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Thromboprophylaxis in Acutely Ill Medical Patients: Results of A Survey Among Italian Physicians
Thrombosis Research 134 (2014) 572–577
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Regular Article
Thromboprophylaxis in Acutely Ill Medical Patients: Results of A Survey Among Italian Physicians Francesco Dentali a,⁎, Fulvio Pomero b, Micaela La Regina c, Francesco Orlandini c, Sara Turato a, Antonino Mazzone d, Carlo Nozzoli e, Andrea Fontanella f, Walter Ageno a, Giancarlo Agnelli g, Mauro Campanini h a
Department of Clinical Medicine Insubria University, Varese, Italy Department of Clinical Medicine, ASO S. Croce e Carle, Cuneo, Italy c Department of Internal Medicine, Presidio Ospedaliero Unico del Levante Ligure, La Spezia, Italy d Department of Internal Medicine, A.O. Ospedale Civile, Legnano, Italy e Department of Internal Medicine, A.O. Careggi, Firenze, Italy f Department of Internal Medicine, Ospedale del Buon Consiglio, Napoli, Italy g Internal and Cardiovascular Medicine and Stroke Unit, University of Perugia, Perugia, Italy h Department of Internal Medicine, AOU Maggiore della Carità, Novara, Italy b
a r t i c l e
i n f o
Article history: Received 1 November 2013 Received in revised form 29 April 2014 Accepted 10 June 2014 Available online 16 June 2014 Keywords: venous thromboembolism bleeding risk thromboprophylaxis RAMs
a b s t r a c t Aims: acutely ill medical patients are at increased risk of venous thromboembolism (VTE) and often require thromboprophylaxis, but patient selection and adequate therapeutic decisions may be difficult due to the heterogeneity and the complexity of this population. We conducted a survey among a large cohort of Italian physicians to assess their approach to some important “grey” areas of VTE prevention in this setting. Methods: a questionnaire was distributed during the meeting of a national society of Internal Medicine (FADOI), held in May 2013. Four clinical scenarios describing areas of clinical uncertainty were administered to participants: the first on a patient with acute ischemic stroke; the second on a patient with severe renal insufficiency; the third on the duration of prophylaxis in the post-acute setting; and the last on a patient at high risk of VTE and at moderate risk of bleeding with preserved mobility. Results: 453 questionnaires were returned (participants mean age 48.5 years). About 70% of participants systematically assess VTE and bleeding risk in their clinical practice, but a minority of them use risk assessment models. Prolonged prophylaxis in the post-acute setting was voted by more than eighty percent of participants; replies to the other three clinical scenarios were more heterogeneous with none of the options selected by more than 60% of participant. Conclusion: physicians approach to “grey” areas of antithrombotic prophylaxis in the medical setting is quite heterogeneous and sometimes partially in contrast to recent guidelines, reinforcing the need for educational programs and high quality studies in this setting. © 2014 Elsevier Ltd. All rights reserved.
Introduction Acutely ill medical patients are at increased risk of venous thromboembolism (VTE), which can occur during hospitalization or after discharge [1]. A number of clinical trials and meta-analyses have shown that pharmacologic prophylaxis with antithrombotic drugs significantly reduces the risk of fatal pulmonary embolism as compared to placebo or no treatment in these patients, with no or minimal increase in the risk of major bleeding [2–4]. Yet, even in recent studies, only about
⁎ Corresponding author at: U.O. Medicina Interna, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy. Tel.: +39 0332 278594; fax: +39 0332 278229. E-mail address: [email protected] (F. Dentali).
http://dx.doi.org/10.1016/j.thromres.2014.06.013 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
half of eligible hospitalized medical patients receive appropriate thromboprophylaxis [5–7]. The heterogeneity of the medical population has always posed a substantial problem in identifying acutely ill patients who could benefit from an appropriate prophylaxis. A number of risk assessment models (RAMs) have been recently proposed to assist clinicians in evaluating the risk of thromboembolic and major bleeding complications [8–11]. Unfortunately, RAMs often included different items (sometimes with conflicting results), and failed to assess risk factors that are commonly encountered in clinical practice and considered relevant by clinicians. Thus, possibly as a consequence of these limitations, are not broadly used. Furthermore, risks and benefits of antithrombotic prophylaxis in special populations, such as underweight or obese patients and patients with severe renal failure [12], remain to be established since these
F. Dentali et al. / Thrombosis Research 134 (2014) 572–577
groups of patients were not included in the randomized controlled trials on this topic. Finally, although it was hypothesized that, in some high risk medical patients, anticoagulant prophylaxis should be continued after discharge, none of the available trials has brought convincing evidence on the potential benefits of prolonged prophylaxis in this population [13]. Thus, since evidences of the literature on several aspects of prophylaxis in medical patients are still not compelling, thus leading to potentially variable approaches in real-life clinical practice, we conducted a survey among a large cohort of Italian physicians to assess their approach to some important “grey” areas of antithrombotic prophylaxis in this setting including acute ischemic stroke, severe renal insufficiency, duration of prophylaxis in the post-acute setting and a concomitance of a substantial risk of VTE and bleeding.
Methods A questionnaire describing 4 different clinical scenarios was distributed during the national meeting of an Italian scientific society of Internal medicine, FADOI (Italian Federation of Internal Medicine), held in Taormina, Italy during May, 2013. FADOI is a large society with more than 2000 affiliates from all the twenty Italian regions. Almost all the FADOI members are clinicians actively working in medical wards in teaching and non-teaching hospitals and they all have direct patient responsibility. The meeting was attended by about 900 participants, nearly all of whom are members of the society. During the first day of the meeting, the questionnaire was introduced to the participants with a brief oral presentation. Nine hundred questionnaires were distributed and then collected at the registration desk throughout the meeting. All answers were entered into a database from which respondent information was dissociated; thus the results of the survey were analyzed in an anonymous fashion. In the first page of the questionnaire we proposed 5 questions aimed to describe the training and the experience of the participants. In particular, participants were asked about their age, date of training, their specialty, and their workplace (hospital, post-acute setting, general practitioner ambulatory). Respondents were also queried about whether they had a special interest in thrombosis and haemostasis (explicitly asking "whether they actually ran a specific ambulatory and/or if he/she is usually “on call” for thrombosis and haemostasis issues in the hospital), if they work with colleagues expert in thrombosis and haemostasis, and, finally, about whether they use RAMs or other clinical or laboratory scores to assess thromboembolic and haemorrhagic risks in their patients. The 4 scenarios described hypothetical patients. For each of the 4 scenarios presented, we proposed 6 or 7 options for the management of the patients. Clinical scenarios and management options are described in Table 1. Briefly, the first scenario described a patient with acute exacerbation of chronic obstructive pulmonary disease (COPD) discharged from the hospital to a post-acute setting in order to continue the intra-venous administration of antibiotic therapy. The second scenario described a patient with an acute, large ischemic cerebral lesion at potentially high risk of hemorrhagic transformation who was treated with low doses of acetyl salicylic acid (ASA). The third scenario described a patient with severe renal insufficiency, urinary tract infection and fever requiring total bed rest. The last scenario described a patient with pneumonia, with preserved mobility, who was defined at high risk of thromboembolic complications by the Padua score [8] and at low risk of bleeding according to the IMPROVE bleeding score [11]. For all these scenarios, participants were asked to decide about the optimal antithrombotic prophylaxis. Continuous variables were expressed as mean plus or minus the standard deviation (SD); Categorical data and qualitative variables are given as counts and percentages.
