Int J Clin Pharm DOI 10.1007/s11096-014-9972-3
RESEARCH ARTICLE
Effectiveness of a pilot intervention to reduce abciximab-related bleeding in patients with acute coronary syndromes Ana de Lorenzo-Pinto • He´ctor Bueno • Ana Herranz-Alonso • Jaime Elizaga-Corrales Cristina Pe´rez-Sanz • Begon˜a Cue´llar-Basterrechea • Francisco Ferna´ndez-Avile´s • Marı´a Sanjurjo-Sa´ez
•
Received: 4 January 2014 / Accepted: 10 June 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background and objective Reducing bleeding events is a priority in patients diagnosed with acute coronary syndromes (ACS). The effectiveness of optimization measures for reducing abciximab-related bleeding was evaluated through the implementation of a pilot program developed by the Pharmacy and the Cardiology Departments at a tertiary-care hospital. Main outcome measure Percentage of bleeding events. Results Intervention was effective in reducing the incidence of the three factors associated with an increased risk of bleeding between the pre-intervention phase (n = 86) and the post-intervention phase (n = 73): unknown body weight (24.4 vs. 1.4 %, p = 0.0001), overdosing (31.4 vs. 0 %, p \ 0.0001) and combination with bivalirudin (12.8 vs. 1.4 %, p = 0.016). Bleeding events associated with these factors were numerically reduced in all three cases but these differences were not statistically significant between both periods. Conclusion The implementation of a multidisciplinary prevention program can reduce situations associated with an increased risk of bleeding in patients treated with abciximab. Larger scale trials are needed to confirm whether such programs can also reduce the incidence of bleeding at a statistically significant level.
A. de Lorenzo-Pinto (&) A. Herranz-Alonso C. Pe´rez-Sanz B. Cue´llar-Basterrechea M. Sanjurjo-Sa´ez Pharmacy Department, Instituto de Investigacio´n Sanitaria Gregorio Maran˜o´n, Hospital General Universitario Gregorio Maran˜o´n, C/Doctor Esquerdo 46, 28007 Madrid, Spain e-mail: [email protected] H. Bueno J. Elizaga-Corrales F. Ferna´ndez-Avile´s Cardiology Department, Instituto de Investigacio´n Sanitaria Gregorio Maran˜o´n, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain
Keywords Abciximab Acute coronary syndrome Bleeding Cardiology Haemorrhage
Impact of findings on practice statements • • •
Patients treated with abciximab might be receiving standard IV doses instead of weight-adjusted doses. For calculating the correct abciximab dose, taking the body weight, or an approximation of it, is essential. The integration of a hospital pharmacist into multidisciplinary teams has the potential to improve patient´s safety outcomes in ACS.
Introduction Bleeding is a frequent non cardiac complication observed in the management of acute coronary syndromes (ACS) and has a decisive influence on prognosis [1]. Major bleeding is associated with a four-fold increased risk of death, a five-fold increased risk of recurrent myocardial infarction, and a three-fold increased risk of stroke at 30 days [1–3]. Therefore, the prevention of bleeding has become equally as important as prevention of ischaemic events in ACS patients. One antithrombotic drug considered a high-alert medication with heightened risk of bleeding is abciximab [4]. This glycoprotein IIb/IIIa receptor inhibitor is a potent antiplatelet agent used in patients undergoing percutaneous coronary intervention, as an adjunct to oral antiplatelet therapy with aspirin and a thienopyridine. Evidence-based guidelines recommend intravenous administration of a 0.25 mg/kg bolus dose followed by a continuous weightadjusted infusion of 0.125 mcg/kg/min (if body weight
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\80 kg) to a maximum of 10 mcg/min for 12 h (if body weight C80 kg) [5, 6]. Due to its antithrombotic effect, abciximab is a drug with a narrow therapeutic index included in the Institute for Safe Medication Practices’ list of high-alert medications [4]. Two factors that may increase the risk of bleeding in patients treated with abciximab are the following: (1) the use of an inaccurate body weight to calculate abciximab dosage and (2) its combination with other antithrombotic drugs. Some studies have reported that some patients are not weighed prior to dosing, that body weight is estimated or recorded inaccurately, or that doses based on a patient’s weight are miscalculated [7–9]. In many cases, ACS patients are immobilized and the urgency to begin the treatment prevents from obtaining this information [10]. Findings in scientific literature show that healthcare professionals inaccurately calculate patient weight by visual estimation [7]. Combination of certain drugs with abciximab may increase bleeding risk. For instance, while some studies have shown that the use of bivalirudin is superior to the combination of heparin plus a glycoprotein IIb/IIIa receptor inhibitor in reducing in-hospital bleeding and late mortality [11, 12], however, the safety profile of the combination of abciximab with bivalirudin is controversial due to a higher incidence of major bleeding when compared with bivalirudin in monotherapy (5.3 vs. 3.0 %, p \ 0.001) [11].
