External validity of placebo-controlled trials of thromboprophylaxis for medical patients cited in clinical practice guidelines

Transcription

1 External validity of placebo-controlled trials of thromboprophylaxis for medical patients cited in clinical practice guidelines S. Morin-Ben Abdallah MD, A. Dutilleul MD, V. Nadon MD, X. Marchand-Sénécal MD, J. Yang MD, M. Laskine MD, MSc and M. Durand MD, MSc, FRCPC Centre Hospitalier de l Université de Montréal- Hôtel-Dieu

2 Introduction! Venous thromboembolism (VTE)! Deep vein thrombosis (DVT) and pulmonary embolism (PE)! Common complication in medical and surgical populations! May be decreased by thromboprophylaxis

3 Introduction! Guidelines for thromboprophylaxis! American College of Chest Physicians (ACCP)! Hospitalized patients at high risk of VTE! Padua score 4

4 Introduction! ACCP guidelines! Based on several randomized controlled trials (RCTs)! May not be representative to most patients hospitalized on medical wards! New studies showing lack of benefit and increased bleeding in cancer patients and elderly

5 Aim of study! Evaluate external validity of the RCTs cited in the ACCP guidelines for the use of pharmacological thromboprophylaxis! Hospitalized, non-surgical, non-critically ill, teaching hospital patients! Identify presence or absence of the inclusion and exclusion criteria used in cited RCTs

6 Hypothesis! External validity of RCTs cited in support of the ACCP guidelines on thromboprophylaxis is low for our population of hospitalized patients

7 ! Divided in 2 Steps Methods! Step 1:Targeted literature review! Identification of inclusion/exclusion criteria! References from ACCP thromboprophylaxis guidelines! Patients hospitalized in a medical setting! Thromboprophylaxis vs placebo! RCTs and meta-analyses

8 Methods! Step 2: Retrospective cohort! All patients admitted to Internal Medicine between July 2013 and June 2014

9 Statistical analysis! Primary outcome! Proportion of our population excluded from the RCTs that underlie clinical care guidelines on thromboprophylaxis

10 Statistical analysis! Descriptive Statistics! Proportion of patients with at least one exclusion criteria to each individual RCT! Weighted average of the proportion of exclusion from studies! Stratified by Padua risk score of 3 or less vs 4 or more

11 Results! From the Targeted Literature Review! 9 RCTs! 28, 793 randomized trial patients! 23 distinct exclusion criteria

12 Results Table&4& &Prevalence&of&exclusion&factors&from&studies&in&429&patients& Exclusion&criteria& Prevalence&in&our& population&(n,&%)& Number&of&studies& (Percentage&of&28793& randomized&patients)& using&exclusion&criteria&& Age%less%than%40% 59%(13.8)% 9%(100)% Women%of%childbearing%age%if% pregnant,%breastfeeding%or%not% using%contraception% 12%(2.8)% 8%(99.7)% Patients%requiring%or%already%on% ACO%or%thromboprophylaxis% 78%(18.2)% 9%(100)% Patient%on%antiplatelets% 124%(28.9)% 5%(26.3)% Bacterial%endocarditis% 2%(0.5)% 4%(20.0)% Cerebral%metastases% 4%(0.9)% 2%(31.8)% HIV% 23%(5.4)% 2%(44.4)% High%risk%of%bleeding% 39%(9.1)% 8%(91.4)% Plt%<%100% 38%(8.9)% 4%(58.3)% Plt%<%50% 11%(2.6)% 1%(8.6)% INR%>1.2% 85%(19.8)% 2%(12.4)% Prothrombin%time%10%seconds% 27%(6.3)% 2%(12.4)% longer%than%control%% Active%bleeding% 23%(5.4)% 5%(82.9)% Planned%invasive%procedure%within%

13 Exclusion&criteria& Results Prevalence&in&our& population&(n,&%)& Number&of&studies& (Percentage&of&28793& randomized&patients)& using&exclusion&criteria&& Planned%invasive%procedure%within% 30%days% 106%(24.7)% 5%(54.3)% Neurosurgical,%Spinal%or% Ophtalmological%surgery%in%last%30% 5%(1.2)% 1%(12.9)% days% Anémie%en%bas%de%80%à%l'admission% 24%(5.6)% 1%(28.9)% Uncontrolled%HTA%(>240/120)% 1%(0.2)% 3%(38.5)% Hypersensitivity%to%heparin/% LMWH%or%HIT% 2%(0.5)% 3%(45.6)% Hepatic%failure%or%active%hepatitis% 53%(12.4)% 2%(53.5)% Renal%failure,%creatinine%clearance% less%than%30ml/min% 46%(10.7)% 4%(44.3)% Hemodialysis% 5%(1.2)% 1%(40.6)% Palliative%care,%defined%as%LOC%4% within%24h%of%admission% 6%(1.4)% 4%(57.4)% No%informed%consent:%altered%LOC,% delirium,%dementia% 31%(7.2)% 1%(28.9)% ***"definitions"and"precisions"to"put"in"footnotes"