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Subgroup analyses including only participants with more clinical experience (who conferred the degree more than 10 years ago), participants working in hospital, and participants with a special interest in thrombosis and haemostasis were performed. Statistical analyses were performed using SPSS version 19.0 Results Four hundred and fifty three of the 900 distributed questionnaires were returned (50.3%). Characteristics of participants are summarized in Table 2. Mean age of participants was 46.1 years (+10.4 years); all but 76 participants (16.8%) had at least one specialty and most of the participants had their specialty in Internal Medicine (61%); 413 of 453 (91.2%) participants work in a hospital; about 40% of participants had a specific interest in thrombosis and haemostasis and 47.5% of participants had at least one colleague expert in this field. The risk of thromboembolic complications is routinely assessed by 321 participants (70.9%) in their clinical practice, although the method used for stratification was specified by only 267 participants. A formal RAM is used by 126 participants and included the Padua score (87 participants, 19.2% of the total number of participants), a score developed by the FADOI scientific society (9 participants, 2.0%), the Geneva score (6 participants, 1.3%) and the IMPROVE score (5 participants, 1.1%) whereas a local evaluation score is used by 19 participants (4.2%) and 141 participants assess the thromboembolic risk with a clinical evaluation (31.1%). The risk of bleeding complications is routinely assessed by 339 participants (74.8%), although the stratification method was specified by only 324 of them. The risk of major bleeding is assessed with a clinical evaluation by 165 participants (36.4% of the total number of participants), whereas 134 participants (29.6%) use the HAS-BLED score, 9 participants (2.0%) use a local evaluation score, and only 16 participants (3.5%) use the IMPROVE score. The results from the four case scenarios are summarized in Fig. 1. In the first scenario, more than 85% of participants would have prescribed extended prophylaxis with LMWH or UFH after discharge for a total of 35 days, whereas only a minority of participants would have stopped anticoagulant prophylaxis after a maximum of 14 days. In the second scenario, about 60% of participants would have prescribed a prophylactic dose of LMWH in association with low doses of aspirin to the patient with acute ischemic stroke, whereas about a quarter would have not added any other pharmacological or nonpharmacological therapy; about 10% would have added clopidogrel to aspirin; and only a minority of participants would have used elastic stockings or intermittent pneumatic compression. In the third scenario, more than 60% of participants would have chosen a reduced prophylactic dose of LMWH or fondaparinux in the patient with severe renal insufficiency, whereas more than 25% of participants would have used a full prophylactic dose of LMWH or fondaparinux; and only a minority of participant would have chosen a prophylactic dose of UFH. In the last scenario, about 40% of participants would have prescribed a reduced prophylactic dose of LMWH or fondaparinux; one third of participants would have used a full prophylactic dose of LMWH or fondaparinux; and more than 10% of participants would have not prescribed any antithrombotic prophylaxis to this patient. Subgroup analyses including only participants with more clinical experience, participants working in hospital, participants with a personal special interest in thrombosis and haemostasis, and those who work with colleagues expert in thrombosis and haemostasis gave results that were only slightly different to those observed in the principal analyses (Appendix 1). Of interest, significantly more participants among those using the Padua prediction score would have prescribed a prophylactic dose of LMWH or fondaparinux to the patient described in case scenario 4, as compared to participants who reported to not use this score (90.8 vs 76.0; p b 0.01).
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Table 1 Clinical scenarios. 1st Scenario
2nd Scenario
3th Scenario
4th Scenario
77-y.o. woman, obese, hypertensive, diabetic, dislipidemic, on insulin and ACE-inhibitors was admitted to hospital for pneumonia and treated with antibiotics for 10 days. As she was hypoxemic, she was also supplemented with oxygen via Venturi mask. During hospital stay she was bedridden, so prophylactic doses of LMWH were prescribed. Platelet count and renal function were normal. After 10 days she was discharged to a subacute facility and antibiotics were prescribed for further 7 days. Because of persistent slight hypoxia at rest, also oxygen by nasal cannula was prescribed. At the time of admission in the sub acute facility she was able to walk to the toilet with some help. Which of the following therapies do you consider appropriate?
73-y.o. man, affected by arterial hypertension and diabetes, on antihypertensive and oral hypoglicemic drugs was healthy until 2 days ago when he woke up in the morning with a faciobrachiocrural hemisyndrome. First brain CT scan was negative for vascular injury. Aspirin 300 mg was administered immediately after CT scan and ASA 100 mg were prescribed for the following days. After 36 hours, the second CT scan showed large ischemic lesion in the territory of the middle cerebral artery. Platelets count and renal function were normal. EKG showed sinus rhythm. Which therapy besides ASA do you consider appropriate for this patient?
83-y.o. woman, weight 53 Kg, affected by arterial hypertension and rheumatoid arthritis since 8 years ago, on treatment with prednisone, calcium-channel blockers and ACE-inhibitors, was admitted for fever and poor general conditions. Urine and blood culture were positive for E. coli and she was treated with cyprophloxacin 500 mg twice a day. Platelet count was normal, and serum creatinine was 1.5 mg/dl, 132 mol/l. Which prophylaxis do you consider appropriate in this patient?