Aim of the study The aim of this study was to evaluate the potential effectiveness of a pilot multidisciplinary intervention designed by the Pharmacy and the Cardiology Department at a tertiary-care hospital in order to reduce the potential risk of bleeding associated with abciximab in patients with ACS.
Ethical approval The study was approved by the Ethics Committee for Clinical Research of the hospital. Informed consent was a non-compulsory requisite, because of the quality improvement nature of the intervention.
Method We designed a pre-post quasi-experimental intervention study using retrospective cohorts. Adult patients diagnosed with ACS admitted to the Cardiology Department and
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treated with abciximab were included. Patients undergoing coronary artery bypass grafting were excluded. The intervention consisted of three specific actions: (1) a mandate for all patients to be weighed before the onset of antithrombotic therapy and weight to be registered in the patient´s medical record. A hoist (Hill-Rom, VIKING model) with weighing scales was acquired for the study and placed in the coronary care unit to be used in patients unable to stand or confined to their beds. As a possible alternative, weight information could be given by the patients themselves (or their carers), a source of information that has been shown to be more reliable than estimates by healthcare staff [7]. There are alternative methods to estimate body weight such as formulae utilising knee height and mid-arm circumference. However, these measures require well-trained professionals, as well as different formulae depending on race, sex or age. (2) The abciximab weight-adjusted dosage table was reviewed and changes communicated to the members of the cath lab and coronary care unit. These are described in the ‘‘Results’’ section. (3) A restrictive protocol for the use of abciximab in patients undergoing percutaneous coronary intervention who were treated with bivalirudin was put in place. All these interventions were communicated to professionals working at the coronary care unit and the hemodynamic laboratory during clinical ground rounds and internal meetings. Besides, these issues were also included in the treatment protocols of ACS approved in the institution. A database was designed to record patient information. It was organized in three modules: Module I: Patient demographics and personal medical history; Module II: Diagnosis and evolution during admission; and Module III: Pharmacological treatment prescribed from the onset of the ischemic event. The lists of patients diagnosed with ACS were provided by the hospital Archive Department. The following sources of information were revised for each patient: electronic medical record (available on the hospital website), paper medical record, analytical results from the ModuLab program, and in-hospital drug prescriptions, collected using the Prescriplant electronic prescribing software available on the hospital website. Bleeding episodes were classified using the new classification proposed by The Bleeding Academic Research Consortium (BARC) 2011 which divides these episodes into five categories according to their severity [13]. A simple classification was also used and bleeding was classified as clinically and nonclinically relevant. Clinically relevant bleeding should meet the criteria for ‘‘major bleeding’’ from the ACUITY, GRACE, GUSTO, HORIZONS-AMI, PLATO and TIMI studies (definition of major bleeding included intracranial haemorrhage, haemoglobin drop of C3 g/dl, bleeding with hemodynamic consequences requiring medical intervention or transfusion and fatal bleeding) [11, 12, 14–17]. BARC
Int J Clin Pharm
bleedings were grouped as follows: non-clinically relevant bleeding: BARC 1 ? BARC 2 and clinically significant bleeding: BARC 3 ? BARC 5. In order to evaluate the impact of our measures, two groups of patients were considered and compared: those belonging to the pre-intervention phase (PRE, from January 2010 to July 2010) and those of the post-intervention phase (POST, between September 2011 and February 2012).
Table 1 Baseline characteristics and antithrombotic treatment during hospitalization
Statistical analysis Categorical variables were expressed as frequencies and percentages, while continuous variables were expressed as means and standard deviation. Numeric variables with non-normal distribution were presented by their median and interquartile range (25th percentile, 75th percentile). Analysis of normality was studied using the Kolmogorov–Smirnov test. For analysis of categorical variables Pearson’s Chi square test or Fisher’s exact were used and continuous variables were analyzed with Student’s t test or the Mann–Whitney test, as appropriate. Differences were statistically significant at p \ 0.05. All statistical analyses were performed using SPSS, version 18.0.