14 Results! Retrospective cohort! 1664 patients admitted! Random sample of 446 patients selected! 17 patients excluded due to admission in service other than Internal Medicine! 429 patients were included in baseline characteristics! 78 patients were anticoagulated! 351 patients included in analysis of prevalence

15 Results! Patient characteristics (N =429)! Age (mean, SD)! 62.3 (18.4)! Male sex (n,%)! 236 (55)! Reason for admission (n,%)! Infection 146 (34.0)! Respiratory 44 (10.3)! Cancer 35 (8.2)! Rheumatological 33 (7.7)! Comborbities (n,%)! Hypertension 221 (51.5)! Diabetes 146 (34.0)! Renal failure 100 (23.3)! COPD 81 (18.9)! Cardiovascular disease 74 (17.3)

16 Results! Indication for thromboprophylaxis (Padua 4 )! 168 patients (39.2%)! Thromboprophylaxis received! 207 patients (48.3%)! Thromboprophylaxis based on Padua score! 4 : 97 patients (57.5%)! 0-3: 110 patients (42.2%)

17 Results! Between 26% and 67% (weighted average 51%) of our patients was excluded from individual studies! When restricting to patients with indication of thromboprophylaxis 21% to 76% (weighted average 55.3%) were excluded from individual studies

18 Results Table&6& &Relative&access&to&9&randomized&controlled&trials&for&351&patients&eligible&for&medical& thromboprophylaxis,&&patients&with&padua&risk&score& 4,&and&thromboprophylaxis&use& & 351%patients%included%in%study% 118%patients%with%Padua 4% Access&categories& Patients% (n,%)% Receiving% thrombo7 prophylaxis% (n,%)% Patients%(n,%)% Receiving% thrombo7 prophylaxis% (n,%)% Patients&excluded&from&& no%trials% 173%trials% 476%trials% 778%trials% all%9%trials& % 88%(25.1)% 25%(7.12)% 118%(33.6)% 45%(12.8)% 75%(21.4)% % % 19%(16.1)% 7%(5.9)% 47%(39.8)% 25%(21.2)% 20%(17.0)% % Patients&excluded&from&& none%of%trial%population*% 1725%%of%trial%population% 26750%%of%trial%population% 51775%%of%trial%population% 75799%%of%trial%population% 100%%of%trial%population& % 88%(25.1)% 3%(0.9)% 65%(18.5)% 84%(23.9)% 39%(10.3)% 75%(21.4)% % 52%(59.1)% 2%(66.7)% 37%(56.9)% 55%(65.5)% 24%(66.7)% 31%(41.3)% % 19%(16.1)% 2%(1.69)% 24%(20.3)% 36%(30.5)% 17%(14.4)% 20%(17.0)% % 13%(68.4)% 1%(50)% 15%(62.5)% 32%(88.9)% 14%(82.4)% 17%(85.0)% *"total"trial"population"="sum"of"all"patients"included"in"the"9"studies,"28793"!!

19 Discussion! When used inappropriately, thromboprophylaxis can cause excess costs, patient discomfort and undue side effects! Trial results can only apply to settings similar to those in which trial was conducted! External validity was low and lower still in patients at higher risk of thrombosis! 17% would have been included in all 9 trials! 61.9% would have been excluded from 50% of trial population

20 Conclusion! Balance of benefits and harm is still not well defined! For majority of our patients level of evidence cannot be considered as IA! Very little is said about exclusion criteria in clinical care guidelines

21 Bibliography! Heit J.A., O Fallon W.M., Petterson T.M., et al. Relative Impact of Risk Factors for Deep Vein Thrombosis and Pulmonary Embolism Arch Intern Med. 2002; 162(11): ! Nijkeuter M., Söhne M., Tick L.W., et al. The natural course of hemodynamically stable pulmonary embolism: Clinical outcome and risk factors in a large prospective cohort study Chest. 2007;131(2):517! Dentali F., Douketis J.D., Gianni M., et al. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146(4):278.! Kahn S.R., Lim W., Dunn A.S., et al. Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2): ! Carrier M., Khorana A.A., Moretto P., et al. Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med Jan;127(1):82-6.e1! Greig M.F., Rochow S.B., Crilly M.A., et al. Routine pharmacological venous thromboembolism prophylaxis in frail older hospitalised patients: where is the evidence? Age Ageing Jul;42(4):428-34! Barbar S., Noventa F., Rossetto V., et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010;8(11): 2450.! Decousus H., Tapson V.F., Bergmann J.F, et al. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest. 2011;139(1):69.