72-y.o man, weight 75 Kg, affected by metastatic prostatic cancer (bone) treated with hormonal therapy. He was admitted to hospital for fever due to right basal pneumonia and was treated with i.v. antibiotics. He was not bedridden. Platelet count was normal and serum creatinine was 1.6 mg/dl (141 mol/l). Which prophylaxis do you consider appropriate for this patient?
1.
2.
3. 4. 5. 6.
1. 2. 3. 4. 5. Prophylactic doses of LMWH up to the recovery of independent ambulation or 6. 7. anyway for no more than 35 days. Prophylactic doses of UFH up to the recovery of independent ambulation or anyway for no more than 35 days. Graduated compression stockings up to the recovery of independent ambulation Prophylactic doses of LMWH or UFH for additional 4 days. Aspirin 100 mg/die up to the recovery of independent ambulation No antithrombotic therapies
prophylactic doses of LMWH prophylactic doses of UFH Therapeutic doses of LMWH or UFH Graduated compression stockings Pneumatic compression devices Clopidogrel 75 mg/die No other therapies in addition to aspirin
Discussion The results of this survey conducted among Italian physicians reflect a substantial heterogeneity in the clinical management of medical patients at risk for VTE. Although most physicians report to routinely assess the risk of VTE and bleeding in their patients, only a minority use a formal RAM in his or her clinical practice. In particular, about one out of five participating clinicians uses the Padua prediction score [8], as suggested by the most recent American College of Chest Physicians (ACCP) guidelines [14]. Furthermore, only few participants used a bleeding risk score [11], although none of the available scores is sufficiently validated and, for this reason, currently recommended by the ACCP guidelines. Interestingly, most physicians who reported to use a bleeding score actually applies the HAS-BLED score, a score developed and validated only to assess the risk of major bleeding complications in patients on oral anticoagulant therapy for atrial fibrillation [15]. Despite the absence of clear evidences to support this strategy, most physicians seem to consider the possibility to extend anticoagulant prophylaxis beyond the period of hospitalization in patients who remain at potentially increased risk of VTE (first scenario). This is clearly in contrast with the ACCP guidelines [14], where prolonged prophylaxis is not recommended based on the negative results of the three RCTs that have compared the LMWH enoxaparin [16]and the oral direct inhibitors rivaroxaban and apixaban [17,18] with placebo after an initial course of prophylaxis for a maximum of 14 days. In all these studies, the potential benefit of extended prophylaxis was offset by an increased risk of major bleeding complications [16–18]. The use of prophylactic doses of LMWH or UFH in association to low dose aspirin in the presence of a large ischemic stroke was selected by the majority of participants (second scenario), although the responses in this case were heterogeneous. Recommendations of recent guidelines on this topic are contrasting, with ACCP guidelines [19] suggesting low
1. 2. 3. 4. 5. 6.
Prophylactic doses of LMWH Graduated compression stockings Pneumatic compression devices Prophylactic doses of UFH Fondaparinux 2.5 mg/die SQ Half of the prophylactic dose of LMWH or fondaparinux 1.5 mg/die SQ
1. 2. 3. 4. 5. 6. 7.
Prophylactic doses of LMWH Prophylactic doses of UFH Fondaparinux 2.5 mg/die No VTE prophylaxis Graduated compression stockings Aspirin 100 mg/die Half of the prophylactic dose of LMWH or fondaparinux 1.5 mg/die
dose of LMWH or UFH in patients with acute ischemic stroke and restricted mobility, and the American Heart Association/American Stroke Association guidelines [20] suggesting against the routine use of anticoagulant prophylaxis in these patients because of the potential risk for hemorrhagic complications. Evidences from the literature are also contrasting [21,22]: in the meta-analysis performed by Sandercock et al, the use of LMWH or UFH reduced the incidence of venous thromboembolic events but at the cost of an increased risk of intracranial and extracranial haemorrhagic complications [21]. Conversely, in the meta-analysis performed by Kamphuisen et al, the risk of major bleeding complications appeared to be related to the doses of the anticoagulant drugs, with no significant increase when a prophylactic dose of UFH or LMWH was used [22]. Of note, very few participants would have prescribed graduated compression stockings or intermittent pneumatic compression to this patient. The use of graduated compression stockings was not associated with a decreased risk of deep vein thrombosis in a large RCT including patients with acute ischemic stroke [23], whereas in a recent RCT, including a similar population, the incidence of deep vein thrombosis was decreased with intermittent pneumatic compression [24]. Unfortunately, this device is not available in many hospitals. The use of a reduced prophylactic dose of LMWH or fondaparinux in a patient with severe renal failure (third scenario) was selected by about 60% of participants, with about 20% of participants selecting a full prophylactic dose, and only a minority of participants selecting UFH. Evidences on the appropriate anticoagulant prophylaxis in patients with severe renal failure are lacking. The manufacturer of enoxaparin recommends a reduced daily dose for patients with a creatinine clearance (CrCl) b 30 mL/min (ref). Higher anti-factor Xa levels were found in patients with renal failure who received repeated oncedaily full prophylactic doses of enoxaparin, although the mean peak and the trough anti-Xa levels were only slightly increased [25]. Information on other LMWHs is even more limited and there are no adequately
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Results from the four case scenarios
Table 2 Baseline characteristics of responders. Number, n Mean Age, years (SD) Specialty
Mean length of service, years (SD) Specific interest in thrombosis and haemostasis n° (%) Work with colleagues expert in thrombosis and haemostasis, n° (%) Workplace, n° (%) Systematic evaluation of thromboembolic risk, n° (%) Thromboembolic risk evaluation, n° (%)
Bleeding risk evaluation, n° (%)
575
453 46.1 y (10.4) Internal Medicine 230 (50.8%) Endocrinology 29 (6.4%) Geriatrics 27 (6.0%) Pneumology 17 (3.8%) Cardiology 16 (3.5%) Gastroenterology 16 (3.5%) Haematology 14 (3.1%) Infectious Disease 12 (2.6%) Anesthesiology 4 (0.9%) Others 10 (2.2%) Resident 30 (6.6%) Undeclared 46 (10.2%) 17.3 y (11.3) 178 (39.3%) 215 (47.5%) Hospital ward 413 (91.2%) Ambulatory 40 (8.8%) 321 (70.9%) Systematic evaluation 321 (70.9%) - Clinical 141 (31.5%) - RAM 126 (27.8%) PADUA score 87 (19.2%) FADOI score 9 (2.0%) Geneva score 6 (1.3%) IMPROVE score 5 (1.1%) Local score 19 (4.2%) - Not specified 54 (11.9%) Systematic evaluation 339 (74.8%) - Clinical 165 (36.4%) - RAM 159 (35.1%) HAS-BLED score 134 (29.6%) IMPROVE score 16 (3.5%) Local score 9 (2.0%) - Undeclared 15 (3.3%)