PRE n = 86
POST n = 73
p value
62.8 ± 12.8
61.5 ± 12.0
0.52
66 (76.7) 20 (23.3)
60 (82.2) 13 (17.8)
0.52
Body weight (Kg) mean ± SD
77.1 ± 14.7
80.0 ± 15.6
0.28
Hypertension n (%)
46 (53.5)
44 (60.3)
0.39
Age (years) mean ± SD Gender n (%) Male Female
Hypercholesterolemia n (%)
46 (53.5)
36 (49.3)
0.54
Diabetes mellitus n (%)
23 (26.7)
12 (16.4)
0.17
No
22 (25.6)
26 (35.6)
0.48
Former smoker
25 (29.1)
15 (20.5)
Yes
Smoking status n (%)
38 (44.2)
32 (43.8)
STEMI diagnosis n (%)
36 (41.9)
49 (67.1)
0.003
Chronic renal failure n (%) Prior antithrombotic therapy n (%)
1 (0.9) 30 (34.9)
1 (1.4) 18 (24.7)
0.55 0.22
History of bleeding n (%)
2 (2.3)
1 (1.4)
0.89
Chronic anemia n (%)
2 (2.3)
0
0.55
PCI n (%)
86 (100.0)
73 (100.0)
–
Femoral approach n (%)
60 (69.8)
39 (53.4)
0.05
0.54
Antithrombotic drugs administered n (%)
Results A total of 159 patients were treated with abciximab during the study period (86 in PRE and 73 in POST). The patient´s baseline characteristics are shown in Table 1. Intervention results (Table 2)
7 Drugs 6 Drugs
1 (1.2) 5 (5.8)
0 6 (8.2)
5 Drugs
31 (36.0)
33 (45,2)
4 Drugs
38 (44.2)
29 (39.7)
3 Drugs
8 (9.3)
5 (6.8)
2 Drugs
1 (1.2)
0
1 Drug
2 (2.3)
0
4 (4–5)
5 (4–5)
Median number of drugs (P25–P75)
0.11
Measurement of body weight The percentage of patients with unknown body weight was reduced from 24.4 % in PRE to 1.4 % in POST (p = 0.0001). Abciximab dosage
Table 2 Effectiveness of the intervention on the three selected targets and related bleedings Results in n (%)
PRE n = 86
POST n = 73
p value
Unknown body weight
21 (24.4)
1 (1.4)
0.0001
Related bleedings
The protocol of abciximab prescription was revised and it was found that all patients who received abciximab infusions were treated with a fixed infusion dose of 10 mcg/min for 12 h (maximum dose). The infusion dose was calculated using a standard weight for all patients (80 kg), which means that patients under 80 kg were systematically overdosed. After this finding, a new protocol for abciximab administration was started with individualized bolus and infusion
9 (42.9)
1 (100.0)
0.58
Abciximab overdosing Related bleedings
23 (31.4) 14 (59.3)
0 0
\0.0001 –
Abciximab ? bivalirudin
11 (12.8)
1 (1.4)
0.016
0
0.87
Related bleedings
8 (72.7 %)
dose based on body weight. After the implementation of the new protocol, the percentage of patients overdosed was reduced from 31.4 % in PRE to 0 % in POST (p \ 0.0001).
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Combination of abciximab and bivalirudin In PRE, abciximab plus bivalirudin was prescribed in 11 patients (12.8 %). After the intervention, in POST, only one patient (1.4 %) was treated with the combination (p = 0.016). Results in bleeding In POST, the total bleeding rate was numerically lower (45.3 % in PRE vs. 32.9 % in POST, p = 0.11) as well as all subtypes of bleeding. No BARC 3c bleeding was observed in either patient group. Non-clinically relevant bleeding was reduced by 25.0 %, while clinically relevant by 41.4 % (Table 3) although the reduction did not reach a statistical significance. The percentage of patients requiring blood transfusion was 5.8 % in PRE and 4.1 % in POST. When bleedings were studied according to the three factors in which the intervention acted (Table 2), we found that in PRE, 9 patients (42.9 %) of the total number of patients with unknown body weight developed bleeding events, 14 (59.3 %) in the group of patients overdosed, and 8 (72.7 %) in the cohort treated with the combination of abciximab plus bivalirudin. In POST, the only one bleeding was associated with unknown body weight, while none occurred associated with abciximab overdosing or combination with bivalirudin.
