesis generating. However, they are in line with pharmacodynamical analyses, that dipyrone comedication in aspirin treated patients impairs aspirin antiplatelet effects [14–16]. Nevertheless, the findings of this pilot study have to be reconfirmed in large scale patient populations.
5. Conclusion In summary, dipyrone medication in aspirin treated coronary artery disease patients is associated with an increased cumulative incidence of death, MI or stroke as well as all-cause mortality and ischemic events.
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This was a hypothesis generating pilot analysis and these data have to be confirmed in larger registries and trials. Funding source Part of this work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University (No. 16-2014) (to A.P.). Ethics committee approval The study conformed to the Declaration of Helsinki and was accepted by the University of Düsseldorf Ethics Committee. Authors' contributions A.P. and T.Z. designed the study, analyzed and interpreted data and wrote the manuscript. A.A., A.M., K.P. and L.D. collected data and revised the manuscript. T.H., B.L. and M.K. supervised the study and revised the manuscript. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgments None. References [1] C.M. Huguley Jr., Agranulocytosis induced by dipyrone, a hazardous antipyretic and analgesic, JAMA 189 (1964) 938–941. [2] G.H. Gislason, S. Jacobsen, J.N. Rasmussen, et al., Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction, Circulation 113 (2006) 2906–2913. [3] J.J. McMurray, S. Adamopoulos, S.D. Anker, et al., ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC, Eur. Heart J. 33 (2012) 1787–1847. [4] G. Montalescot, U. Sechtem, S. Achenbach, et al., 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the Management of Stable Coronary Artery Disease of the European Society of Cardiology, Eur. Heart J. 34 (2013) 2949–3003. [5] J.R. Laporte, L. Ibanez, X. Vidal, L. Vendrell, R. Leone, Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents, Drug Saf. 27 (2004) 411–420. [6] J.R. Laporte, X. Carne, X. Vidal, V. Moreno, J. Juan, Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan countries study on upper gastrointestinal bleeding, Lancet 337 (1991) 85–89. [7] U. Grundmann, C. Wornle, A. Biedler, S. Kreuer, M. Wrobel, W. Wilhelm, The efficacy of the non-opioid analgesics parecoxib, paracetamol and metamizol for postoperative pain relief after lumbar microdiscectomy, Anesth. Analg. 103 (2006) 217–222 (table of contents). [8] A. Saray, U. Buyukkocak, I. Cinel, A.T. Tellioglu, U. Oral, Diclofenac and metamizol in postoperative analgesia in plastic surgery, Acta Chir. Plast. 43 (2001) 71–76. [9] L. Hearn, S. Derry, R.A. Moore, Single dose dipyrone (metamizole) for acute postoperative pain in adults, Cochrane Database Syst. Rev. 4 (2016), CD011421. [10] U.P. Schwabe, D. Arzneiverordnungs-Report 2014: Aktuelle Daten, Kosten, Trends Und Kommentare, Springer Verlag, Germany, 2014. [11] S. Garcia, M. Canoniero, G. Lopes, A.O. Soriano, Metamizole use among Hispanics in Miami: report of a survey conducted in a primary care setting, South. Med. J. 99 (2006) 924–926. [12] J.L. Bonkowsky, J.K. Frazer, K.F. Buchi, C.L. Byington, Metamizole use by Latino immigrants: a common and potentially harmful home remedy, Pediatrics 109 (2002), e98. [13] T. Hohlfeld, N. Zimmermann, A.A. Weber, et al., Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis, J. Thromb. Haemost. 6 (2008) 166–173. [14] A. Polzin, T. Zeus, K. Schror, M. Kelm, T. Hohlfeld, Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease, J. Am. Coll. Cardiol. 62 (2013) 1725–1726.
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Please cite this article as: A. Achilles, et al., Analgesic medication with dipyrone in patients with coronary artery disease: Relation to MACCE, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.02.122