powered trials evaluating the risk of bleeding with these compounds in patients with severe renal failure [12]. Fondaparinux is nearly completely dependent on renal clearance and it should be used with extreme caution in patients with moderate to severe renal insufficiency [12]. A reduced dose (1.5 mg/die) of fondaparinux showed a good profile of safety and efficacy in a recent prospective cohort of more than two hundred acutely ill medical patients with a creatinine clearance between 20 and 50 ml/min [26]. Nearly half participants would have prescribed a reduced prophylactic dose of LMWH or fondaparinux for the patient described in the last clinical scenario, with more than 10% of participants who would have not prescribed any prophylaxis. Although we did not collect information on the rationale of the answers, we may hypothesize that this patient was perceived to be at low risk of thromboembolic complications due to his preserved mobility. However, this patient results to be at high risk according to the Padua score (acute infection disease, age, and metastatic cancer on hormone therapy), with an estimated 11.0% risk of VTE in the absence of anticoagulant prophylaxis. Interestingly, when we only considered the subgroup who used a formal RAM, significantly more participants would have used full dose antithrombotic prophylaxis. Taken together, the results of this survey suggest that physicians approach to acutely ill medical patients in some “grey” areas of antithrombotic prophylaxis remains heterogeneous and sometimes partially in contrast to current recommendations. Both the lack of familiarity with published guidelines and the lack of clear evidences from RCTs in some areas may explain the heterogeneous behaviour of physicians in clinical practice. Several reasons have been claimed why clinical guidelines and RCTs may have a limited effect on changing clinicians attitude: barriers to physicians adherence - lack of awareness, lack of familiarity,
400 350 300 250 200 150 100 50
S4 S3 S2 S1
0 1
2
3 Items
4
5
6
7
Fig. 1. Answers to the four clinical scenarios.
lack of agreement, self-efficacy, outcome expectancy, previous practice, inertia of previous practice, external barriers, guideline-related barriers, patient-related barriers, environmental related barriers [27]. Unfortunately, as previously underlined, the structure of this survey did not allow to gather explanations for the different answers. However, these results allow to assess, in a large group of physicians, the current knowledge on these important areas of antithrombotic prophylaxis and to provide information on physicians’ attitude for different use of antithrombotic prophylaxis in different clinical situations. Thus, information derived from our study may be used to plan dedicated educational programs and new studies in this field. Our survey has strengths and limitations. First the response rate was high (more than 50%) and physician with different background and with different experience fulfilled the survey. Thus, our results are likely to be valid and the external validity of our study is supposed to be good. On the other hand, our survey include only Italian physicians and any extrapolation to different healthcare system may be questionable. Furthermore, physicians may have incorrectly interpreted the questions and we can not be sure that participants gave answers reproducing their conduct in clinical practice. To avoid these potential bias we tried to keep the survey as simple and less equivocal as possible and we collected the answers anonymously. In conclusions, the results of our survey providing real-world data on the current clinical management of antithrombotic prophylaxis in some “grey” areas of medical setting show that physicians approach is quite heterogeneous and sometimes partially in contrast to the recent evidence of the literature reinforcing the need for educational programs and high quality studies in this setting.
Conflict of Interest The authors have no any conflict of interest to declare.
Acknowledgment We thank Dr Nicola Mumoli, Dr Paola Gnerre, Dr Grazia Panigada and Dr Roberto Frediani for their invaluable help in promoting and collecting questionnaires.
87 (40%) 1 (0%) 13 (6%) 24 (11%) 15 (7%) 10 (5%) 60 (28%) 136 (63%) 12 (6%) 21 (10%) 0 (0%) 8 (4%) 44 (20%) 41 (19%) 27 (13%) 12 (6%) 13 (6%) 11 (5%) 4 (2%) 116 (54%) 3 (1%) 6 (3%) 19 (9%) 7 (3%) 176 (82%)
10 (5%)
68 (38%) 0 (0%) 12 (7%) 20 (11%) 17 (10%) 10 (6%) 49 (28%) 109 (61%) 9 (5%) 16 (9%) 0 (0%) 4 (2%) 40 (22%) 25 (14%) 16 (9%) 10 (6%) 12 (7%) 13 (7%) 4 (2%) 106 (54%) 5 (3%) 4 (2%) 19 (11%) 8 (4%)
Working in hospital [412], n° (%) Interest in thrombosis and haemostasis [178], n° (%) Colleagues expert in thrombosis and haemostasis [215], n° (%)
138 (78%)
11 (6%)
2 (1%) 2 (0%) 17 (6%) 28 (7%) 33 (11%) 58 (14%) 22 (7%) 30 (7%) 14 (5%) 23 (6%) 78 (26%) 102 (25%) 189 (63%) 272 (66%) 18 (6%) 20 (5%) 18 (6%) 28 (7%) 1 (0%) 2 (0%) 11 (4%) 12 (3%) 71 (24%) 89 (22%) 43 (14%) 64 (14%) 38 (13%) 53 (12%) 9 (3%) 16 (4%) 20 (7%) 40 (9%) 13 (4%) 18 (4%) 6 (2%) 8 (2%) 182 (61%) 254 (62%) 4 (1%) 7 (2%) 6 (2%) 7 (2%) 21 (7%) 25 (6%) 17 (6%) 23 (6%) 13 (4%) 17 (4%) 251 (84%) 347 (84%) Clinical experience ≥10 years [299], n° (%)
6 2 (0%) 5 30 (7%) 4 60 (13%) All [453], n° (%)
1 383 (85%)
2 19 (4%)
3 28 (6%)
4 26 (6%)
5 8 (2%)
6 8 (2%)
1 267 (59%)
2 8 (2%)
3 25 (6%)
4 40 (9%)
5 16 (4%)
6 53 (12%)
7 64 (14%)
1 103 (23%)
2 15 (3%)
3 2 (0%)
4 31 (76%)
5 23 (5%)
6 291 (64%)
1 112 (25%)
2 26 (6%)
3 34 (8%)
CASE 4 CASE 3 CASE 2 CASE 1
Appendix 1
129 (43%) 167 (41%)
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7 184 (41%)
576
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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Regular Article
Thromboprophylaxis in Acutely Ill Medical Patients: Results of A Survey Among Italian Physicians Francesco Dentali a,⁎, Fulvio Pomero b, Micaela La Regina c, Francesco Orlandini c, Sara Turato a, Antonino Mazzone d, Carlo Nozzoli e, Andrea Fontanella f, Walter Ageno a, Giancarlo Agnelli g, Mauro Campanini h a
Department of Clinical Medicine Insubria University, Varese, Italy Department of Clinical Medicine, ASO S. Croce e Carle, Cuneo, Italy c Department of Internal Medicine, Presidio Ospedaliero Unico del Levante Ligure, La Spezia, Italy d Department of Internal Medicine, A.O. Ospedale Civile, Legnano, Italy e Department of Internal Medicine, A.O. Careggi, Firenze, Italy f Department of Internal Medicine, Ospedale del Buon Consiglio, Napoli, Italy g Internal and Cardiovascular Medicine and Stroke Unit, University of Perugia, Perugia, Italy h Department of Internal Medicine, AOU Maggiore della Carità, Novara, Italy b
a r t i c l e
i n f o
Article history: Received 1 November 2013 Received in revised form 29 April 2014 Accepted 10 June 2014 Available online 16 June 2014 Keywords: venous thromboembolism bleeding risk thromboprophylaxis RAMs