Discussion Our intervention was effective in obtaining body weights in most patients, in reducing abciximab overdosing and in Table 3 Incidence, bleeding characteristics, need for blood transfusion and length of stay before and after the intervention
Total bleeding n (%)
PRE n = 86
POST n = 73
p value
39 (45.3)
24 (32.9)
0.11
Bleeding classification according to BARC n (%) BARC 1
15 (17.4)
7 (9.6)
BARC 2
18 (20.9)
14 (19.2)
BARC 3a
2 (2.3)
1 (1.4)
BARC 3b
3 (3.5)
2 (2.7)
BARC 5
1 (1.2)
0
0.84
Clinical significance of bleeding, n (%) Non-clinically relevant
33 (38.4)
21 (28.8)
0.27
Clinically relevant
6 (7.0)
3 (4.1)
0.66
5 (5.8) 5 (5.8)
3 (4.1) 1 (1.4)
0.82 0.30
Need for blood transfusion n (%) Red cell transfusion Platelet transfusion
1 (1.2)
2 (2.7)
0.89
Plasma transfusion
1 (1.2)
0
0.93
5.0 ± 6.2
4.8 ± 3.4
0.87
Mean length of stay (days ± SD)
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reducing the use of abciximab with bivalirudin. These three factors had been previously identified as associated with higher bleeding risk in our patients but, once they were corrected, the incidence of the total bleeding rate and all subtypes of bleeding were numerically reduced although none of the differences were statistically significant. All antithrombotic drugs used in the treatment of ACS are included in the list of high-alert medications elaborated by the Institute for Safe Medication Practices [4]. These drugs have a narrow therapeutic index and a high level of complexity, so the dosage of many of them is calculated according to the patient’s body weight in order to avoid serious and even fatal medication errors. Therefore, one objective of the study was the mandatory measurement of body weight before the initiation of treatment with abciximab and, in POST, the majority of patients were weighed. These results demonstrate the usefulness of the implementation of a hoist with weighing scales in the coronary care unit and the responsible involvement in the development of safer practices of all health professionals working at the unit. No published information is available to confirm the percentage of patients with ACS usually weighed by means of accurate methods. Most studies are based on large clinical trials in which, unlike real clinical practice, weight record is usually mandatory. However, in routine practice, medical personnel often need to estimate a patient’s weight rapidly to administer pharmacologic agents, despite the fact that this practice is discouraged by some authors [18, 19]. For this reason, studies like ours highlight the importance of verifying the measurement of body weight using accurate methods. One major consequence of the intervention was the development of a new treatment protocol that individualizes abciximab bolus and infusion dose according to body weight. Consultation of several drug information sources, undertaken as part of this study, identified other institutions using a dose of 10 mcg/min regardless of patient weight [20]. However, this recommendation does not meet the regimen described either in the summary of product characteristics or in the main clinical practice guidelines [5, 6, 21]. It is difficult to find the source of the error, but one possible explanation for its persistence and dissemination could be the difficulty of revising and modifying highly integrated practices that are easy to apply to all patients, since they are similarly carried out. For this reason, Cardiology and Pharmacy Departments must revise treatment protocols in order to check the dosage schedule of abciximab in each institution. The use of abciximab with bivalirudin is an option for consideration in some patients recommended by guidelines [5]. However, the benefits in bleeding risk were found when bivalirudin was compared with heparin ? glycoprotein IIb/ IIIa receptor inhibitor, but no evidence about the safety of
Int J Clin Pharm
bivalirudin ? glycoprotein IIb/IIIa receptor inhibitor was available at that time. After the implementation of these interventions for abciximab use optimization, the percentage of patients overdosed was reduced to 0 % in POST. The total bleeding rate was numerically lower in POST and so were all subtypes of bleeding and in particular, the clinically significant ones. Although these reductions did not reach statistical significance due to the small sample size, some studies have already shown a relationship between any excess dose of glycoprotein IIb/IIIa receptor inhibitors and an increased risk of major bleeding [22]. Limitations of retrospective observational studies are well known. The most frequent bias is the difficulty of validating the information obtained from medical records, as it may either be wrong or may not have been recorded. However, reliability is improved when the study includes two groups of patients (case and control) where the bias magnitude is similar in both. Another limitation is that a pre-post comparison study includes unintended changes in the patterns of care as well as in patient characteristics. Nevertheless, the study did not show differences in risk factors associated with bleeding between both groups. Finally, this was a pilot study because it was the first step of a potential project to reduce bleeding episodes in patients hospitalized for ACS, in which we wanted to identify potential areas of improvement. For this reason, a small sample size was included and we did not have estimations to make power calculations. Therefore, the study lacked statistical power to show differences in bleeding reduction. However, our results indicate the potential benefit of the interventions implemented (all bleeding rates were numerically lower in POST) and, also, a high level of acceptance of the interventions proposed.
Conclusion In conclusion, this study shows that a multidisciplinary intervention may improve the use of abciximab and, likewise, potentially improve patient outcomes (i.e. reduce related bleeding risk). However, the real value of these types of interventions should be evaluated in prospective studies ideally randomized and with larger cohorts of patients. Acknowledgments This study is a collaborative effort of the staff working at the coronary care unit (especially to Antonia de Prado), hemodynamic laboratory (Marina), Pharmacy Department, Jose Ma Bello´n, Archives Department and Ana Luna. Funding This project was funded by a Grant of the Ministerio de Salud, Polı´tica Social e Igualdad (SAS/2377/2010, Project Code: EC10-028).
Conflict of interest He´ctor Bueno has received advisory/consulting fees from AstraZeneca, Bayer, Daichii-Sankyo, Eli-Lilly, Novartis, Roche, and research grants from AstraZeneca. All other authors have nothing to disclose.
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Int J Clin Pharm contemporary thrombolytic therapy for myocardial infarction. The global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) I investigators. Circulation. 1997;95:2508–16. 16. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57. 17. Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999;100:1593–601. 18. Corbo J, Canter M, Grinberg D, Bijur P. Who should be estimating a patient’s weight in the emergency department? Acad Emerg Med. 2005;12(3):262–6.