22 Table&5& &Proportion&of&our&patients&excluded&from&each&study& Study& Intervention& Study& sample& size&(n,&%)& Patients& meeting& exclusion& criteria& (n,%)& Patients& with& Padua& >=4& meeting& exclusion& criteria& (n,&%)& Total&number&in&column& & 28793& 351& 118& Heparin%5%000%U% Belch%et%al.%Prevention%of%deep%vein% SC%q8h%vs.% thrombosis%in%medical%patients%by% nothing% low7dose%heparin.%1981& Until%fully%mobile% 100%(0.3)% 91%(25.9)% %25%(21.2)% Cohen%et%al.%Efficacy%and%safety%of% fondaparinux%for%the%prevention%of% venous%thromboembolism%in%older% acute%medical%patients:%randomised% placebo%controlled%trial.%2006& Dahan%et%al.%Prevention%of%deep%vein% thrombosis%in%elderly%medical%in7 patients%by%a%low%molecular%weight% heparin:%a%randomized%double7blind% trial.%1986& Gärdlund%B%et%al.%Randomised,% controlled%trial%of%low7dose%heparin% for%prevention%of%fatal%pulmonary% embolism%in%patients%with%infectious% diseases.%1996% Kakkar%et%al.%Low7molecular7weight% heparin%and%mortality%in%acutely%ill% medical%patients.%2011%% Lederle%et%al.%The%prophylaxis%of% medical%patients%for% thromboembolism%pilot%study.%2006% Leizorovicz%et%al.%Randomized,% placebo7controlled%trial%of%dalteparin% for%the%prevention%of%venous% thromboembolism%in%acutely%ill% medical%patients.%2004& Mahé%et%al.%Lack%of%effect%of%a%low7 molecular7weight%heparin% (nadroparin)%on%mortality%in% bedridden%medical%in7patients:%a% prospective%randomised%double7 blind%study.%2005% Samama%et%al.%A%comparison%of% enoxaparin%with%placebo%for%the% Fondaparinux%2.5% mg%sc%die%vs.% placebo% For%6714%days% Enoxaparin%60%mg% SC%die%vs.%placebo% For%10%days% Heparin%5%000%U% SC%q12h%vs.% nothing% For%21%days% maximum% Enoxaparin%40%mg% SC%die%vs.%placebo% For%10%+/7%4%days% Enoxaparin%40%mg% SC%die%vs.%placebo% Until%discharge% Dalteparin%5%000% IU%die%vs.%placebo% For%14%days% Nadroparin%7%500% anti7xa%iu%vs.% placebo% For%21%days% maximum% Enoxaparin%40%mg% SC%die%vs.% 849%(2.9)% 220%(62.7)% 89%(75.4)% 270%(0.9)% 179%(51.0)% 68%(57.6)% 11693%(40.6)% 147%(41.9)% 49%(41.5)% 8319%(28.9)% 181%(51.6)% 69%(58.5)% 280%(1.0)% 223%(63.5)% 85%(72.0)% 3706%(12.9)% 235%(67.0)% 88%(74.6)% 2474%(8.6)% 232%(66.1)% 90%(76.3)% 1102%(3.8)% 157%(44.7)% 57%(48.3)%

23 prevention%of%venous% thromboembolism%in%acutely%ill% medical%patients.%1999% Enoxaparin%20%mg% SC%die%vs.%placebo% For%6714%days% & % Total& randomized& patients% Weighted**& average&for& 351&pts% Weighted**& average&for& 118&pts% Total&from&all&studies& N/A% 28793% 51.0% 55.3% *"78"patients"already"anticoagulated"at"admission"were"removed"from"study"sample"" **"weighted"average"calculated"as"mean"of"percentages"of"patients"with"exclusion"criteria"for"each" individual"studies"weighted"by"the"sample"size"of"each"study"!