a b s t r a c t Aims: acutely ill medical patients are at increased risk of venous thromboembolism (VTE) and often require thromboprophylaxis, but patient selection and adequate therapeutic decisions may be difficult due to the heterogeneity and the complexity of this population. We conducted a survey among a large cohort of Italian physicians to assess their approach to some important “grey” areas of VTE prevention in this setting. Methods: a questionnaire was distributed during the meeting of a national society of Internal Medicine (FADOI), held in May 2013. Four clinical scenarios describing areas of clinical uncertainty were administered to participants: the first on a patient with acute ischemic stroke; the second on a patient with severe renal insufficiency; the third on the duration of prophylaxis in the post-acute setting; and the last on a patient at high risk of VTE and at moderate risk of bleeding with preserved mobility. Results: 453 questionnaires were returned (participants mean age 48.5 years). About 70% of participants systematically assess VTE and bleeding risk in their clinical practice, but a minority of them use risk assessment models. Prolonged prophylaxis in the post-acute setting was voted by more than eighty percent of participants; replies to the other three clinical scenarios were more heterogeneous with none of the options selected by more than 60% of participant. Conclusion: physicians approach to “grey” areas of antithrombotic prophylaxis in the medical setting is quite heterogeneous and sometimes partially in contrast to recent guidelines, reinforcing the need for educational programs and high quality studies in this setting. © 2014 Elsevier Ltd. All rights reserved.
Introduction Acutely ill medical patients are at increased risk of venous thromboembolism (VTE), which can occur during hospitalization or after discharge [1]. A number of clinical trials and meta-analyses have shown that pharmacologic prophylaxis with antithrombotic drugs significantly reduces the risk of fatal pulmonary embolism as compared to placebo or no treatment in these patients, with no or minimal increase in the risk of major bleeding [2–4]. Yet, even in recent studies, only about
⁎ Corresponding author at: U.O. Medicina Interna, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy. Tel.: +39 0332 278594; fax: +39 0332 278229. E-mail address: [email protected] (F. Dentali).
http://dx.doi.org/10.1016/j.thromres.2014.06.013 0049-3848/© 2014 Elsevier Ltd. All rights reserved.
half of eligible hospitalized medical patients receive appropriate thromboprophylaxis [5–7]. The heterogeneity of the medical population has always posed a substantial problem in identifying acutely ill patients who could benefit from an appropriate prophylaxis. A number of risk assessment models (RAMs) have been recently proposed to assist clinicians in evaluating the risk of thromboembolic and major bleeding complications [8–11]. Unfortunately, RAMs often included different items (sometimes with conflicting results), and failed to assess risk factors that are commonly encountered in clinical practice and considered relevant by clinicians. Thus, possibly as a consequence of these limitations, are not broadly used. Furthermore, risks and benefits of antithrombotic prophylaxis in special populations, such as underweight or obese patients and patients with severe renal failure [12], remain to be established since these
F. Dentali et al. / Thrombosis Research 134 (2014) 572–577
groups of patients were not included in the randomized controlled trials on this topic. Finally, although it was hypothesized that, in some high risk medical patients, anticoagulant prophylaxis should be continued after discharge, none of the available trials has brought convincing evidence on the potential benefits of prolonged prophylaxis in this population [13]. Thus, since evidences of the literature on several aspects of prophylaxis in medical patients are still not compelling, thus leading to potentially variable approaches in real-life clinical practice, we conducted a survey among a large cohort of Italian physicians to assess their approach to some important “grey” areas of antithrombotic prophylaxis in this setting including acute ischemic stroke, severe renal insufficiency, duration of prophylaxis in the post-acute setting and a concomitance of a substantial risk of VTE and bleeding.
Methods A questionnaire describing 4 different clinical scenarios was distributed during the national meeting of an Italian scientific society of Internal medicine, FADOI (Italian Federation of Internal Medicine), held in Taormina, Italy during May, 2013. FADOI is a large society with more than 2000 affiliates from all the twenty Italian regions. Almost all the FADOI members are clinicians actively working in medical wards in teaching and non-teaching hospitals and they all have direct patient responsibility. The meeting was attended by about 900 participants, nearly all of whom are members of the society. During the first day of the meeting, the questionnaire was introduced to the participants with a brief oral presentation. Nine hundred questionnaires were distributed and then collected at the registration desk throughout the meeting. All answers were entered into a database from which respondent information was dissociated; thus the results of the survey were analyzed in an anonymous fashion. In the first page of the questionnaire we proposed 5 questions aimed to describe the training and the experience of the participants. In particular, participants were asked about their age, date of training, their specialty, and their workplace (hospital, post-acute setting, general practitioner ambulatory). Respondents were also queried about whether they had a special interest in thrombosis and haemostasis (explicitly asking "whether they actually ran a specific ambulatory and/or if he/she is usually “on call” for thrombosis and haemostasis issues in the hospital), if they work with colleagues expert in thrombosis and haemostasis, and, finally, about whether they use RAMs or other clinical or laboratory scores to assess thromboembolic and haemorrhagic risks in their patients. The 4 scenarios described hypothetical patients. For each of the 4 scenarios presented, we proposed 6 or 7 options for the management of the patients. Clinical scenarios and management options are described in Table 1. Briefly, the first scenario described a patient with acute exacerbation of chronic obstructive pulmonary disease (COPD) discharged from the hospital to a post-acute setting in order to continue the intra-venous administration of antibiotic therapy. The second scenario described a patient with an acute, large ischemic cerebral lesion at potentially high risk of hemorrhagic transformation who was treated with low doses of acetyl salicylic acid (ASA). The third scenario described a patient with severe renal insufficiency, urinary tract infection and fever requiring total bed rest. The last scenario described a patient with pneumonia, with preserved mobility, who was defined at high risk of thromboembolic complications by the Padua score [8] and at low risk of bleeding according to the IMPROVE bleeding score [11]. For all these scenarios, participants were asked to decide about the optimal antithrombotic prophylaxis. Continuous variables were expressed as mean plus or minus the standard deviation (SD); Categorical data and qualitative variables are given as counts and percentages.