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19. del Garcı´a MMR, Morales Laborı´as ME, Ferna´ndez Lo´pez I, Rodrı´guez Delgado E, Dı´az Castellanos MA. Subjective estimation of patient weight and height in the ICU. Non-advisable measures. Med Intensiva. 2013;37:50–2. 20. The Clinician’s Ultimate Reference. [cited 2011 Sep 5]. http:// www.globalrph.com/abciximab_dilution.htm. 21. Reopro. Summary of product characteristics. [cited 2011 Jun 5]. http://www.aemps.gob.es/cima/especialidad.do?metodo=verFicha WordPdf&codigo=60660&formato=pdf&formulario=FICHAS& file=ficha.pdf. 22. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, Allen-LaPointe NM, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294(24):3108–16.
RESEARCH ARTICLE
Effectiveness of a pilot intervention to reduce abciximab-related bleeding in patients with acute coronary syndromes Ana de Lorenzo-Pinto • He´ctor Bueno • Ana Herranz-Alonso • Jaime Elizaga-Corrales Cristina Pe´rez-Sanz • Begon˜a Cue´llar-Basterrechea • Francisco Ferna´ndez-Avile´s • Marı´a Sanjurjo-Sa´ez
•
Received: 4 January 2014 / Accepted: 10 June 2014 Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2014
Abstract Background and objective Reducing bleeding events is a priority in patients diagnosed with acute coronary syndromes (ACS). The effectiveness of optimization measures for reducing abciximab-related bleeding was evaluated through the implementation of a pilot program developed by the Pharmacy and the Cardiology Departments at a tertiary-care hospital. Main outcome measure Percentage of bleeding events. Results Intervention was effective in reducing the incidence of the three factors associated with an increased risk of bleeding between the pre-intervention phase (n = 86) and the post-intervention phase (n = 73): unknown body weight (24.4 vs. 1.4 %, p = 0.0001), overdosing (31.4 vs. 0 %, p \ 0.0001) and combination with bivalirudin (12.8 vs. 1.4 %, p = 0.016). Bleeding events associated with these factors were numerically reduced in all three cases but these differences were not statistically significant between both periods. Conclusion The implementation of a multidisciplinary prevention program can reduce situations associated with an increased risk of bleeding in patients treated with abciximab. Larger scale trials are needed to confirm whether such programs can also reduce the incidence of bleeding at a statistically significant level.
A. de Lorenzo-Pinto (&) A. Herranz-Alonso C. Pe´rez-Sanz B. Cue´llar-Basterrechea M. Sanjurjo-Sa´ez Pharmacy Department, Instituto de Investigacio´n Sanitaria Gregorio Maran˜o´n, Hospital General Universitario Gregorio Maran˜o´n, C/Doctor Esquerdo 46, 28007 Madrid, Spain e-mail: [email protected] H. Bueno J. Elizaga-Corrales F. Ferna´ndez-Avile´s Cardiology Department, Instituto de Investigacio´n Sanitaria Gregorio Maran˜o´n, Hospital General Universitario Gregorio Maran˜o´n, Madrid, Spain
Keywords Abciximab Acute coronary syndrome Bleeding Cardiology Haemorrhage
Impact of findings on practice statements • • •
Patients treated with abciximab might be receiving standard IV doses instead of weight-adjusted doses. For calculating the correct abciximab dose, taking the body weight, or an approximation of it, is essential. The integration of a hospital pharmacist into multidisciplinary teams has the potential to improve patient´s safety outcomes in ACS.
Introduction Bleeding is a frequent non cardiac complication observed in the management of acute coronary syndromes (ACS) and has a decisive influence on prognosis [1]. Major bleeding is associated with a four-fold increased risk of death, a five-fold increased risk of recurrent myocardial infarction, and a three-fold increased risk of stroke at 30 days [1–3]. Therefore, the prevention of bleeding has become equally as important as prevention of ischaemic events in ACS patients. One antithrombotic drug considered a high-alert medication with heightened risk of bleeding is abciximab [4]. This glycoprotein IIb/IIIa receptor inhibitor is a potent antiplatelet agent used in patients undergoing percutaneous coronary intervention, as an adjunct to oral antiplatelet therapy with aspirin and a thienopyridine. Evidence-based guidelines recommend intravenous administration of a 0.25 mg/kg bolus dose followed by a continuous weightadjusted infusion of 0.125 mcg/kg/min (if body weight
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Int J Clin Pharm
\80 kg) to a maximum of 10 mcg/min for 12 h (if body weight C80 kg) [5, 6]. Due to its antithrombotic effect, abciximab is a drug with a narrow therapeutic index included in the Institute for Safe Medication Practices’ list of high-alert medications [4]. Two factors that may increase the risk of bleeding in patients treated with abciximab are the following: (1) the use of an inaccurate body weight to calculate abciximab dosage and (2) its combination with other antithrombotic drugs. Some studies have reported that some patients are not weighed prior to dosing, that body weight is estimated or recorded inaccurately, or that doses based on a patient’s weight are miscalculated [7–9]. In many cases, ACS patients are immobilized and the urgency to begin the treatment prevents from obtaining this information [10]. Findings in scientific literature show that healthcare professionals inaccurately calculate patient weight by visual estimation [7]. Combination of certain drugs with abciximab may increase bleeding risk. For instance, while some studies have shown that the use of bivalirudin is superior to the combination of heparin plus a glycoprotein IIb/IIIa receptor inhibitor in reducing in-hospital bleeding and late mortality [11, 12], however, the safety profile of the combination of abciximab with bivalirudin is controversial due to a higher incidence of major bleeding when compared with bivalirudin in monotherapy (5.3 vs. 3.0 %, p \ 0.001) [11].
Aim of the study The aim of this study was to evaluate the potential effectiveness of a pilot multidisciplinary intervention designed by the Pharmacy and the Cardiology Department at a tertiary-care hospital in order to reduce the potential risk of bleeding associated with abciximab in patients with ACS.
Ethical approval The study was approved by the Ethics Committee for Clinical Research of the hospital. Informed consent was a non-compulsory requisite, because of the quality improvement nature of the intervention.
Method We designed a pre-post quasi-experimental intervention study using retrospective cohorts. Adult patients diagnosed with ACS admitted to the Cardiology Department and
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treated with abciximab were included. Patients undergoing coronary artery bypass grafting were excluded. The intervention consisted of three specific actions: (1) a mandate for all patients to be weighed before the onset of antithrombotic therapy and weight to be registered in the patient´s medical record. A hoist (Hill-Rom, VIKING model) with weighing scales was acquired for the study and placed in the coronary care unit to be used in patients unable to stand or confined to their beds. As a possible alternative, weight information could be given by the patients themselves (or their carers), a source of information that has been shown to be more reliable than estimates by healthcare staff [7]. There are alternative methods to estimate body weight such as formulae utilising knee height and mid-arm circumference. However, these measures require well-trained professionals, as well as different formulae depending on race, sex or age. (2) The abciximab weight-adjusted dosage table was reviewed and changes communicated to the members of the cath lab and coronary care unit. These are described in the ‘‘Results’’ section. (3) A restrictive protocol for the use of abciximab in patients undergoing percutaneous coronary intervention who were treated with bivalirudin was put in place. All these interventions were communicated to professionals working at the coronary care unit and the hemodynamic laboratory during clinical ground rounds and internal meetings. Besides, these issues were also included in the treatment protocols of ACS approved in the institution. A database was designed to record patient information. It was organized in three modules: Module I: Patient demographics and personal medical history; Module II: Diagnosis and evolution during admission; and Module III: Pharmacological treatment prescribed from the onset of the ischemic event. The lists of patients diagnosed with ACS were provided by the hospital Archive Department. The following sources of information were revised for each patient: electronic medical record (available on the hospital website), paper medical record, analytical results from the ModuLab program, and in-hospital drug prescriptions, collected using the Prescriplant electronic prescribing software available on the hospital website. Bleeding episodes were classified using the new classification proposed by The Bleeding Academic Research Consortium (BARC) 2011 which divides these episodes into five categories according to their severity [13]. A simple classification was also used and bleeding was classified as clinically and nonclinically relevant. Clinically relevant bleeding should meet the criteria for ‘‘major bleeding’’ from the ACUITY, GRACE, GUSTO, HORIZONS-AMI, PLATO and TIMI studies (definition of major bleeding included intracranial haemorrhage, haemoglobin drop of C3 g/dl, bleeding with hemodynamic consequences requiring medical intervention or transfusion and fatal bleeding) [11, 12, 14–17]. BARC
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bleedings were grouped as follows: non-clinically relevant bleeding: BARC 1 ? BARC 2 and clinically significant bleeding: BARC 3 ? BARC 5. In order to evaluate the impact of our measures, two groups of patients were considered and compared: those belonging to the pre-intervention phase (PRE, from January 2010 to July 2010) and those of the post-intervention phase (POST, between September 2011 and February 2012).
Table 1 Baseline characteristics and antithrombotic treatment during hospitalization
Statistical analysis Categorical variables were expressed as frequencies and percentages, while continuous variables were expressed as means and standard deviation. Numeric variables with non-normal distribution were presented by their median and interquartile range (25th percentile, 75th percentile). Analysis of normality was studied using the Kolmogorov–Smirnov test. For analysis of categorical variables Pearson’s Chi square test or Fisher’s exact were used and continuous variables were analyzed with Student’s t test or the Mann–Whitney test, as appropriate. Differences were statistically significant at p \ 0.05. All statistical analyses were performed using SPSS, version 18.0.