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Subgroup analyses including only participants with more clinical experience (who conferred the degree more than 10 years ago), participants working in hospital, and participants with a special interest in thrombosis and haemostasis were performed. Statistical analyses were performed using SPSS version 19.0 Results Four hundred and fifty three of the 900 distributed questionnaires were returned (50.3%). Characteristics of participants are summarized in Table 2. Mean age of participants was 46.1 years (+10.4 years); all but 76 participants (16.8%) had at least one specialty and most of the participants had their specialty in Internal Medicine (61%); 413 of 453 (91.2%) participants work in a hospital; about 40% of participants had a specific interest in thrombosis and haemostasis and 47.5% of participants had at least one colleague expert in this field. The risk of thromboembolic complications is routinely assessed by 321 participants (70.9%) in their clinical practice, although the method used for stratification was specified by only 267 participants. A formal RAM is used by 126 participants and included the Padua score (87 participants, 19.2% of the total number of participants), a score developed by the FADOI scientific society (9 participants, 2.0%), the Geneva score (6 participants, 1.3%) and the IMPROVE score (5 participants, 1.1%) whereas a local evaluation score is used by 19 participants (4.2%) and 141 participants assess the thromboembolic risk with a clinical evaluation (31.1%). The risk of bleeding complications is routinely assessed by 339 participants (74.8%), although the stratification method was specified by only 324 of them. The risk of major bleeding is assessed with a clinical evaluation by 165 participants (36.4% of the total number of participants), whereas 134 participants (29.6%) use the HAS-BLED score, 9 participants (2.0%) use a local evaluation score, and only 16 participants (3.5%) use the IMPROVE score. The results from the four case scenarios are summarized in Fig. 1. In the first scenario, more than 85% of participants would have prescribed extended prophylaxis with LMWH or UFH after discharge for a total of 35 days, whereas only a minority of participants would have stopped anticoagulant prophylaxis after a maximum of 14 days. In the second scenario, about 60% of participants would have prescribed a prophylactic dose of LMWH in association with low doses of aspirin to the patient with acute ischemic stroke, whereas about a quarter would have not added any other pharmacological or nonpharmacological therapy; about 10% would have added clopidogrel to aspirin; and only a minority of participants would have used elastic stockings or intermittent pneumatic compression. In the third scenario, more than 60% of participants would have chosen a reduced prophylactic dose of LMWH or fondaparinux in the patient with severe renal insufficiency, whereas more than 25% of participants would have used a full prophylactic dose of LMWH or fondaparinux; and only a minority of participant would have chosen a prophylactic dose of UFH. In the last scenario, about 40% of participants would have prescribed a reduced prophylactic dose of LMWH or fondaparinux; one third of participants would have used a full prophylactic dose of LMWH or fondaparinux; and more than 10% of participants would have not prescribed any antithrombotic prophylaxis to this patient. Subgroup analyses including only participants with more clinical experience, participants working in hospital, participants with a personal special interest in thrombosis and haemostasis, and those who work with colleagues expert in thrombosis and haemostasis gave results that were only slightly different to those observed in the principal analyses (Appendix 1). Of interest, significantly more participants among those using the Padua prediction score would have prescribed a prophylactic dose of LMWH or fondaparinux to the patient described in case scenario 4, as compared to participants who reported to not use this score (90.8 vs 76.0; p b 0.01).
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Table 1 Clinical scenarios. 1st Scenario
2nd Scenario
3th Scenario
4th Scenario
77-y.o. woman, obese, hypertensive, diabetic, dislipidemic, on insulin and ACE-inhibitors was admitted to hospital for pneumonia and treated with antibiotics for 10 days. As she was hypoxemic, she was also supplemented with oxygen via Venturi mask. During hospital stay she was bedridden, so prophylactic doses of LMWH were prescribed. Platelet count and renal function were normal. After 10 days she was discharged to a subacute facility and antibiotics were prescribed for further 7 days. Because of persistent slight hypoxia at rest, also oxygen by nasal cannula was prescribed. At the time of admission in the sub acute facility she was able to walk to the toilet with some help. Which of the following therapies do you consider appropriate?
73-y.o. man, affected by arterial hypertension and diabetes, on antihypertensive and oral hypoglicemic drugs was healthy until 2 days ago when he woke up in the morning with a faciobrachiocrural hemisyndrome. First brain CT scan was negative for vascular injury. Aspirin 300 mg was administered immediately after CT scan and ASA 100 mg were prescribed for the following days. After 36 hours, the second CT scan showed large ischemic lesion in the territory of the middle cerebral artery. Platelets count and renal function were normal. EKG showed sinus rhythm. Which therapy besides ASA do you consider appropriate for this patient?
83-y.o. woman, weight 53 Kg, affected by arterial hypertension and rheumatoid arthritis since 8 years ago, on treatment with prednisone, calcium-channel blockers and ACE-inhibitors, was admitted for fever and poor general conditions. Urine and blood culture were positive for E. coli and she was treated with cyprophloxacin 500 mg twice a day. Platelet count was normal, and serum creatinine was 1.5 mg/dl, 132 mol/l. Which prophylaxis do you consider appropriate in this patient?
72-y.o man, weight 75 Kg, affected by metastatic prostatic cancer (bone) treated with hormonal therapy. He was admitted to hospital for fever due to right basal pneumonia and was treated with i.v. antibiotics. He was not bedridden. Platelet count was normal and serum creatinine was 1.6 mg/dl (141 mol/l). Which prophylaxis do you consider appropriate for this patient?