PRE n = 86
POST n = 73
p value
62.8 ± 12.8
61.5 ± 12.0
0.52
66 (76.7) 20 (23.3)
60 (82.2) 13 (17.8)
0.52
Body weight (Kg) mean ± SD
77.1 ± 14.7
80.0 ± 15.6
0.28
Hypertension n (%)
46 (53.5)
44 (60.3)
0.39
Age (years) mean ± SD Gender n (%) Male Female
Hypercholesterolemia n (%)
46 (53.5)
36 (49.3)
0.54
Diabetes mellitus n (%)
23 (26.7)
12 (16.4)
0.17
No
22 (25.6)
26 (35.6)
0.48
Former smoker
25 (29.1)
15 (20.5)
Yes
Smoking status n (%)
38 (44.2)
32 (43.8)
STEMI diagnosis n (%)
36 (41.9)
49 (67.1)
0.003
Chronic renal failure n (%) Prior antithrombotic therapy n (%)
1 (0.9) 30 (34.9)
1 (1.4) 18 (24.7)
0.55 0.22
History of bleeding n (%)
2 (2.3)
1 (1.4)
0.89
Chronic anemia n (%)
2 (2.3)
0
0.55
PCI n (%)
86 (100.0)
73 (100.0)
–
Femoral approach n (%)
60 (69.8)
39 (53.4)
0.05
0.54
Antithrombotic drugs administered n (%)
Results A total of 159 patients were treated with abciximab during the study period (86 in PRE and 73 in POST). The patient´s baseline characteristics are shown in Table 1. Intervention results (Table 2)
7 Drugs 6 Drugs
1 (1.2) 5 (5.8)
0 6 (8.2)
5 Drugs
31 (36.0)
33 (45,2)
4 Drugs
38 (44.2)
29 (39.7)
3 Drugs
8 (9.3)
5 (6.8)
2 Drugs
1 (1.2)
0
1 Drug
2 (2.3)
0
4 (4–5)
5 (4–5)
Median number of drugs (P25–P75)
0.11
Measurement of body weight The percentage of patients with unknown body weight was reduced from 24.4 % in PRE to 1.4 % in POST (p = 0.0001). Abciximab dosage
Table 2 Effectiveness of the intervention on the three selected targets and related bleedings Results in n (%)
PRE n = 86
POST n = 73
p value
Unknown body weight
21 (24.4)
1 (1.4)
0.0001
Related bleedings
The protocol of abciximab prescription was revised and it was found that all patients who received abciximab infusions were treated with a fixed infusion dose of 10 mcg/min for 12 h (maximum dose). The infusion dose was calculated using a standard weight for all patients (80 kg), which means that patients under 80 kg were systematically overdosed. After this finding, a new protocol for abciximab administration was started with individualized bolus and infusion
9 (42.9)
1 (100.0)
0.58
Abciximab overdosing Related bleedings
23 (31.4) 14 (59.3)
0 0
\0.0001 –
Abciximab ? bivalirudin
11 (12.8)
1 (1.4)
0.016
0
0.87
Related bleedings
8 (72.7 %)
dose based on body weight. After the implementation of the new protocol, the percentage of patients overdosed was reduced from 31.4 % in PRE to 0 % in POST (p \ 0.0001).
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Combination of abciximab and bivalirudin In PRE, abciximab plus bivalirudin was prescribed in 11 patients (12.8 %). After the intervention, in POST, only one patient (1.4 %) was treated with the combination (p = 0.016). Results in bleeding In POST, the total bleeding rate was numerically lower (45.3 % in PRE vs. 32.9 % in POST, p = 0.11) as well as all subtypes of bleeding. No BARC 3c bleeding was observed in either patient group. Non-clinically relevant bleeding was reduced by 25.0 %, while clinically relevant by 41.4 % (Table 3) although the reduction did not reach a statistical significance. The percentage of patients requiring blood transfusion was 5.8 % in PRE and 4.1 % in POST. When bleedings were studied according to the three factors in which the intervention acted (Table 2), we found that in PRE, 9 patients (42.9 %) of the total number of patients with unknown body weight developed bleeding events, 14 (59.3 %) in the group of patients overdosed, and 8 (72.7 %) in the cohort treated with the combination of abciximab plus bivalirudin. In POST, the only one bleeding was associated with unknown body weight, while none occurred associated with abciximab overdosing or combination with bivalirudin.