1.
2.
3. 4. 5. 6.
1. 2. 3. 4. 5. Prophylactic doses of LMWH up to the recovery of independent ambulation or 6. 7. anyway for no more than 35 days. Prophylactic doses of UFH up to the recovery of independent ambulation or anyway for no more than 35 days. Graduated compression stockings up to the recovery of independent ambulation Prophylactic doses of LMWH or UFH for additional 4 days. Aspirin 100 mg/die up to the recovery of independent ambulation No antithrombotic therapies
prophylactic doses of LMWH prophylactic doses of UFH Therapeutic doses of LMWH or UFH Graduated compression stockings Pneumatic compression devices Clopidogrel 75 mg/die No other therapies in addition to aspirin
Discussion The results of this survey conducted among Italian physicians reflect a substantial heterogeneity in the clinical management of medical patients at risk for VTE. Although most physicians report to routinely assess the risk of VTE and bleeding in their patients, only a minority use a formal RAM in his or her clinical practice. In particular, about one out of five participating clinicians uses the Padua prediction score [8], as suggested by the most recent American College of Chest Physicians (ACCP) guidelines [14]. Furthermore, only few participants used a bleeding risk score [11], although none of the available scores is sufficiently validated and, for this reason, currently recommended by the ACCP guidelines. Interestingly, most physicians who reported to use a bleeding score actually applies the HAS-BLED score, a score developed and validated only to assess the risk of major bleeding complications in patients on oral anticoagulant therapy for atrial fibrillation [15]. Despite the absence of clear evidences to support this strategy, most physicians seem to consider the possibility to extend anticoagulant prophylaxis beyond the period of hospitalization in patients who remain at potentially increased risk of VTE (first scenario). This is clearly in contrast with the ACCP guidelines [14], where prolonged prophylaxis is not recommended based on the negative results of the three RCTs that have compared the LMWH enoxaparin [16]and the oral direct inhibitors rivaroxaban and apixaban [17,18] with placebo after an initial course of prophylaxis for a maximum of 14 days. In all these studies, the potential benefit of extended prophylaxis was offset by an increased risk of major bleeding complications [16–18]. The use of prophylactic doses of LMWH or UFH in association to low dose aspirin in the presence of a large ischemic stroke was selected by the majority of participants (second scenario), although the responses in this case were heterogeneous. Recommendations of recent guidelines on this topic are contrasting, with ACCP guidelines [19] suggesting low
1. 2. 3. 4. 5. 6.
Prophylactic doses of LMWH Graduated compression stockings Pneumatic compression devices Prophylactic doses of UFH Fondaparinux 2.5 mg/die SQ Half of the prophylactic dose of LMWH or fondaparinux 1.5 mg/die SQ
1. 2. 3. 4. 5. 6. 7.
Prophylactic doses of LMWH Prophylactic doses of UFH Fondaparinux 2.5 mg/die No VTE prophylaxis Graduated compression stockings Aspirin 100 mg/die Half of the prophylactic dose of LMWH or fondaparinux 1.5 mg/die
dose of LMWH or UFH in patients with acute ischemic stroke and restricted mobility, and the American Heart Association/American Stroke Association guidelines [20] suggesting against the routine use of anticoagulant prophylaxis in these patients because of the potential risk for hemorrhagic complications. Evidences from the literature are also contrasting [21,22]: in the meta-analysis performed by Sandercock et al, the use of LMWH or UFH reduced the incidence of venous thromboembolic events but at the cost of an increased risk of intracranial and extracranial haemorrhagic complications [21]. Conversely, in the meta-analysis performed by Kamphuisen et al, the risk of major bleeding complications appeared to be related to the doses of the anticoagulant drugs, with no significant increase when a prophylactic dose of UFH or LMWH was used [22]. Of note, very few participants would have prescribed graduated compression stockings or intermittent pneumatic compression to this patient. The use of graduated compression stockings was not associated with a decreased risk of deep vein thrombosis in a large RCT including patients with acute ischemic stroke [23], whereas in a recent RCT, including a similar population, the incidence of deep vein thrombosis was decreased with intermittent pneumatic compression [24]. Unfortunately, this device is not available in many hospitals. The use of a reduced prophylactic dose of LMWH or fondaparinux in a patient with severe renal failure (third scenario) was selected by about 60% of participants, with about 20% of participants selecting a full prophylactic dose, and only a minority of participants selecting UFH. Evidences on the appropriate anticoagulant prophylaxis in patients with severe renal failure are lacking. The manufacturer of enoxaparin recommends a reduced daily dose for patients with a creatinine clearance (CrCl) b 30 mL/min (ref). Higher anti-factor Xa levels were found in patients with renal failure who received repeated oncedaily full prophylactic doses of enoxaparin, although the mean peak and the trough anti-Xa levels were only slightly increased [25]. Information on other LMWHs is even more limited and there are no adequately
F. Dentali et al. / Thrombosis Research 134 (2014) 572–577
Results from the four case scenarios
Table 2 Baseline characteristics of responders. Number, n Mean Age, years (SD) Specialty
Mean length of service, years (SD) Specific interest in thrombosis and haemostasis n° (%) Work with colleagues expert in thrombosis and haemostasis, n° (%) Workplace, n° (%) Systematic evaluation of thromboembolic risk, n° (%) Thromboembolic risk evaluation, n° (%)
Bleeding risk evaluation, n° (%)
575
453 46.1 y (10.4) Internal Medicine 230 (50.8%) Endocrinology 29 (6.4%) Geriatrics 27 (6.0%) Pneumology 17 (3.8%) Cardiology 16 (3.5%) Gastroenterology 16 (3.5%) Haematology 14 (3.1%) Infectious Disease 12 (2.6%) Anesthesiology 4 (0.9%) Others 10 (2.2%) Resident 30 (6.6%) Undeclared 46 (10.2%) 17.3 y (11.3) 178 (39.3%) 215 (47.5%) Hospital ward 413 (91.2%) Ambulatory 40 (8.8%) 321 (70.9%) Systematic evaluation 321 (70.9%) - Clinical 141 (31.5%) - RAM 126 (27.8%) PADUA score 87 (19.2%) FADOI score 9 (2.0%) Geneva score 6 (1.3%) IMPROVE score 5 (1.1%) Local score 19 (4.2%) - Not specified 54 (11.9%) Systematic evaluation 339 (74.8%) - Clinical 165 (36.4%) - RAM 159 (35.1%) HAS-BLED score 134 (29.6%) IMPROVE score 16 (3.5%) Local score 9 (2.0%) - Undeclared 15 (3.3%)
powered trials evaluating the risk of bleeding with these compounds in patients with severe renal failure [12]. Fondaparinux is nearly completely dependent on renal clearance and it should be used with extreme caution in patients with moderate to severe renal insufficiency [12]. A reduced dose (1.5 mg/die) of fondaparinux showed a good profile of safety and efficacy in a recent prospective cohort of more than two hundred acutely ill medical patients with a creatinine clearance between 20 and 50 ml/min [26]. Nearly half participants would have prescribed a reduced prophylactic dose of LMWH or fondaparinux for the patient described in the last clinical scenario, with more than 10% of participants who would have not prescribed any prophylaxis. Although we did not collect information on the rationale of the answers, we may hypothesize that this patient was perceived to be at low risk of thromboembolic complications due to his preserved mobility. However, this patient results to be at high risk according to the Padua score (acute infection disease, age, and metastatic cancer on hormone therapy), with an estimated 11.0% risk of VTE in the absence of anticoagulant prophylaxis. Interestingly, when we only considered the subgroup who used a formal RAM, significantly more participants would have used full dose antithrombotic prophylaxis. Taken together, the results of this survey suggest that physicians approach to acutely ill medical patients in some “grey” areas of antithrombotic prophylaxis remains heterogeneous and sometimes partially in contrast to current recommendations. Both the lack of familiarity with published guidelines and the lack of clear evidences from RCTs in some areas may explain the heterogeneous behaviour of physicians in clinical practice. Several reasons have been claimed why clinical guidelines and RCTs may have a limited effect on changing clinicians attitude: barriers to physicians adherence - lack of awareness, lack of familiarity,
400 350 300 250 200 150 100 50
S4 S3 S2 S1
0 1
2
3 Items
4
5
6
7
Fig. 1. Answers to the four clinical scenarios.
lack of agreement, self-efficacy, outcome expectancy, previous practice, inertia of previous practice, external barriers, guideline-related barriers, patient-related barriers, environmental related barriers [27]. Unfortunately, as previously underlined, the structure of this survey did not allow to gather explanations for the different answers. However, these results allow to assess, in a large group of physicians, the current knowledge on these important areas of antithrombotic prophylaxis and to provide information on physicians’ attitude for different use of antithrombotic prophylaxis in different clinical situations. Thus, information derived from our study may be used to plan dedicated educational programs and new studies in this field. Our survey has strengths and limitations. First the response rate was high (more than 50%) and physician with different background and with different experience fulfilled the survey. Thus, our results are likely to be valid and the external validity of our study is supposed to be good. On the other hand, our survey include only Italian physicians and any extrapolation to different healthcare system may be questionable. Furthermore, physicians may have incorrectly interpreted the questions and we can not be sure that participants gave answers reproducing their conduct in clinical practice. To avoid these potential bias we tried to keep the survey as simple and less equivocal as possible and we collected the answers anonymously. In conclusions, the results of our survey providing real-world data on the current clinical management of antithrombotic prophylaxis in some “grey” areas of medical setting show that physicians approach is quite heterogeneous and sometimes partially in contrast to the recent evidence of the literature reinforcing the need for educational programs and high quality studies in this setting.
Conflict of Interest The authors have no any conflict of interest to declare.
Acknowledgment We thank Dr Nicola Mumoli, Dr Paola Gnerre, Dr Grazia Panigada and Dr Roberto Frediani for their invaluable help in promoting and collecting questionnaires.
87 (40%) 1 (0%) 13 (6%) 24 (11%) 15 (7%) 10 (5%) 60 (28%) 136 (63%) 12 (6%) 21 (10%) 0 (0%) 8 (4%) 44 (20%) 41 (19%) 27 (13%) 12 (6%) 13 (6%) 11 (5%) 4 (2%) 116 (54%) 3 (1%) 6 (3%) 19 (9%) 7 (3%) 176 (82%)
10 (5%)
68 (38%) 0 (0%) 12 (7%) 20 (11%) 17 (10%) 10 (6%) 49 (28%) 109 (61%) 9 (5%) 16 (9%) 0 (0%) 4 (2%) 40 (22%) 25 (14%) 16 (9%) 10 (6%) 12 (7%) 13 (7%) 4 (2%) 106 (54%) 5 (3%) 4 (2%) 19 (11%) 8 (4%)
Working in hospital [412], n° (%) Interest in thrombosis and haemostasis [178], n° (%) Colleagues expert in thrombosis and haemostasis [215], n° (%)
138 (78%)
11 (6%)
2 (1%) 2 (0%) 17 (6%) 28 (7%) 33 (11%) 58 (14%) 22 (7%) 30 (7%) 14 (5%) 23 (6%) 78 (26%) 102 (25%) 189 (63%) 272 (66%) 18 (6%) 20 (5%) 18 (6%) 28 (7%) 1 (0%) 2 (0%) 11 (4%) 12 (3%) 71 (24%) 89 (22%) 43 (14%) 64 (14%) 38 (13%) 53 (12%) 9 (3%) 16 (4%) 20 (7%) 40 (9%) 13 (4%) 18 (4%) 6 (2%) 8 (2%) 182 (61%) 254 (62%) 4 (1%) 7 (2%) 6 (2%) 7 (2%) 21 (7%) 25 (6%) 17 (6%) 23 (6%) 13 (4%) 17 (4%) 251 (84%) 347 (84%) Clinical experience ≥10 years [299], n° (%)
6 2 (0%) 5 30 (7%) 4 60 (13%) All [453], n° (%)
1 383 (85%)
2 19 (4%)
3 28 (6%)
4 26 (6%)
5 8 (2%)
6 8 (2%)
1 267 (59%)
2 8 (2%)
3 25 (6%)
4 40 (9%)
5 16 (4%)
6 53 (12%)
7 64 (14%)
1 103 (23%)
2 15 (3%)
3 2 (0%)
4 31 (76%)
5 23 (5%)
6 291 (64%)
1 112 (25%)
2 26 (6%)
3 34 (8%)
CASE 4 CASE 3 CASE 2 CASE 1
Appendix 1
129 (43%) 167 (41%)
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7 184 (41%)
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