Discussion Our intervention was effective in obtaining body weights in most patients, in reducing abciximab overdosing and in Table 3 Incidence, bleeding characteristics, need for blood transfusion and length of stay before and after the intervention
Total bleeding n (%)
PRE n = 86
POST n = 73
p value
39 (45.3)
24 (32.9)
0.11
Bleeding classification according to BARC n (%) BARC 1
15 (17.4)
7 (9.6)
BARC 2
18 (20.9)
14 (19.2)
BARC 3a
2 (2.3)
1 (1.4)
BARC 3b
3 (3.5)
2 (2.7)
BARC 5
1 (1.2)
0
0.84
Clinical significance of bleeding, n (%) Non-clinically relevant
33 (38.4)
21 (28.8)
0.27
Clinically relevant
6 (7.0)
3 (4.1)
0.66
5 (5.8) 5 (5.8)
3 (4.1) 1 (1.4)
0.82 0.30
Need for blood transfusion n (%) Red cell transfusion Platelet transfusion
1 (1.2)
2 (2.7)
0.89
Plasma transfusion
1 (1.2)
0
0.93
5.0 ± 6.2
4.8 ± 3.4
0.87
Mean length of stay (days ± SD)
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reducing the use of abciximab with bivalirudin. These three factors had been previously identified as associated with higher bleeding risk in our patients but, once they were corrected, the incidence of the total bleeding rate and all subtypes of bleeding were numerically reduced although none of the differences were statistically significant. All antithrombotic drugs used in the treatment of ACS are included in the list of high-alert medications elaborated by the Institute for Safe Medication Practices [4]. These drugs have a narrow therapeutic index and a high level of complexity, so the dosage of many of them is calculated according to the patient’s body weight in order to avoid serious and even fatal medication errors. Therefore, one objective of the study was the mandatory measurement of body weight before the initiation of treatment with abciximab and, in POST, the majority of patients were weighed. These results demonstrate the usefulness of the implementation of a hoist with weighing scales in the coronary care unit and the responsible involvement in the development of safer practices of all health professionals working at the unit. No published information is available to confirm the percentage of patients with ACS usually weighed by means of accurate methods. Most studies are based on large clinical trials in which, unlike real clinical practice, weight record is usually mandatory. However, in routine practice, medical personnel often need to estimate a patient’s weight rapidly to administer pharmacologic agents, despite the fact that this practice is discouraged by some authors [18, 19]. For this reason, studies like ours highlight the importance of verifying the measurement of body weight using accurate methods. One major consequence of the intervention was the development of a new treatment protocol that individualizes abciximab bolus and infusion dose according to body weight. Consultation of several drug information sources, undertaken as part of this study, identified other institutions using a dose of 10 mcg/min regardless of patient weight [20]. However, this recommendation does not meet the regimen described either in the summary of product characteristics or in the main clinical practice guidelines [5, 6, 21]. It is difficult to find the source of the error, but one possible explanation for its persistence and dissemination could be the difficulty of revising and modifying highly integrated practices that are easy to apply to all patients, since they are similarly carried out. For this reason, Cardiology and Pharmacy Departments must revise treatment protocols in order to check the dosage schedule of abciximab in each institution. The use of abciximab with bivalirudin is an option for consideration in some patients recommended by guidelines [5]. However, the benefits in bleeding risk were found when bivalirudin was compared with heparin ? glycoprotein IIb/ IIIa receptor inhibitor, but no evidence about the safety of
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bivalirudin ? glycoprotein IIb/IIIa receptor inhibitor was available at that time. After the implementation of these interventions for abciximab use optimization, the percentage of patients overdosed was reduced to 0 % in POST. The total bleeding rate was numerically lower in POST and so were all subtypes of bleeding and in particular, the clinically significant ones. Although these reductions did not reach statistical significance due to the small sample size, some studies have already shown a relationship between any excess dose of glycoprotein IIb/IIIa receptor inhibitors and an increased risk of major bleeding [22]. Limitations of retrospective observational studies are well known. The most frequent bias is the difficulty of validating the information obtained from medical records, as it may either be wrong or may not have been recorded. However, reliability is improved when the study includes two groups of patients (case and control) where the bias magnitude is similar in both. Another limitation is that a pre-post comparison study includes unintended changes in the patterns of care as well as in patient characteristics. Nevertheless, the study did not show differences in risk factors associated with bleeding between both groups. Finally, this was a pilot study because it was the first step of a potential project to reduce bleeding episodes in patients hospitalized for ACS, in which we wanted to identify potential areas of improvement. For this reason, a small sample size was included and we did not have estimations to make power calculations. Therefore, the study lacked statistical power to show differences in bleeding reduction. However, our results indicate the potential benefit of the interventions implemented (all bleeding rates were numerically lower in POST) and, also, a high level of acceptance of the interventions proposed.
Conclusion In conclusion, this study shows that a multidisciplinary intervention may improve the use of abciximab and, likewise, potentially improve patient outcomes (i.e. reduce related bleeding risk). However, the real value of these types of interventions should be evaluated in prospective studies ideally randomized and with larger cohorts of patients. Acknowledgments This study is a collaborative effort of the staff working at the coronary care unit (especially to Antonia de Prado), hemodynamic laboratory (Marina), Pharmacy Department, Jose Ma Bello´n, Archives Department and Ana Luna. Funding This project was funded by a Grant of the Ministerio de Salud, Polı´tica Social e Igualdad (SAS/2377/2010, Project Code: EC10-028).
Conflict of interest He´ctor Bueno has received advisory/consulting fees from AstraZeneca, Bayer, Daichii-Sankyo, Eli-Lilly, Novartis, Roche, and research grants from AstraZeneca. All other authors have nothing to disclose.
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